NZ623100B2 - 8 - carbamoyl - 2 - (2,3- di substituted pyrid - 6 - yl) -1,2,3,4 -tetrahydroisoquinoline derivatives as apoptosis - inducing agents for the treatment of cancer and immune and autoimmune diseases - Google Patents

Abstract

Disclosed are compounds of formula (I) which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which Bcl-xL proteins are expressed, e.g. cancer. X is heteroaryl; Y1 is phenylene or heteroarylene; L1 is a linker; Y2 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; Z1 is C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, etc. In one embodiment, the compound of formula (I) is 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.13,7]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic acid. s cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; Z1 is C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, etc. In one embodiment, the compound of formula (I) is 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.13,7]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic acid.

Description

ation] sak 8 - CARBAMOYL (2,3- DI SUBSTITUTED PYRID YL) -1,2,3,4 -TETRAHYDROISOQUINOLINE DERIVATIVES AS APOPTOSIS - INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND MUNE DISEASES This application claims priority to United States Provisional Application Serial No. 162, filed October 14, 2011, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION This invention pertains to compounds which inhibit the ty of Bcl-xL anti-apoptotic proteins, compositions containing the compounds, and methods of treating diseases during which anti-apoptotic Bcl-xL proteins are expressed.

BACKGROUND OF THE ION Apoptosis is recognized as an essential biological process for tissue homeostasis of all living species. In mammals in particular, it has been shown to regulate early embryonic development. Later in life, cell death is a default mechanism by which potentially dangerous cells (e.g, cells carrying cancerous defects) are removed. Several apoptotic pathways have been uncovered, and one of the most important involves the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called "intrinsic") pathway of apoptosis. See, Danial, N.N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. The structural homology domains BH1, BH2, BH3 and BH4 are characteristic of this family of proteins. The Bcl-2 family of proteins can be further classified into three subfamilies depending on how many of the homology domains each protein contains and on its biological activity (i.e., whether it has pro- or anti- apoptotic function).

The first subgroup ns proteins having all 4 gy domains, i.e., BH1, BH2, BH3 and BH4. Their general effect is anti-apoptotic, that is to preserve a cell from starting a cell death process. Proteins such as, for example, Bcl-2, Bcl-w, , Mcl-1 and Bfl-l/Al are members of this first subgroup. Proteins belonging to the second subgroup contain the three homology domains BH1, BH2 and BH3, and have a pro-apoptotic effect. The two main entative ns of this second subgroup are Bax and Bak. Finally, the third subgroup is composed of proteins containing only the BH3 domain and members of this subgroup are usually referred to as "BH3-only proteins." Their biological effect on the cell is pro- apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third subfamily of proteins. The exact mechanism by which the Bcl-2 family proteins te cell death is still not entirely known and understanding this ism is an active area of research in the science community. In one hypothesis of regulation of cell death by Bcl-2 family proteins, the ly proteins are r categorized as either "activator" (e.g, Bim [Annotation] sak and Bid) or "sensitizer" (e.g, Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteins depending on their regulatory function.

The key to tissue homeostasis is ing the delicate balance in the ctions among the three subgroups of protein in cells. Recent studies have tried to elucidate the mechanisms by which pro-apoptotic and anti-apoptotic subgroups of Bcl-2 family proteins interact to allow a cell to undergo programmed cell death. After receiving intra- or extra- cellular signals in cells, post-translational or transcriptional activation of BH3-only proteins occurs. The BH3-only proteins are the y inducers of an apoptotic cascade that includes, as one step, the activation of the pro-apoptotic proteins Bax and Bak on the mitochondrial membrane in cells. Upon activation of Bax and/or Bak that are either already anchored to the mitochondrial membrane or migrate to this membrane, Bax and/or Bak erize to result in mitochondrial outer ne permeabilization (MOMP), the release of cytochrome C, and downstream activation of effector caspases, to ultimately result in cell apoptosis. Some chers hypothesize that certain BH3 -only proteins (e.g., Puma, Bim, Bid) are ators" in that these proteins directly engage pro-apoptotic proteins Bax and Bak to initiate MOMP, while other BH3-only proteins (e.g, Bad, Bik and Noxa) are "sensitizers" and induce Bax and Bak oligomerization indirectly by binding anti-apoptotic proteins (e.g, Bcl-2, Bcl-xL, Bcl-w, Mcl-l) and displacing and "freeing-up" the "activator" BH3-only proteins, which subsequently bind to and activate pro-apoptotic proteins (e.g, Bax, Bak) to induce cell death. Other researchers suggest that anti-apoptotic proteins engage and seqeuester Bax and Bak directly and all BH3 -only proteins regulates this interaction by binding to poptotic proteins (e.g, Bcl-2, Bcl-xL, Bcl-w, Mcl-l) which results in the release Bax and Bak . See, Adams, J.M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis, S.N. et al. Science (2007) 315, 85 6-85 9. Although the exact interactions through which the anti- and pro-apoptotic Bcl-2 family proteins regulate apoptosis remain under debate, there is a large body of scientific evidence to show that compounds which inhibit the binding of BH3- only proteins to anti-apoptotic Bcl-2 family ns promote apoptosis in cells.

Dysregulated apoptotic pathways have been ated in the pathology of many significant diseases such as neurodegenerative conditions (up-regulated apoptosis), such as for example, Alzheimer's disease; and proliferative diseases (down-regulated apoptosis) such as for example, cancer, autoimmune es and pro-thrombotic conditions.

In one aspect, the implication that down-regulated apoptosis (and more particularly the Bcl-2 family of proteins) is involved in the onset of cancerous ancy has revealed a novel way of targeting this still elusive disease. Research has shown, for example, the anti- apoptotic proteins, Bcl-2 and Bcl-xL, are xpressed in many cancer cell types. See, Zhang J.Y., Nature Reviews/Drug Discovery, (2002) l, 101; , V. et a]. Biochimica et Biophysica Acta (2004) 1644, 229-249; and Amundson, S.A. et a]. Cancer Research (2000) ation] sak 60, 6101-6110. The effect of this lation is the survival of d cells which would otherwise have undergone sis in normal conditions. The repetition of these defects associated with unregulated eration is thought to be the starting point of cancerous evolution. onally, research has shown that BH3-only proteins can act as tumor suppressors when expressed in diseased animals.

These findings as well as numerous others have made possible the emergence of new strategies in drug discovery for targeting cancer. If a small molecule that could mimic the effect of BH3 -only proteins were able to enter the cell and overcome the anti-apoptotic protein over-expression, then it could be possible to reset the apoptotic process. This strategy can have the advantage that it can alleviate the problem of drug resistance which is usually a consequence of tic deregulation (abnormal survival).

Researchers also have demonstrated that platelets also n the necessary apoptotic machinery (e.g, Bax, Bak, Bcl-xL, Bcl-2, cytochrome c, caspase-9, caspase-3 and APAF-l) to execute programmed cell death through the intrinsic apoptotic pathway. Although ating platelet production is a normal physiological process, a number of diseases are caused or exacerbated by excess of, or undesired activation of, platelets. The above suggests that eutic agents capable of inhibiting anti-apoptotic proteins in platelets and reducing the number of platelets in mammals maybe useful in treating pro-thrombotic ions and diseases that are characterized by an excess of, or undesired activation of, platelets.

We have developed a class of small molecule BH3 -only protein mimetics, z’.e., ABT- 737 and ABT-263, that bind strongly to a subset of anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w and Bcl-xL, but only weakly to Mcl-l and Al, and exhibits mechanism-based cytotoxicity. These compounds were tested in animal studies and trated cytotoxic activity in certain xenograft models as single agents, as well as enhanced the effects of a number of chemotherapeutic agents on other xenograft models when used in combination.

See, Tse, C. et a]. Cancer Res (2008) 68, 3421-3428; and van Delft, M.F. et a]. Cancer Cell (2006) 10, 389-399. These in vivo studies suggest the potential y of inhibitors of anti- apoptotic Bcl-2 family proteins for the treatment of es that involve a dysregulated tic pathway.

The natural expression levels of anti-apoptotic Bcl-2 family proteins members vary in different cell types. For e, in young platelets, Bcl-xL protein is highly expressed and plays an important role in regulating cell death (life span) of platelets. Also, in certain cancer cell types, the cancer cell's survival is attributed to the dysregulation of the apoptotic pathway caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members.

In view of the important role for Bcl-2 family of proteins in regulating apoptosis in both cancerous and normal (z'.e., non-cancerous) cells, and the recognized cell type variability of Bcl-2 family n expression, it is advantageous to have a small molecule inhibitor that [Annotation] sak selectively targets and ably binds to one type or a subset of anti-apoptotic Bcl-2 protein(s), for example, to an anti-apoptotic Bcl-2 family member that overexpressed in a certain cancer type. Such a selective compound also may confer certain advantages in the clinical setting, by providing, for example, the flexibility to select a dosing regimen, a reduced on-target toxic effect in normal cells, among others (e.g, lymphopenia has been observed in Bcl-2 deficient mice). See, Nakayama, K. et al. PNAS (1994) 91, 3700-3704.

In View of the above, there is a need in the art for small molecules therapeutics that can selectively inhibit the ty of one type or a subset of anti-apoptotic Bcl-2 proteins, for example, of a Bcl-xL anti-apoptotic protein. The present invention fulfills at least this need.

SUMMARY OF THE INVENTION One embodiment of this invention, therefore, pertains to compounds or therapeutically acceptable salts thereof, which are useful as inhibitors of poptotic Bcl-xL proteins, the compounds having Formula (1) (R1)... (R2)n I ’1 \ N N 21 \E \I} 0 (R3)p// Yl-Ll-v2 Hi Formula (I) wherein X is heteroaryl; wherein the heteroaryl represented by X is ally substituted with one, two, three, or four R4; Y1 is phenylene or C5_6 heteroarylene; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3. gheterocycloalkane, and C3_g heterocycloalkene; wherein Y1 is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, 5, 5, OC(O)OR5, NHZ, NHRS, N(R5)2, R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, )N(R5)2, 2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, )S-NR6AC(O)- )r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A- (CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; ation] sak Y2 is C344 cycloalkyl, C344 lkenyl, C344 heterocycloalkyl, or C344 cycloalkenyl; optionally fused to one or two rings selected from the group consisting of C33 cycloalkane, C33 cycloalkene, benzene, C54 heteroarene, C3_3 heterocycloalkane, and C33 heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group ting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, 2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(0)NR8s02R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR1°C(O)R“, NR1°C(O)NR1°R“, OC(O)NR10R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group ting of I 0 j: O4 o ,N “a, g “‘21 OH \N'N '11..- EN—0, KAN \ 9 9 9 9 H H O O O O 0 O OH O ,N \\// II N S k _ _ / OH '71../ ‘Nl Rk .111. O KANJLRI‘ E E H H O ‘11.“ 9 9 9 9 O O O O “HA ,OH "RA /\/OH 5%in \/\OH ”RAN,0\Rk H a H a H 9 H a / o O ' O O\ 00 \ I )L ,\\S/’0 )L \‘ ’N\Rk \ \ ’ x '11; N / Rk N N “a,“ N \\ ”L‘L H , ,and ; R1, at each occurrence, is independently selected from the group consisting of halo, C14 alkyl, C24 l, C24 alkynyl, and C14 haloalkyl; R2, at each occurrence, is independently selected from the group consisting of ium, halo, C14 alkyl, C24 alkenyl, C24 l, and C14 haloalkyl; two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C14 alkyl, C24 alkenyl, C24 l, and C14 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, S(0)R14 and R14; [Annotation] sak R5, at each occurrence, is independently selected from the group consisting of Ci_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is independently selected from the group consisting of hydrogen, C1_6 alkyl, CM l, CM alkynyl, and C1_6 haloalkyl; R6 and R7, at each ence, are each independently selected from the group consisting of hydrogen, R”, on”, SR”, 5, soZR”, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NHZ, NHRIS, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, 2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, IS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SOZR16, C(O)R16, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, 2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSOZR16, 16SOZR16, SOZNHZ, SOZNHRm, SOZN(R16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, heterocyclyl, cycloalkyl, and lkenyl are optionally substituted with one, two, or three tuents independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; R9 is selected from the group consisting of C1_6 alkyl, CM l, CM alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)1_4 phenyl; and R10 and R“, at each occurrence, are each independently selected from the group ting of hydrogen, C1_6 alkyl, CM alkenyl, CM l, C3_6 cycloalkyl, C1_6 haloalkyl, phenyl and (CH2)1_4-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each ence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; [Annotation] sak R12 and R”, at each occurrence, are each independently selected from the group consisting of hydrogen, C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl and (CH2)1_4 phenyl; R14, at each occurrence, is independently selected from the group ting of C1_4 alkyl, C24 alkenyl, C24 alkynyl and C1_4 haloalkyl; R12 and R”, or R12 and R”, at each occurrence, together with the atom to which each is attached, are optionally combined to form a cyclyl; R15, at each occurrence, is independently selected from the group ting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are ally substituted with one, two, or three substituents independently selected from the group ting of 4 alkyl), NHZ, C(O)NH2, , C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1_4 alkyl, C24 l, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one substituent independently selected from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, l, or 2; mis 0,1, 2, or 3; n is 0,1, 2, 3, 4, 5, or 6; and p is 0, l, or 2.

In r embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl.

In another embodiment of Formula (I), Y1 is pyridinyl or phenyl.

In another embodiment of Formula (I), X is X is d]thiazolyl, thiazolo[5,4- b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl, and X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 idinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (I), Y1 is pyridinyl or phenyl, and X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- ation] sak c]pyridinyl, imidazo [ l ,2 idinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted With one, two, three or four R4.

In another embodiment of a (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl; and Z1 is O HN’hL O O\ 0 EAOH \ EJQN’N ’/ selected from the group consisting of , ,and RAE/Shh. another embodiment of Formula (I), Y1 is pyridinyl or phenyl; and Z1 is selected from the O HN’N‘ O O\\ / O EAOH «51%N,N / , a ”RAE/Shh . group consisting of In another embodiment of Formula (I), Y1 is pyridinyl or phenyl; L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl, and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is l or 2. In r embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or lyl; L1 is (CR6R7)q; and Y2 is selected from the group consisting of Cg_14 lkyl, and Cg_14 heterocycloalkyl; wherein R6 and R7, at each ence, are hydrogen; and q is 1 or 2.

In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl; L1 is selected from the group consisting of (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)s-C(O)NR6A- )r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of Cg.14 cycloalkyl and Cg_14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen. In another embodiment of Formula (I), Y1 is pyridinyl or ; L1 is selected from the group consisting R7)S-O-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)s-S(O)2- (CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A- (CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of Cg.14 cycloalkyl, and eterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

Still another embodiment pertains to a compound haVing Formula (I), selected from the group consisting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l { l - [tricyclo [3 .3 . l . 13’7]dec-l -ylmethyl]- l H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] [3,5- dimethyl- l -(tricyclo[3.3. l .13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] [5- (tricyclo [3 .3. l . l 3’7]dec- l -ylmethyl)- l H-pyrazolyl]pyridinecarboxylic acid; ation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -[1- (Spiro [3 .5 ]n0ny1methyl)- 1 H-pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]—3-(1-{[3,5 - dimethyltricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazolyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - hydroxytricyclo[3.3.1.13’7]decyl]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 .13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( ]—3 -(1- {[3-(2- yethoxy)tricyclo[3.3.1.13’7]decy1]methy1}-1H—pyrazo1y1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {1 - [(3 ,5,7-trimethyltricyc10[3.3.1.13’7]decy1)methyl]—1H-pyrazoly1}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -[1- (tricyclo [3 .3 . 1 . 13 y1methy1)- 1 H-pyrazo1y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - bromotricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - (propan-Z-yloxy)tricyclo [3 .3 . 1 .13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 -[1-(2 - 0xatricyc10[3.3. 1 . 13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6- [8-(1 ,3 -benzothiazol-Z-y1carbam0yl)-4,4-dimethy1-3 ,4-dihydI0is0quinolin-2( 1 H)- y1] [5 -methy1(tricyc10[3.3.1 .13’7]decy1methyl)-1H-pyrazoly1]pyridine-Z-carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - (morpholinyl)tricyclo[3.3.1.13’7]decy1]methy1}-1H-pyrazolyl)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 . 13 ’7] decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridine-2 -carb0xylic acid; -benzothiazolyl) {6- [(methylsulfonyl)carbamoyl] -5 - [5 -methyl (tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; [Annotation] sak N-(1,3-benzothiazol-2 -y1)-2 - {6-[(cyclopropy1su1f0ny1)carbam0yl] -5 - [5-methy1 c10[3.3.1.13’7]decy1methy1)—1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; N-(l ,3-benzothiazol-2 -y1) {5-[5-methy1(tricyc10[3.3. 1 .13’7]decy1methy1)— 1 H- pyrazoly1](2H-tetrazol-5 -y1)pyridiny1} - 1 ,2,3 ,4-tetrahydr0isoquinoline-8 - carboxamide; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)—3 ,4-dihydI0is0quinolin-2(1H)—y1]—3 - {2 - methyl [tricyclo [3 .3 . 1 3’7] decy1meth0xy]pheny1 } pyridinecarb0xy1ic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)—3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {2 - methyl-3 - [tricyclo [3 .3 . 1 . 1 3’7] decy1meth0xy]pheny1 } pyridinecarb0xy1ic acid; 1,3 -benzothiazol-Z-y1carbam0yl)—3 ,4-dihydI0is0quinolin-2(1H)—y1]—3 - {3 - [tricyc10[3.3.1.13’7]decy1meth0xy]phenyl}pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 H)-y1]—3 - [5 -cyan0- y1(tricyc10[3.3. 1 . 13’7]decy1methy1)—1H-pyrr01-3 -y1]pyridinecarb0xylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[5 ,4-b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)—3 ,4-dihydrois0quinolin-2( 1 H)-y1] -2'- (tricyc10[3.3.1.13’7]decylmeth0xy)-3 ,4'-bipyridinecarb0xylic acid; 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -[1-({3-[2- (morpholinyl)ethoxy]tricyc10[3.3.1.13’7]decy1}methyl)—1H-pyrazoly1]pyridine carboxylic acid; 1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 '-methyl- 2'—(tricyc10[3.3.1.13’7]decy1meth0xy)—3,4'-bipyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]—3-{2- methyl[tricyc10[3.3. 1 . 13’7]decy10xy]pheny1}pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {5 -cyan0- cyc10[3.3.1.13’7]decy1methy1]—1H-pyrazoly1}pyridinecarb0xylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[4,5 -b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[4,5 idiny1carbam0y1)—3,4-dihydI0is0quinolin-2(1H)-y1]pyridine ylic acid; 6-[8-(1,3 -benzothiazoly1carbam0y1)—3,4-dihydI0is0quin01in-2(1H)-y1]—3-(1-{[3,5 - dimethyltricyclo [3 .3 . 1 . 1 3’7]decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridinecarb0xy1ic acid; ation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(1- {[3 - (1 , 1 -dioxidothiomorpholiny1)tricyc10 [3 .3 - 1 H-pyrazol . 1 . 13’7]decy1]methy1} y1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {5 -cyan0- 2-methy1[2-(tricyc10[3.3.1.13’7]decy1)ethy1]—1H-pyrr01y1}pyridinecarb0xylic acid; N-(l,3-benzothiazolyl){5-[5-cyan0methy1(tricyc10[3.3.1.13’7]dec ylmethyl)-1H-pyrr01y1][(methylsulfonyl)carbam0y1]pyridiny1} -1 ,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl){5-[5-cyan0methy1(tricyc10[3.3.1.13’7]dec y1)- 1 01-3 -y1][(cyclopropylsulfonyl)carbamoyl]pyridiny1}-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyclo[3.3.1.13’7]decyl]methyl}- -methyl- 1 H-pyrazolyl)[(methylsulfonyl)carbamoy1]pyridiny1}-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3-benzothiazol-Z-y1carbam0yl)-3 ,4-dihydrois0quinolin-2(1H)-y1]—3-(1-{[3- methoxy-S ,7-dimethy1tricyc10[3.3. 1 . 13’7]decy1]methy1} methy1- 1H-pyrazol yl)pyridinecarb0xylic acid; N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyclo[3.3.1.13’7]decyl]methyl}- -methyl-1H-pyrazoly1)[(morpholiny1su1f0ny1)carbamoyl]pyridin-2 -y1} -1 ,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; -benzothiazolyl)[5-(1-{[3-meth0xytricyclo[3.3.1.13’7]decy1]methyl}-5 - methyl-1H-pyrazoly1) {[(trifluoromethyl)sulfonyl]carbam0y1}pyridiny1]-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l ,3-benzothiazolyl) { 6- [(cyclopropylsulfonyl)carbamoyl]-5 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 . 13’7]dec-1 -y1]methy1}-5 -methy1-1H-pyrazolyl)pyridiny1}-1,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {5 - ch10r0[tricyc10[3.3.1.13’7]decy1methyl]—1H-pyrazoly1}pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)methy1-3,4-dihydrois0quinolin-2(1H)-y1]—3 - [5 -methyl(tricyc10 [3 .3 . 1 .13’7]decy1methyl)-1H-pyrazolyl]pyridinecarb0xylic acid; 1,3-benzothiazoly1carbam0y1)(1,1 -2H2)-3,4-dihydrois0quinolin-2(1H)-yl]—3 - [5 -methyl(tricyc10 [3 .3 . 1 decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[3-(2- methoxyethoxy)tricyclo [3 .3 . 1 . 1 3’7]decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridine ylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[1-(2- methoxyethyl)cyc100cty1]methy1} methy1-1H-pyrazolyl)pyridinecarb0xy1ic acid; [Annotation] sak 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {2-cyan0- 3-[tricyc10[3.3.1.13’7]decy1amin0]phenyl}pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - n0[tricyc10[3 .3 . 1 .13’7]decy1su1fany1]pheny1}pyridinecarb0xylic acid; 6-[8-(imidazo[1,2-a]pyridiny1carbam0yl)-3 ,4-dihydI0is0quin01in-2(1 H)-y1]—3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - {[tricyclo [3 . 3. 1 . 13’7]decy1carb0ny1]amin0}phenyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1]—3 - {2 - methyl[tricyc10[3.3.1.13’7]decy1su1fam0y1]phenyl}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - {methyl clo [3 . 3. 1 . 13’7]decy1carb0ny1]amino}phenyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -(5 - methyl {[3 -(tetrahydro-ZH-pyrany1meth0xy)tricyclo[3.3.1.13’7]decy1]methyl}-1H- pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {2 - methyl[tricyc10[3.3.1.13’7]decy1carbam0y1]pheny1}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - {methyl clo [3 . 3. 1 . 13’7]decy1methyl]amino } phenyl)pyridinecarb0xy1ic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[2-(2- methoxyethyl)tricyclo [3 .3 - 1 H-pyrazoly1)pyridinecarb0xy1ic . 1 . 1 3’7]decy1]methyl} acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 - methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-1,2,3 -triazoly1]pyridinecarb0xy1ic acid; 1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 H)-y1]—3 -(5 -cyan0- 1- { [3 -meth0xytricyc10[3.3.1.13’7]decy1]methy1}methyl-1H-pyrr01yl)pyridine carboxylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - [5 - methyl-1 -(2-0xatricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 H)-y1]—3 - [2-cyan0- 3 -(tricyc10 [3 . 3 . 1 .13’7]decy1su1f0ny1)phenyl]pyridine-2 -carb0xylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)-3 ,4-dihydrois0quinolin-2( 1 H)-y1] -2'- [cycloocty1(methyl)amino] -3'-methy1-3,4'-bipyridinecarb0xy1ic acid; [Annotation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)-y1]-3 -[1-({3-[2- (2-meth0xyethoxy)ethoxy]tricyc10[3.3.1.13’7]decy1}methy1)—5-methy1-1H-pyrazol y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 -(2- methyl-3 - {methyl yclo [3 .3 . 1 . 13’7]dec-2 -y1] carbamoyl }pheny1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]-3 - [5 - methyl({ methy1su1f0ny1)ethoxy]cyc100cty1}methy1)—1H-pyrazoly1]pyridine carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 - [5 - methyl(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-1,2,3 -triazoly1]pyridine carboxylic acid; ethy1(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-pyrazoly1]—6-[8- ([1,3]thia2010[5 ,4-b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]—3 - {2 - methyl-3 y1(2-0xatricyc10 [3 .3 . 1 .13’7]decy1carb0ny1)amino]pheny1}pyridine carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]-3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. 1 . 1 3’7]decy1]sulfamoyl}pher1y1)py1‘idinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2( 1 H)-y1] -3 '-methy1- 2'—(tricyc10[3.3.1.13’7]decy1su1f0ny1)-3,4'-bipyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]-3 - [5 -cyan0- 2-methy1(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-pyrr01-3 -y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]-3 - {5 -cyan0- 2-methy1[(3 -methy10xatricyc10[3.3.1.13’7]decy1)methy1]—1H-pyrr01y1}pyridine carboxylic acid; 6-[8-(imidazo[1,2-a]pyraziny1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]-3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2( 1 H)-y1] -3 '-methy1- 2'-(tricyc10[3.3.1.13’7]decy1su1fany1)-3 ,4'-bipyridinecarb0xy1ic acid; 2- {6- ylsulfonyl)carbamoyl] -5 - [5 -methy1-1 yc10 [3 . 3 .1 .13’7]decy1methy1)- azoly1]pyridiny1}-N-([1,3]thiazolo[5,4-b]pyridiny1)—1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; [Annotation] sak 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 '-methyl- 2'—(tricyclo [3 .3. l . 13’7]dec-l no)-3,4'-bipyridinecarboxylic acid; 6- [ 8-(imidazo [l ,2-b]pyridazinylcarbamoyl)-3,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [5 -methyl(tricyclo [3 .3 . l .13’7]dec- l -ylmethyl)- l H-pyrazolyl]pyridine-2 -carboxylic acid; 3-[5-methyl-l-(tricyclo[3.3.l.13’7]dec-l-ylmethyl)—lH-pyrazolyl]—6-[8- ([l ,3 ]thiazolo [5 yridin-2 -ylcarbamoyl)—3 ,4-dihydroisoquinolin-2 ( l H)-yl]pyridine carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2 ( l H)-yl] -3 - { l - [(5 - methoxyspiro [2 . 5 ]oct-5 thyl] -5 -methyl- 1 H-pyrazolyl } pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -( l - {[3 - {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo [3 .3. l . l 3’7]dec- l thyl} -5 -methyl- 1 H- pyrazolyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)—3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -(5 - -l- {[3 -(methylsulfonyl)tricyclo [3 .3 . l - l H-pyrazolyl)pyridine- . l 3’7]dec- l -yl]methyl} 2-carboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 -[l-( { 3,5- dimethyl[2-(methylamino)ethoxy]tricyclo [3 . 3 . l .13’7]dec-l-yl}methyl)methyl- 1 H- pyrazolyl]pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)—3,4-dihydroisoquinolin-2( l H)-yl] -3 -(5 - methyl-l-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.l.13’7]dec-l- yl]methyl } - l H-pyrazolyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [ l -( { 8- [(benzyloxy)carbonyl] azabicyclo [3 .2 . l ]oct-3 -yl } methyl)- 1 zolyl]pyridine-2 - carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -6'-oxo-l '- (tricyclo [3 .3 . l . 13’7]dec-l -ylmethyl)—l ',6'—dihydro-3 ,3'-bipyridinecarboxylic acid; 6-[8-(1 ,3 -benzothiazolylcarbamoyl)—3,4-dihydroisoquinolin-2(lH)-yl]—3-( l - {[3,5 - dimethyl(2- {2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3 .3. l .13’7]dec- l - yl]methyl} -5 -methyl- 1 H-pyrazolyl)pyridinecarboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.

Another embodiment pertains to a composition for ng bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal , esophageal cancer, hepatocellular cancer, lymphoblastic ia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell , melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic cytic ia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of a nd of a (I).

Another ment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, id ancies of T-cell or B-cell , melanoma, enous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer, brain cancer, breast cancer, bone marrow , cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular , blastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung , chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Another ment pertains to a pharmaceutical composition sing an excipient and a therapeutically effective amount of a compound of the invention or therapeutically acceptable salt of a compound of the invention.

Another embodiment pertains to a nd of the invention or therapeutically acceptable salt of a compound of the invention for use in the cture of a medicament for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, c lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer.

Another embodiment pertains to a compound of the invention or therapeutically acceptable salt of a compound of the ion, and a therapeutically ive amount of one additional therapeutic agent or more than one additional therapeutic agent, for use in the manufacture of a medicament for treating bladder cancer, brain cancer, breast , bone marrow cancer, al cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of 11173815.sak T-cell or B-cell origin, melanoma, myelogenous leukemia, a, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen .

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take ent over any dictionary or sic definition. In this application, the use of "or" means "and/or" unless stated ise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. With reference to the use of the words "comprise" or "comprises" or ising" in this patent application (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than ively, and that Applicants intend each of those words to be so interpreted in construing this patent application, ing the claims below. For a variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents are permissible only if such combinations result in stable compounds. Stable 11173815.sak [Annotation] sak compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.

It is meant to be understood that proper valences are ined for all combinations herein, that monovalent moieties having more than one atom are attached h their left ends, and that divalent moieties are drawn from left to right.

As used in the specification and the appended , unless ied to the contrary, the following terms have the meaning indicated: The term "alkyl" (alone or in combination With another term(s)) means a straight-or branched-chain ted hydrocarbyl substituent lly containing from 1 to about 10 carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.

The term "alkenyl" (alone or in combination With another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and lly from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, l,4-pentadienyl, l,4-butadienyl, l-butenyl, 2-butenyl, and 3-butenyl and the like.

The term "alkynyl" (alone or in combination With another term(s)) means a straight- or ed-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3- propynyl, 2-butynyl, and 3-butynyl and the like.

The term "carbocyclyl" (alone or in combination With another term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or tely unsaturated (i.e., "aryl") arbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic tuent). A carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.

A carbocyclyl may be a single ring ure, Which typically contains from 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.

Examples of such single-ring carbocyclyls include cyclopropyl propanyl), cyclobutyl (cyclobutanyl), entyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, cyclooxtanyl, and phenyl. A carbocyclyl may alternatively be clic (i.e., may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic [Annotation] sak carbocyclyl, one atom is common to two different rings. Examples of yclic carbocyclyls include spiropentanyl, spiro[3.5]nonanyl, and spiro[2.5]octanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of d carbocyclyls include o[2.2.1]heptanyl, bicyclo [2.2.1]heptenyl, and adamantanyl (tricyclo[3.3.1.13’7]decanyl). In a fused-ring carbocyclyl system, two or more rings may be fused er, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

The term "cycloalkyl" (alone or in combination With r term(s)) means a saturated cyclic hydrocarbyl tuent ning from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, Which typically contains from 3 to 8 carbon ring atoms and more typically from 3 to 6 ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, exyl, cycloheptanyl, and cyclooctanyl. A cycloalkyl may altematiVely be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls. Examples of bridged cycloalkyls include adamantanyl (tricyclo[3.3.1.13’7]decanyl), and bicyclo [3. l . l ]heptanyl.

The term "CK-Cy cycloalkyl" means a cycloalkyl ring system containing from x to y carbon atoms. For example "C3-C7 cycloalkyl" means a lkyl ring system containing from 3 to 7 carbon atoms.

The term "cycloalkenyl" (alone or in combination With another term(s)) means a partially saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.

A cycloalkenyl may be a single carbon ring, Which typically contains from 3 to 8 carbon ring atoms and more typically from 4 to 6 ring atoms. Examples of single-ring cycloalkenyls include cyclopentenyl, and cyclohexenyl. A lkenyl may altematiVely be polycyclic or contain more than one ring. Examples of polycyclic cycloalkenyls include d, fused, and spirocyclic carbocyclyls. Examples of bridged lkenyls e bicyclo[2.2.1]hept- 2-enyl.

The term "CK-Cy cycloalkenyl" means a cycloalkenyl ring system containing from x to y carbon atoms. For e "C4-C7 cycloalkenyl" means a cycloalkenyl ring system containing from 4 to 7 carbon atoms.

The term "aryl" (alone or in combination With another term(s)) means an ic carbocyclyl containing from 6 to 14 carbon ring atoms. An aryl may be monocyclic or polycyclic (i.e., may contain more than one ring). In the case of polycyclic aromatic rings, only one ring the polycyclic system is required to be unsaturated While the remaining ring(s) may be saturated, partially saturated or unsaturated. Examples of aryls include phenyl, naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.

[Annotation] sak The term "arylene" means a divalent arene.

The term “phenylene” means a divalent e.

In some instances, the number of carbon atoms in a substituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl) is indicated by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms. Thus, for example, "C1-C6-alkyl"refers to an alkyl containing from 1 to 6 carbon atoms. Illustrating further, -cycloalkyl" means a saturated arbyl ring containing from 3 to 8 carbon ring atoms.

The term "Cx_y branched chain alkyl" means a saturated hydrocarbyl substituent containing from x to y carbons wherein attachment occurs through a dialkyl trivalent- or trialkyl tetravalent- carbon l. Examples of such substituents include tanyl (pentanyl), neopentanyl (2,2-dimethylpropanyl), heptanyl, and 2,6-dimethylheptan The term, "C3.“ branched chain alkyl" means a ted hydrocarbyl substituent containing from 3 to 11 carbons wherein attachment occurs through a l trivalent- or trialkyl tetravalent- carbon radical.

The term "hydrogen" (alone or in combination with r term(s)) means a hydrogen radical, and may be depicted as -H.

The term "hydroxy" (alone or in combination with another term(s)) means -OH.

The term "carboxy" (alone or in combination with another term(s)) means -C(O)—OH.

The term "amino" (alone or in combination with another term(s)) means -NH2.

The term "halogen" or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as - Cl), e l (which may be depicted as -Br), or iodine radical (which may be depicted as -I).

If a substituent is bed as being "substituted", a non-hydrogen radical is in the place of hydrogen radical on a carbon or en of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).

If a substituent is described as being "optionally substituted", the substituent may be either (1) not tuted or (2) tuted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, [Annotation] sak ver is less. Thus, for example, if a substituent is described as a heteroaryl ally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally tuted with up to one non-hydrogen radical. To rate further, if an amino nitrogen is described as being optionally tuted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.

This patent application uses the terms "substituent" and "radical" interchangeably.

The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen l. Examples of haloalkyls include chloromethyl, l-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,l-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one n radical, those halogen radicals may be identical or different (unless otherwise stated).

The prefix "perhalo" indicates that every hydrogen l on the substituent to which the prefix is ed is replaced with independently selected n radicals, i.e., each hydrogen radical on the substituent is replaced with a n radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term "perfluoro" means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To rate, the term "perfluoroalkyl" means an alkyl substituent wherein a fluorine radical is in the place of each en radical.

The term "carbonyl" (alone or in combination with another term(s)) means -C(O)—.

The term "aminocarbonyl" (alone or in combination with another term(s)) means - The term "oxo" (alone or in ation with another term(s)) means (=0).

The term "oxy" (alone or in combination with r term(s)) means an ether substituent, and may be depicted as -O-.

The term "hydroxyalkyl" (alone or in ation with another term(s)) means — alkyl-OH.

The term "alkylamino" (alone or in combination with another term(s)) means —alkyl- NHZ.

The term "alkyloxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy ( CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[Annotation] sak The term "alkylcarbonyl" (alone or in combination With another term(s)) means - C(O)-alkyl.

The term alkylcarbonyl" (alone or in combination With another term(s)) means -C(O)—alkyl-NH2.

The term oxycarbonyl" (alone or in combination With another term(s)) means - C(O)-O-alkyl.

The term "carbocyclylcarbonyl" (alone or in combination With another term(s)) means -C(O)—carbocyclyl.

Similarly, the term "heterocyclylcarbonyl" (alone or in combination With another term(s)) means -C(O)-heterocyclyl.

The term "carbocyclylalkylcarbonyl" (alone or in combination With another )) means -C(O)-alkyl-carbocyclyl.

Similarly, the term "heterocyclylalkylcarbonyl" (alone or in ation With another term(s)) means -C(O)—alkyl-heterocyclyl.

The term cyclyloxycarbonyl" (alone or in combination With another term(s)) means -C(O)—O-carbocyclyl.

The term "carbocyclylalkyloxycarbonyl" (alone or in combination With another term(s)) means -C(O)-O-alkyl-carbocyclyl.

The term "thio" or "thia" (alone or in combination With another term(s)) means replacement by a sulfur radical, z'. e. a thiaether substituent means an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. For example, "alkyl-thio-alkyl" means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).

The term "thiol" or "sulfliydryl" (alone or in combination With another term(s)) means a sulmydryl tuent, and may be depicted as -SH.

The term "(thiocarbonyl)" (alone or in combination With another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.

The term "sulfonyl" (alone or in combination With another term(s)) means -S(O)2-.

The term "aminosulfonyl" (alone or in combination With another term(s)) means - S(O)2-NH2.

The term nyl" or "sulfoxido" (alone or in ation With another )) means -S(O)-.

The term "heterocyclyl" (alone or in combination With another term(s)) means a saturated (z'.e., "heterocycloalkyl"), lly saturated (z'.e., "heterocycloalkenyl"), or completely unsaturated (z'.e., "heteroaryl") ring ure ning a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (z'.e., oxygen, nitrogen, or sulfur), With the remaining ring atoms being independently selected from the group consisting of carbon, [Annotation] sak oxygen, nitrogen, and sulfur. A heterocyclyl may be a single-ring yclic) or polycyclic ring structure.

A heterocyclyl may be a single ring, which lly contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of -ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, lidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, linyl, isothiazolinyl, lidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including l,2,3,4-oxatriazolyl or l,2,3,5- azolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), 1,4-dioxanyl, dioxothiomorpholinyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4- diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3- triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3 -oxazinyl, or l,4-oxazinyl)), oxathiazinyl (including oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or l,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5- oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, pyridonyl (including pyrid-2( lH)-onyl and pyrid-4(lH)-onyl), furan-2(5H)-onyl, donyl (including pyramid- 2(lH)-onyl and pyramid-4(3H)-onyl), oxazol-2(3H)-onyl, lH—imidazol-2(3H)-onyl, pyridazin-3(2H)-onyl, and pyrazin-2(lH)-onyl.

A heterocyclyl may atively be polycyclic (i.e., may n more than one ring).

Examples of polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls.

In a spirocyclic heterocyclyl, one atom is common to two different rings. In a bridged heterocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged heterocyclyls include 2-oxatricyclo[3.3.1.13’7]decane. In a fused-ring heterocyclyl, two or more rings may be fused together, such that two rings share one common bond. Examples of fused ring cyclyls containing two or three rings include imidazopyrazinyl (including imidazo[ l ,2-a]pyrazinyl), imidazopyridinyl (including o[ l ,2-a]pyridinyl), imidazopyridazinyl (including imidazo[l,2-b]pyridazinyl), thiazolopyridinyl (including thiazolo [5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, lo[4,5 -b]pyridinyl, and thiazolo [4,5 - c]pyridinyl), indolizinyl, pyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridinyl (including pyrido[3,4-b]—pyridinyl, pyrido[3,2-b]—pyridinyl, or pyrido[4,3-b]— pyridinyl), and inyl. Other es of fused-ring cyclyls include benzo-fused cyclyls, such as dihydrochromenyl, tetrahydroisoquinolinyl, indolyl, isoindolyl [Annotation] sak (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1 -benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2- benzodiazinyl) or quinazolinyl (1 ,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1- benzoxazinyl, or 3,1,4-benzoxazinyl), benzo[d]thiazolyl, and benzisoxazinyl (including 1,2- benzisoxazinyl or 1,4-benzisoxazinyl).

The term "heterocycloalkyl" (alone or in combination With another term(s)) means a saturated heterocyclyl.

The term "CK-Cy heterocycloalkyl" means a heterocycloalkyl ring system containing from x to y ring atoms. For example “C3-C7 heterocycloalkyl” means a heterocycloalkyl ring system containing 3 to 7 ring atoms.

The term "heterocycloalkenyl" (alone or in combination With another term(s)) means a lly saturated cyclyl.

The term "CK-Cy heterocycloalkenyl" means a heterocycloalkenyl ring system containing from x to y ring atoms. For example "C3-C7 heterocycloalkenyl" means a heterocycloalkenyl ring system containing from 3 to 7 ring atoms.

The term oaryl" (alone or in combination With another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A aryl may be a single ring or 2 or 3 fused rings. Examples of aryls include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and , 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as triazolyl, pyrrolyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, , 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5- membered fused ring substituents such as imidazopyrazinyl (including imidazo[1,2- a]pyrazinyl) imidazopyridinyl (including imidazo[1 ,2-a]pyridinyl), opyridazinyl (including o[ 1 ,2-b]pyridazinyl), thiazolopyridinyl (including thiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, and thiazolo[4,5 -c]pyridinyl), benzo[d]thiazolyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl. Heteroaryls may also be heterocyles having aromatic (4N+2 pi electron) resonance contributors such as pyridonyl (including pyrid-2(1H)-onyl and pyrid- 4(1H)-onyl), pyrimidonyl ding pyramid-2(1H)-onyl and pyramid-4(3H)-onyl), pyridazin-3(2H)-onyl and pyrazin-2(1H)-onyl.

The term "CK-Cy heteroaryl" means a heteroaryl ring system containing from x to y ring atoms. For example "C5-C6 aryl" means a aryl ring system containing from 5 to 6 ring atoms.

The term oarylene" means a divalent heteroarene.

[Annotation] sak A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, the C1-C6- prefix on C1-C6-alkylcycloalkyl means that the alkyl ent of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6-prefix does not describe the lkyl component. To illustrate further, the prefix "halo" on kyloxyalkyl tes that only the alkyloxy component of the alkyloxyalkyl tuent is substituted with one or more halogen radicals. If n substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be bed as "halogen-substituted alkyloxyalkyl" rather than lkyloxyalkyl." And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkyloxyhaloalkyl." The terms ", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

The terms "prevent", "preventing" and ntion" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its ant symptoms and reducing a subj ect's risk of acquiring a disease.

The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or er being treated.

The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of a kinase. "Modulation", as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, t, delay activation, inactivate, itize, or down regulate signal transduction. Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal uction.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the ed amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. ation] sak The "subj ect" is defined herein to include animals such as s, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.

The term "NH protecting group," as used herein, means oroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, uryl-oxycarbonyl, ylmethoxycarbonyl, l,l- dimethylpropoxy-carbonyl, poxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, ladamantyloxycarbonyl , 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2- nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5 obenzylidene, 2-hydroxy-l -naphthyl- methylene, 3-hydroxypyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5 -oxycyclo-hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyloxo-2H-l ,3 -dioxolyl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term H protecting group," as used herein, means methyl, ethyl, n-propyl, isopropyl, l,l-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, , diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para- methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloro- ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, ylthioethyl, phenylthiomethyl, l,l-dimethylpropenyl, 3-methyl- 3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, utyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

The term "OH or SH protecting group," as used herein, means benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, l l -dimethylpropoxycarbonyl, poxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2- (triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, l-adamantyloxycarbonyl, [Annotation] sak vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, yl, l, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, l,l-dimethylpropenyl, 3-methylbutenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, ydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, l-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, lisopropylsilyl, tert-butyldimethylsilyl, utyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds Geometric isomers may exist in the present compounds. Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as ined by the Cahn-Ingold—Prelog Priority Rules. The compounds of this invention may also exist as a mixture of “E” and “Z” s. Substituents around a cycloalkyl or heterocycloalkyl are sometimes designated as being of cis or trans configuration.

Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in Which the terms "R" and "S" are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms With equal s of R and S configurations are racemic at those carbon atoms. Atoms With an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention includes racemic mixtures, relative and te stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope Enriched or Labeled Compounds nds of the invention can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in . Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as en, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32F, 358, 18F, 36Cl, and 1251.

Compounds that n other isotopes of these and/or other atoms are Within the scope of this invention.

[Annotation] sak In another ment, the isotope-labeled compounds contain deuterium (2H), tritium (3H) or 14C isotopes. Isotope-labeled compounds of this invention can be prepared by the l methods well known to persons having ordinary skill in the art. Such isotope- 1abe1ed compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some ces, compounds may be treated with isotope-labeled reagents to ge a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as DZSO4/DZO. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al., Drugs Fur, , 1116 (1996); Brickner, S J et al., JMed Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications W01997010223, W02005099353, W01995007271, W02006008754; US Patent Nos. 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; and US Patent ation Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471 the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as rds to determine the effectiveness of Bcl-xL inhibitors in binding assays. Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).

Such metabolic studies are ant in the design of safe, effective therapeutic drugs, either because the in viva active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, ic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., :927-932 (1995); Kushner et al., Can. J. Physiol.

Pharmacol., 77, 79-88 (1999).

In addition, non-radio active isotope containing drugs, such as deuterated drugs called “heavy drugs,” can be used for the ent of diseases and conditions related to Bcl-xL activity. Increasing the amount of an isotope t in a compound above its l abundance is called enrichment. Examples of the amount of enrichment include from about 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9,10,12,16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15% of normal atom with a heavy e has been ed and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse s (Czajka D M and Finkel A J, Ann. NY. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M eta1., Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%- [Annotation] sak 23% in human fluids with deuterium was found not to cause toxicity (Blagoj evic N et al. in "Dosimetry & Treatment ng for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical hing, Madison Wis. pp. 125-1 34; Diabetes Metab. 23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region ed in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the al and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of lism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.

Suitable groups for X, Y1, L1, Y2, 21, R1, R2, R3, m, n, and p in compounds of Formula (I) are ndently selected. The described embodiments of the t ion may be combined. Such combination is contemplated and within the scope of the present invention. For example, it is contemplated that embodiments for any of X, Y1, L1, Y2, 21, R1, R2, R3, m, n, and p can be combined with embodiments defined for any other of X, Y1, L1, Y2, 21, R1, R2, R3, m, n, and p.

One ment of this invention, therefore, pertains to nds and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (I) (R1)m (R2)n I /j \ N N 21 H171 0 / Yl-Ll-Y2 (R3)P X Formula (I), X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Y1 is phenylene or C5_6 heteroarylene; optionally fused to one or two rings ed from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3. gheterocycloalkane, and C3_g heterocycloalkene; wherein Y1 is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of R5, 0R5, [Annotation] sak SR5, S(O)R5, SOzR5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, )R5, NHS(O)2R5, NRSS(O)2R5, OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, OH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, 5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S- C(O)—(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)- (CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A- (CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g cycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, )R8, NHS(O)2R8, NRgs(O)2R8, OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(0)NR8s02R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR1°C(O)R“, 0)NR1°R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=N0R1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, 9, S(O)2NR1°R11,N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is ed from the group consisting of N O N ,N ,N HN’ \\ I O HN‘ ’N ‘LL N WAOH )OQ—OH )OL kN] N N H .RL 9 9 .111— 9 “‘11- 9 H H O O O O O OH O ,N \\// 0 II N S\ k _ _ / OH y: N’( k a{fl\¢A\OJ{ “{J\N Rk E E H H 0 ‘11,.“ 9 9 9 9 )CJ: 0 O O ,OH EAL /\/OH ,O\ “a / \/«DH “(kN N H 9 H 9 H 9 H 9 / o O O | O I QLN \\ /O O 8‘’ ”ELN’S“\\ N \\S/\/ , \ k / R 14 N N R H H H , ,md R1, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; [Annotation] sak R2, at each occurrence, is independently selected from the group ting of deuterium, halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, )R14, 14, S(0)R14 and R14; R5, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM l, CM alkynyl, C1_6 haloalkyl, C1_6 yalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is independently ed from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM l, and C1_6 haloalkyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R”, on”, SR”, S(O)R15, soZR”, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NHZ, NHRIS, N(R15)2, NHC(O)R15, NR15C(O)R15, 2R15, O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, SOZNHRIS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is ndently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SOng, C(O)R16, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NH2, NHC(O)NHR16, NHC(O)N(R16)2, O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSOZR16, C(O)NR16SOZR16, SOZNHZ, SOZNHRm, SOZN(R16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, cyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; [Annotation] sak R9 is selected from the group consisting of C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)14 phenyl; and R10 and R“, at each occurrence, are each independently selected from the group consisting of hydrogen, C14 alkyl, C2_6 alkenyl, C2_6 alkynyl, C34 lkyl, C14 haloalkyl, phenyl and (CH2)14-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C14 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C14 haloalkyl; R12 and R”, at each occurrence, are each independently selected from the group consisting of en, C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl and (CH2)14 phenyl; R“, at each occurrence, is ndently selected from the group consisting of C14 alkyl, C24 l, C24 l and C14 haloalkyl; R12 and R”, or R12 and R14, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, C14 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, and C14 hydroxyalkyl are optionally substituted with one, two, or three substituents ndently selected from the group consisting of O-(C14 , NH2, 2, SO2NH2, C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C14 alkyl, C24 alkenyl, C24 alkynyl, C14 kyl, C14 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, aryl, cycloalkyl, and cycloalkenyl; wherein the R16 C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, and C14 hydroxyalkyl are optionally substituted with one substituent independently selected from the group ting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, 1, or 2; mis 0,1, 2, or 3; n is 0,1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2.

In one embodiment ofFormula (I), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (I), n is 0, 1, or 2. In another embodiment of ation] sak Formula (I), n is 0, l, or 2; and each R2 is independently deuterium or C1_6 alkyl. In another ment of Formula (I), m, n, and p are 0.

In one embodiment of Formula (I), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (I), X is heteroaryl, which is unsubstituted. In another embodiment of Formula (I), X is heteroaryl, which is substituted with one R4. In another embodiment of Formula (I), X is heteroaryl, which is substituted with two R4. In another embodiment of Formula (I), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or halogen. In another ment of Formula (I), X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (I), X is heteroaryl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In r embodiment of Formula (I), X is heteroaryl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (I), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (I), X is d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are tuted with one R4. In another embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[l yrazinyl, or imidazo[l ,2- dazinyl, which are substituted with two R4. In another embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- dinyl, imidazo [ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, o[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another ment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, o [ l ,2 -a]pyridinyl, lo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, [Annotation] sak o[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (I), X is benzo[d]thiazolyl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (I), X is benzo[d]thiazolyl, which is tituted. In another embodiment of Formula (I), X is benzo[d]thiazolyl, which is substituted with one R4. In r embodiment of Formula (I), X is d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (I), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another ment of Formula (I), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is ndently F.

In one embodiment of Formula (I), Z1 is selected from the group consisting of C(O)OR9, C(O)NR1°R“, C(O)R“, NR10C(O)R“, NR10C(O)NR10R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR10C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R10)S(O)2R“,NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR10)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N O (N / HN \\ | o HN’N o N C) N m1 OH \ n’ /L§Q>—OH /K\ \N “a H N .111. 9 9 “.11“ 9 .111“ 9 g 9 O O O OH O O O ,N \\ ’/ 0 EMU}? 3.2LNJL M MOHN S\ k Rk 2_ _fi OH af N4Rk H H O .111“ 9 9 9 9 9 O O O O x H r \ H 9 H 9 H 9 H 9 /' O O o I O\\S’/O I RAN/“5:0/ \ )Jx /\\S’N\Rk / \N N Rk "'1!“ N H \\O I‘LL!— H H , ,and In another embodiment of Formula (I), Z1 is 0 R O 0 O A HN,No )L J‘s/’0 0“ m| ,N ”a k N \ R ”I'LL OH \ Rk N H '1)?- N \\ , m, , ,or H In another O IN 0 HN 9N Q\ 40 A \ , ,s\ ‘9. 0H “a N ““L N Rk ment of a (I), Z 1 is or ’ ’ H ’ In another [Annotation] sak or \11k , H . embodiment of Formula (I), Z1 is In another EAOH embodiment of Formula (I), Z1 is In one embodiment of Formula (I), Y1 is phenylene or C5_6 heteroarylene; optionally fused to one or two rings selected from the group ting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y1 is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOzRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, )R5, NHS(O)2R5, )2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, R5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and I. In another embodiment of Formula (I), Y1 is phenylene or C5_6 heteroarylene; n the phenylene and C5_6 heteroarylene represented by Y1 are optionally substituted with one or two substituents independently selected from the group consisting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (I), Y1 is phenylene or C5_6 heteroarylene; wherein the phenylene and C5_6 heteroarylene represented by Y1 are ally substituted with one or two substituents independently selected from the group ting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl.

In another ment of a (I), Y1 is pyrrolyl, lyl, triazolyl, pyridinyl, or phenyl. In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl, In another embodiment of Formula (I), Y1 is pyridinyl or phenyl. In r embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, triazolyl, pyridinyl, or phenyl; wherein the pyrrolyl, pyrazolyl, triazolyl, pyridinyl, and phenyl represented by Y1 are optionally substituted with one or two substituents independently selected from the group consisting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, triazolyl, pyridinyl, or phenyl; wherein the pyrrolyl, pyrazolyl, lyl, pyridinyl, and phenyl represented by Y1 are optionally substituted with one or two substituents ndently selected from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl.

In one ment of a (I), L1 is selected from the group consisting of (CR6R7)q, (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)—(CR6R7)r, )s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or C344 [Annotation] sak heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, 8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, )R8, NHS(O)2R8, )2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(O)NR8802R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In another embodiment of a (I), L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is l or 2. In another embodiment of Formula (I), L1 is selected from the group consisting of (CR6R7)s-O-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)S- S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, ),- NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of C344 cycloalkyl, and Cg.14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

In another embodiment of Formula (I), X is heteroaryl; Y1 is phenylene or C5_6 heteroarylene; n Y1 is ally substituted with one, or two substituents independently selected from the group consisting of R5, CN, F, Cl, Br and L1 is selected from the group ting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)S- S—(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A- (CR6R7)r, )s-NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is Cg_14 lkyl, or Cg_14 heterocycloalkyl; wherein Y2 is optionally substituted with one, two, or three tuents independently selected from the group consisting of R8, 0R8, SOZRg, CO(O)R8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of O 0 HN[Ii O\\ , O RAOH EkN’N / and RAE/Shk , , ; R2, at each occurrence, is independently C1_6 alkyl; R5, at each occurrence, is independently C1_6 alkyl; R6A is independently selected from the group ting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; [Annotation] sak R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl and cyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR”, SOZRM, and NHR16; Rk, at each ence, is independently selected from the group consisting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, aryl, and heterocycloalkyl; wherein the R16 C1_4 alkyl is optionally substituted with one substituent independently ed from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is l or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0,1, or 2; and p is 0.

Still another embodiment pertains to a compound having Formula (I) selected from the group ting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] { l - [tricyclo [3 .3 . l . 13’7]dec-l -ylmethyl]- l H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] [3,5- dimethyl- l -(tricyclo[3.3. l .13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] [5- methyl(tricyclo [3 .3. l . l 3’7]dec- l -ylmethyl)- l H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-[l- (spiro [3 .5]nonylmethyl)- l H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1 ,3 thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-( l - {[3,5 - dimethyltricyclo[3.3.1.13’7]dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] ( l - {[3- hydroxytricyclo [3 .3. l dec- l -yl]methyl}- l H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] ( l - {[3- methoxytricyclo[3.3. l dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]-3 -( l - {[3-(2- methoxyethoxy)tricyclo [3 .3. l . l 3’7]dec- l thyl}- lH—pyrazolyl)pyridinecarboxylic acid; [Annotation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {1 - [(3 ,5,7-trimethyltricyc10[3.3.1.13’7]decy1)methyl]—1H-pyrazoly1}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ydI0is0quinolin-2(1H)-y1]—3 -[1- clo [3 .3 . 1 . 13 ’7]decy1methy1)- 1 H-pyrazo1y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - bromotricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - (propan-Z-yloxy)tricyclo [3 .3 . 1 .13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 -[1-(2 - cyc10[3.3. 1 . 13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6- [8-(1 ,3 -benzothiazol-Z-y1carbam0yl)-4,4-dimethy1-3 ,4-dihydI0is0quinolin-2( 1 H)- y1] [5 -methy1(tricyc10[3.3.1 .13’7]decy1methyl)-1H-pyrazoly1]pyridine-Z-carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - (morpholinyl)tricyclo[3.3.1.13’7]decy1]methy1}-1H-pyrazolyl)pyridinecarb0xylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 . 13’7] decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridine-2 -carb0xylic acid; N-(1,3-benzothiazolyl) {6- [(methylsulfonyl)carbamoyl] -5 - [5 -methyl c10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; N-(1,3-benzothiazol-2 -y1)-2 - {6-[(cyclopropy1su1f0ny1)carbam0yl] -5 - [5-methy1 (tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl){5-[5-methy1(tricyc10[3.3.1.13’7]decylmethyl)-1H- pyrazoly1](2H-tetrazol-5 -y1)pyridiny1} - 1 ,2,3 ,4-tetrahydr0isoquinoline-8 - amide; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {2 - methyl [tricyclo [3 .3 . 1 3’7] decy1meth0xy]pheny1 } pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {2 - methyl-3 - [tricyclo [3 .3 . 1 . 1 3’7] decy1meth0xy]pheny1 } pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {3 - [tricyc10[3.3.1.13’7]decy1meth0xy]phenyl}pyridinecarb0xylic acid; [Annotation] sak 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 —3 - [5 -cyan0- 2-methy1(tricyc10[3.3. 1 . 13’7]decy1methy1)—1H-pyrr01-3 -y1]pyridinecarb0xylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[5 ,4-b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)—3 ,4-dihydrois0quinolin-2( 1 H)-y1] -2'- (tricyc10[3.3.1.13’7]decylmeth0xy)-3 pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -[1-({3-[2- (morpholinyl)ethoxy]tricyc10[3.3.1.13’7]decy1}methyl)—1H-pyrazoly1]pyridine carboxylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 '-methyl- 2'—(tricyc10[3.3.1.13’7]decy1meth0xy)—3,4'-bipyridinecarb0xylic acid; 1,3-benzothiazoly1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]—3-{2- [tricyc10[3.3.1.13’7]decy10xy]phenyl}pyridinecarb0xylic acid; 1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {5 -cyan0- 1-[tricyc10[3.3.1.13’7]decy1methy1]—1H-pyrazoly1}pyridinecarb0xylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[4,5 -b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)—1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[4,5 -c]pyridiny1carbam0y1)—3,4-dihydI0is0quinolin-2(1H)-y1]pyridine carboxylic acid; 6-[8-(1,3 -benzothiazoly1carbam0y1)—3,4-dihydI0is0quin01in-2(1H)-y1]—3-(1-{[3,5 - dimethyltricyclo [3 .3 . 1 3 ’7]decy1]methy1} . 1 -5 -methy1-1H-pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(1- {[3 - (1 , 1 -dioxidothiomorpholiny1)tricyc10 [3 .3 - 1 H-pyrazol . 1 . 13 ’7]decy1]methy1} y1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {5 -cyan0- 2-methy1[2-(tricyc10[3.3.1.13’7]decy1)ethy1]—1H-pyrr01y1}pyridinecarb0xylic acid; N-(l,3-benzothiazolyl)—2-{5-[5-cyan0methy1(tricyc10[3.3.1.13’7]dec ylmethyl)-1H-pyrr01y1][(methylsulfonyl)carbam0y1]pyridiny1} -1 ,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl)—2-{5-[5-cyan0methy1(tricyc10[3.3.1.13’7]dec y1)- 1 H-pyrr01-3 -y1][(cyclopropylsulfonyl)carbamoyl]pyridiny1}-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; [Annotation] sak N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyclo[3.3.1.13’7]decyl]methyl}- -methyl- 1 H-pyrazolyl)[(methylsulfonyl)carbamoy1]pyridiny1}-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3-benzothiazol-Z-y1carbam0yl)-3 ,4-dihydrois0quinolin-2(1H)-y1]—3-(1-{[3- methoxy-S ,7-dimethy1tricyc10[3.3. 1 . 13’7]decy1]methy1} methy1- 1H-pyrazol y1)pyridinecarb0xylic acid; N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyclo[3.3.1.13’7]decyl]methyl}- -methyl-1H-pyrazoly1)[(morpholiny1su1f0ny1)carbamoyl]pyridin-2 -y1} -1 ,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl)[5-(1-{[3-meth0xytricyc10[3.3.1.13’7]decy1]methyl}-5 - methyl-1H-pyrazoly1) {[(trifluoromethyl)sulfonyl]carbam0y1}pyridin-2 -y1] -1 ,2,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l ,3-benzothiazolyl) { 6- [(cyclopropylsulfonyl)carbamoyl]-5 -( 1 - { [3 - ytricyc10[3 .3 . 1 . 13’7]dec-1 -y1]methy1}-5 -methy1-1H-pyrazolyl)pyridiny1}-1,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {5 - [tricyc10[3.3.1.13’7]decy1methyl]—1H-pyrazoly1}pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)methy1-3,4-dihydrois0quinolin-2(1H)-y1]—3 - [5 -methyl(tricyc10 [3 .3 . 1 .13’7]decy1methyl)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)(1,1 -2H2)-3,4-dihydrois0quinolin-2(1H)-yl]—3 - [5 -methyl(tricyc10 [3 .3 . 1 .13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[3-(2- methoxyethoxy)tricyclo [3 .3 . 1 . 1 3’7]decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridine carboxylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[1-(2- methoxyethyl)cyc100cty1]methy1} methy1-1H-pyrazolyl)pyridinecarb0xy1ic acid; 1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - n0- 3-[tricyc10[3.3.1.13’7]decy1amin0]phenyl}pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {2-cyan0- 3 -[tricyc10[3 .3 . 1 .13’7]decy1su1fany1]pheny1}pyridinecarb0xylic acid; 6-[8-(imidazo[1,2-a]pyridiny1carbam0yl)-3 ,4-dihydrois0quin01in-2(1 H)-y1]—3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - yclo [3 . 3. 1 . ecy1carb0ny1]amin0}phenyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1]—3 - {2 - methyl[tricyclo[3.3.1.13’7]decy1su1fam0yl]pheny1}pyridinecarb0xy1ic acid; [Annotation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. 1 . 13’7]decy1carb0ny1]amino}phenyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -(5 - methyl {[3 -(tetrahydro-ZH-pyrany1meth0xy)tricyclo[3.3.1.13’7]decy1]methyl}-1H- pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {2 - [tricyc10[3.3.1.13’7]decy1carbam0y1]pheny1}pyridinecarb0xylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. 1.13’7]decy1methy1]amino}pheny1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( ]—3 -(1- {[2-(2- methoxyethyl)tricyclo [3 .3 - 1 H-pyrazoly1)pyridinecarb0xy1ic . 1 . 1 3’7]decy1]methyl} acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 - methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-1,2,3 -triazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 H)-y1]—3 -(5 -cyan0- 1- { [3 -meth0xytricyc10[3.3.1.13’7]decy1]methy1}methyl-1H-pyrr01yl)pyridine carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - [5 - methyl-1 -(2-0xatricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1 H)-y1]—3 - [2-cyan0- 3 -(tricyc10 [3 . 3 . 1 .13’7]decy1su1f0ny1)phenyl]pyridine-2 -carb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydrois0quinolin-2( 1 H)-y1] -2'- [cycloocty1(methyl)amino] -3'-methy1-3,4'-bipyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - [5 - (tricyc10[3.3. 1 . 13’7]decy1methyl)-1H-pyrazoly1]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -[1-({3-[2- (2-meth0xyethoxy)ethoxy]tricyclo [3 . 3 . 1 .13’7]dec-1 -y1}methy1)methy1- 1H-pyrazol yl]pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ydI0is0quinolin-2(1H)-y1]—3 -(2- methyl-3 - l [(tricyclo [3 .3 . 1 . 13’7]dec-2 -y1]carbamoyl}pheny1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 - methyl({ 1 - [2-(methy1su1fony1)eth0xy] cycloocty1}methyl)- 1 H-pyrazoly1]pyridine carboxylic acid; ation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 - [5 - methyl(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-1,2,3 -triazoly1]pyridine carboxylic acid; 3-[5-methy1(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-pyrazoly1]—6-[8- ([1,3]thia2010[5 ,4-b]pyridiny1carbam0y1)—3 ,4-dihydI0is0quin01in-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]—3 - {2 - methyl-3 -[methy1(2-0xatricyc10 [3 .3 . 1 decy1carb0ny1)amino]pheny1}pyridine ylic acid; 6-[8-(1,3 thiazol-Z-y1carbam0y1)—3 ,4-dihydI0is0quin01in-2(1H)—y1]-3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. 1 . 1 3’7]decy1]sulfamoyl}pher1y1)py1‘idinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2( 1 H)-y1] -3 '-methy1- 2'—(tricyc10[3.3.1.13’7]decy1su1f0ny1)-3,4'-bipyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)—y1]-3 - [5 -cyan0- 2-methy1(2-0xatricyc10[3.3.1.13’7]decy1methy1)—1H-pyrr01-3 -y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)—y1]-3 - {5 -cyan0- 2-methy1[(3 -methy10xatricyc10[3.3.1.13’7]decy1)methy1]—1H-pyrr01y1}pyridine carboxylic acid; 6-[8-(imidazo[1,2-a]pyraziny1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]-3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2( 1 H)-y1] -3 '-methy1- 2'—(tricyc10[3.3.1.13’7]decy1su1fany1)-3 ,4'-bipyridinecarb0xy1ic acid; 2- {6- [(methylsulfonyl)carbamoyl] -5 - [5 -methy1-1 -(tricyc10 [3 . 3 .1 .13’7]decy1methy1)- 1H-pyrazoly1]pyridiny1}-N-([1,3]thiazolo[5,4-b]pyridiny1)—1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3 thiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2( 1 H)-y1] -3 '-methy1- 2'—(tricyc10[3.3.1.13’7]decy1amin0)—3,4'-bipyridinecarb0xy1ic acid; 6- [ 8-(imidazo [1 ,2-b]pyridazin-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 - [5 -methy1(tricyc10 [3 .3 . 1 .13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; ethy1(tricyc10[3.3.1.13’7]decy1methy1)—1H-pyrazoly1]—6-[8- ([1,3]thia2010[5 ,4-c]pyridiny1carbam0y1)—3,4-dihydI0is0quin01in-2(1H)-y1]pyridine carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 - {1 -[(5 - methoxyspiro [2 . 5 ]0ct-5 -y1)methy1] -5 -methy1-1H-pyrazoly1}pyridinecarb0xy1ic acid; [Annotation] sak 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -( l - {[3 - {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo [3 .3. l . l 3’7]dec- l -yl]methyl} -5 -methyl- 1 H- pyrazolyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -(5 - methyl-l- {[3 -(methylsulfonyl)tricyclo [3 .3 . l 3 ’7]dec- l -yl]methyl} - l zolyl)pyridine- 2-carboxylic acid; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3 -[l-( { 3,5- dimethyl[2-(methylamino)ethoxy]tricyclo [3 . 3 . l .13’7]dec-l-yl}methyl)methyl- 1 H- pyrazolyl]pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 -(5 - methyl-l-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.l.13’7]dec-l- yl]methyl } - l H-pyrazolyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3 ,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [ l -( { 8- [(benzyloxy)carbonyl] azabicyclo [3 .2 . l ]oct-3 -yl } methyl)- 1 H-pyrazolyl]pyridine-2 - carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -6'-oxo-l '- clo [3 .3 . l . 13’7]dec-l -ylmethyl)-l ',6'—dihydro-3 pyridinecarboxylic acid; 6-[8-(1 ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-( l - {[3,5 - dimethyl(2- {2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3 .3. l .13’7]dec- l - yl]methyl} -5 -methyl- 1 H-pyrazolyl)pyridinecarboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula (II) (R)m (R2)n WEIN\E/N/ \)(RX)0 \1\Y2 Formula (II) and therapeutically acceptable salts, metabolites, gs, salts of metabolites, and salts of prodrugs thereof, wherein X, L1, Y2, 21, R1, R2, R3, m, n, and p are as described herein for a (I); Rx is as described herein for substituents on Y1, and o is 0, l, 2, or 3.

One ment of this invention pertains to compounds, and therapeutically able salts f, Which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (II) [Annotation] sak (R)m\ (R2)n I (R3)pl// Formula (11), wherein X is heteroaryl; n the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, )R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is ed from the group consisting of (CR6R7)q, )S-O-(CR6R7)r, )S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, )S-NR6AC(O)- (CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A- (CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 heterocycloalkenyl; optionally fused to one or two rings selected from the group ting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 arene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, SOZRg, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8, NR8C(O)N(R8)2, 2, C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8, C(O)NHSOZR8, C(O)NR8802R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR1°C(O)R“, O)NR1°R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of [Annotation] sak N O | >=O HN’Nx O’N\ 0 “‘9. g ”H1 OH \N'N «51 N 9 .111. KM 9 9 9 H H O O o o o 0 OH 0 ,N \\// N S\ EMO’R II k EANA E_S | / OH '1': N4 Rk H H LLLL‘ 9 9 9 9 O O 0 ”RA ,OH RANK/OH .71“in \/\OH j]: ,0\ .171. N Rk H 9 H 9 H 9 H 9 / O O O | og/P | )L \ O S\ \ “Ll—L Nis: )L ,\\s’N‘Rk k N \\ 1'1/ N N R '11?— H O , ,and ; R1, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R2, at each occurrence, is independently selected from the group consisting of deuterium, halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; two R2 that are attached to the same carbon atom, together With said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, S(0)R14 and R14; R5, at each ence, is independently selected from the group consisting of C1_6 alkyl, CM l, CM alkynyl, C1_6 kyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is ndently selected from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM l, and C1_6 haloalkyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R”, on”, SR”, S(O)R15, soZR”, 5, CO(O)R15, OC(O)R15, OC(O)OR15, NHZ, NHR”, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, OR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, SOZNHRIS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, lkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are ation] sak optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, 6, SO2R16, C(O)R16, CO(O)R16, OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, OH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16, 16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are ally tuted with one, two, or three substituents independently ed from the group consisting of C14 alkyl, C26 alkenyl, C26 alkynyl, C14 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and I; R9 is selected from the group consisting of C14 alkyl, C26 alkenyl, C26 alkynyl, C14 haloalkyl, cycloalkyl, phenyl and (CH2)14 phenyl; and R10 and R“, at each occurrence, are each independently selected from the group ting of hydrogen, C14 alkyl, C2_6 l, C2_6 alkynyl, C34 cycloalkyl, C14 haloalkyl, phenyl and (CH2)14-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C14 alkyl, C2_6 alkenyl, C2_6 l, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C14 haloalkyl; R12 and R”, at each ence, are each independently selected from the group consisting of hydrogen, C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl and (CH2)14 phenyl; R“, at each occurrence, is independently selected from the group ting of C14 alkyl, C24 alkenyl, C24 alkynyl and C14 haloalkyl; R12 and R”, or R12 and R”, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, C14 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, and C14 hydroxyalkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of O-(C14 alkyl), NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, 3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, C14 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; n the R16 C14 alkyl, C24 alkenyl, C24 alkynyl, C14 haloalkyl, and C14 hydroxyalkyl are optionally substituted with one [Annotation] sak tuent independently selected from the group consisting of OCH3, OCH2CH20CH3, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, l, or 2; mis 0,1, 2, or 3; nis 0,1, 2, 3, 4, 5, or 6; o is 0,1, 2, or 3; and p is 0, l, or 2.

In one embodiment ofFormula (II), in is 0, l, 2, or 3; n is 0, l, 2, 3, 4, 5, or 6; and p is 0, l, or 2. In another embodiment of Formula (II), n is 0, l, or 2. In another embodiment of a (II), n is 0, l, or 2; and each R2 is ndently deuterium or C1_6 alkyl. In another embodiment of Formula (II), m, n, and p are 0.

In one embodiment of Formula (11), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (11), X is heteroaryl, which is unsubstituted. In another embodiment of Formula (II), X is heteroaryl, which is substituted with one R4. In another ment of Formula (II), X is heteroaryl, which is substituted with two R4. In another embodiment of Formula (11), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or n. In another embodiment of Formula (II), X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or n.

In another embodiment of a (11), X is heteroaryl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (11), X is aryl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (11), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, o[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[ l ,2- a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [l ,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4. In r embodiment of [Annotation] sak Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5 -c]pyridinyl, imidazo[ l ,2 idinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 idinyl, imidazo [ l ,2 - zinyl, or imidazo[l ,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or halogen. In another embodiment of a (II), X is benzo[d]thiazolyl, thiazolo[5,4- dinyl, lo[4,5-c]pyridinyl, imidazo[ l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l,2-a]pyrazinyl, or o[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, imidazo [ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo [5 ,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2-a]pyridinyl, thiazolo [5 ,4- c]pyridinyl, thiazolo [4,5 idinyl, imidazo [ l ,2 -a]pyrazinyl, or imidazo [l ,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (II), X is benzo[d]thiazolyl, which is optionally substituted with one, two, three or four R4. In another embodiment of a (II), X is benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (II), X is benzo[dc]thiazolyl, which is substituted with one R4. In another embodiment of Formula (II), X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (11), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OK12 or halogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of a (II), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (II), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is ndently F.

In one ment of Formula (II), Z1 is selected from the group consisting of C(O)OR9, C(O)NR1°R“, C(O)R“, NR1°C(O)R“, O)NR1°R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=NOR10)NR1°R“, NR10C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of ation] sak N /N \ 0 I )=0 HN’I‘LN ‘N “a N ”‘1 OH \ I \ )OL HN\Nl H N fig—OH “a , , “a , a , g H O O O O O OH O ,N \\// 0 M MonN S\ EMU}?k JL Rk _ _ “hf N4 “a N E E OH R H O K H 9 9 9 9 9 O O O O “RAN,OH KAN/VOH «ELAN/V \/\OH ”IRAN,O\Rk H a H a H 9 H a /' O O 0 | OJ) | )L 9/0/ \N N )L \‘s/MRk /S‘N “'1‘ \Rk “a. N’“O a; H , ,wd In another embodiment of Formula (II), Z1 is 0 R O 0 HN’N O I /J\ /fl\ %40 (%,N\ N’ %L N’\ ,s Rk ‘1 OH \N' Rk ”La, N \\ H 0 , 1'2 or , , H In another O ,N /fl\(%¢oO HN A 0N \ , ,s\ “Hz 0H ~51 N ”'71. N Rk ment of a (II), Z1 is ’ ’ H ' In another 0 0 o him; ”KAN \\/O8/ or \Rk H ' embodiment of Formula (II), Z1 is ’ In another EAOH embodiment of Formula (II), Z1 is In one embodiment of Formula (II), o is 0. In r embodiment of Formula (II), o is 0, l, 2, or 3. In another embodiment of Formula (II), o is l, 2, or 3; and Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, S, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1. In another embodiment of Formula (II), o is l, 2, or 3; and Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (II), o is 1, 2, or 3; and Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl. In r embodiment of Formula (II), o is l or 2; Rx is R5 or CN; and R5 is CH3. In another embodiment of ation] sak Formula (II), o is 1; and RK is CN. In another embodiment of a (II), o is 1; and RK is Cl. In another embodiment of a (II), o is 1; Rx is R5; and R5 is CH3.

In one embodiment of Formula (II), L1 is selected from the group consisting of (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S-C(O)-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S- S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)SNR6A- )r, (CR6R7)S-S(O)2NR6A-(CR6R7)r, and (CR6R7)S-NR6AS(0)2-(CR6R7)r; and Y2 is C344 cycloalkyl, C344 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, e, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, SOZRg, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, 2R8, NR88(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, OR8, C(O)NHSOZR8, C(O)NR8802R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In r embodiment of Formula (II), L1 is (CR6R7)q; and Y2 is ed from the group consisting of C344 cycloalkyl, and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2. In another embodiment of Formula (11), L1 is selected from the group consisting of (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-C(O)NR6A- (CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of C344 cycloalkyl, and Cg_14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

In another embodiment of Formula (II), X is heteroaryl; Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; L1 is ed from the group consisting of (CR6R7)q, (CR6R7)S-S(O)2-(CR6R7)I, )S-C(O)NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is Cg_14 cycloalkyl, or Cg_14 heterocycloalkyl; n Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, 0R8, SOZRg, CO(O)R8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of O HN’N‘ O O\\ O HILAOH EJQN,N RAE/$11k// and , , ; [Annotation] sak R2, at each occurrence, is independently C1_6 alkyl; R5, at each occurrence, is independently C1_6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl and heterocyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR16, SOZRm, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 kyl; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, aryl, and heterocycloalkyl; wherein the R16 C1_4 alkyl is optionally substituted with one substituent independently selected from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is l or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, l, or 2; o is 0,1, or 2; and p is 0.

Still another embodiment ns to a compound haVing Formula (11) selected from the group consisting of 1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 -[5 - 2-methyl- l -(tricyclo [3 .3. l . l 3’7]dec- l -ylmethyl)- l H-pyrrol-3 -yl]pyridinecarboxylic acid; 6- [8-(1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] {5 - 2-methyl- l - [2-(tricyclo [3 .3 - l H-pyrrolyl}pyridinecarboxylic acid; . l . l 3’7]dec- l -yl)ethyl] N-(l,3-benzothiazolyl){5-[5-cyanomethyl-l-(tricyclo[3.3.l .13’7]dec-l- yl)- l H-pyrrol-3 -yl] ylsulfonyl)carbamoyl]pyridinyl} -l ,2 ,3 ,4- tetrahydroisoquinolinecarboxamide; -benzothiazolyl){5-[5-cyanomethyl-l-(tricyclo[3.3.l .13’7]dec-lylmethyl )- l H-pyrrol-3 -yl][(cyclopropylsulfonyl)carbamoyl]pyridinyl}-1,2,3 ,4- tetrahydroisoquinolinecarboxamide; 6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 -(5 -cyano- l- { [3 -methoxytricyclo[3 .3. l . l 3’7]dec- l -yl]methyl}methyl- l H-pyrrolyl)pyridine carboxylic acid; [Annotation] sak 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [5 -cyano- 2-methyl- l atricyclo [3 .3 . l . l 3’7]dec-l -ylmethyl)- l H-pyrrol-3 -yl]pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 - {5 - 2-methyl- l - [(3 -methyloxatricyclo [3 .3. l . 13’7]dec- l -yl)methyl]— l H-pyrrolyl}pyridine carboxylic acid; and therapeutically acceptable salts, metabolites, gs, salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula (111) (R1)m\ (R2)n P1533TN; R), I (R3)p/ NL1\Y2 Formula (111) and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof, wherein X, L1, Y2, 21, R1, R2, R3, m, n, and p are as described herein for a (I); Rx is as described herein for substituents on Y1, and o is 0, 1, or 2.

One embodiment of this invention pertains to compounds, and therapeutically acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (111) (R1)m\ (R2)n WECNILi?R), I (R3)p/ Formula (111), wherein X is heteroaryl; wherein the heteroaryl represented by X is ally substituted with one, two, three, or four R4; Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, )NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, SOZR5, C(O)NRSSOZR5, SOzNHz, S, SOzN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; [Annotation] sak L1 is selected from the group consisting of (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)- (CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A- )r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; Y2 is C344 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 cycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, SOZRg, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, 2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, R8, C(O)N(R8)2, C(O)NHOH, OR8, C(O)NHSOZR8, C(0)NR8s02R8, SOZNHZ, SOgNHRg, 8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; z1 is selected from the group consisting of C(O)OR9, 1°R“, C(O)R“, NR1°C(O)R“, NR1°C(O)NR1°R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=N0R1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N O ,N HN \ I O HN’N\ O/N\ O \ '71,, N $OH \ ’N MOH )L \N, H N .111. 9 9 ‘31. 9 I111" 9 g O O O OH O O O ,N \\ // 0 II N S\ k _ _ / OH “a{ N4 N03 mgLN Rn g s H H 0 I111- 9 9 9 9 9 O O O O “Ll—AN O/ H I‘LL N/\/OH $NNO\/\OH “HAN O Rkl \ H 9 H 9 H 9 H 9 / O O | O I ”EJLN \\ 40 O (ls/1 \\ ’ ‘ \ k \ 8‘ R / N N R QLN’SV ”11. H O H .

H and i i 2 R1, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R2, at each occurrence, is independently selected from the group ting of deuterium, halo, C1_6 alkyl, CM l, CM alkynyl, and C1_6 haloalkyl; two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, cycloalkenyl, cycloalkyl, and cycloalkenyl; [Annotation] sak R3, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, S(0)R14 and R14; R5, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and lkenyl; R6A is independently selected from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 kyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R”, on”, SR”, S(O)R15, soZR”, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NHZ, NHRIS, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, OH, OR15, C(O)NHSOZR15, C(O)NRISSOZR15, , SOZNHRIS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 kyl, aryl, heterocyclyl, cycloalkyl, and lkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SOZR16, C(O)R16, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSOZR16, 16SOZR16, , SOZNHRm, SOZN(R16)2, , C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents ndently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; R9 is selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)1_4 phenyl; and R10 and R“, at each occurrence, are each independently selected from the group ting of en, C1_6 alkyl, CM alkenyl, CM alkynyl, C3_6 cycloalkyl, C1_6 haloalkyl, phenyl and (CH2)1_4-phenyl; or [Annotation] sak R10 and R“, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C3_7 heterocycloalkyl, C3_7 lkyl and C1_6 kyl; R12 and R”, at each occurrence, are each independently selected from the group consisting of hydrogen, C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl and (CH2)1_4 phenyl; R“, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl and C1_4 haloalkyl; R12 and R”, or R12 and R14, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 l, C24 l, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one, two, or three substituents ndently selected from the group consisting of O-(C1_4 alkyl), NHZ, C(O)NH2, , C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one substituent independently selected from the group ting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, l, or 2; mis 0,1, 2, or 3; nis 0,1, 2, 3, 4, 5, or 6; o is 0,1, or 2; and p is 0, l, or 2.

In one embodiment ula (III), m is 0, l, 2, or 3; n is 0, l, 2, 3, 4, 5, or 6; and p is 0, l, or 2. In another embodiment of Formula (III), n is 0, l, or 2. In another embodiment of Formula (III), n is 0, l, or 2; and each R2 is independently deuterium or C1_6 alkyl. In another embodiment of Formula (III), m, n, and p are 0.

In one embodiment of Formula (III), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (III), X is heteroaryl, [Annotation] sak which is unsubstituted. In another ment of Formula (III), X is heteroaryl, which is substituted with one R4. In another embodiment of Formula (III), X is heteroaryl, which is substituted with two R4. In another ment of Formula (III), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (III), X is aryl, which is tuted with two R4, and each R4 is independently on12 or halogen. In another embodiment of Formula (III), X is heteroaryl, which is tuted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (III), X is heteroaryl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of a (III), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[ l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (III), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2- dinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [l ,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are tuted with two R4. In r embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 - a]pyrazinyl, or imidazo[l ,2-b]pyridazinyl, which are substituted with one R4, and R4 is on12 or halogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4- b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another ment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, imidazo [ l ,2 idinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo [5 ,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, o [l ,2 -a]pyridinyl, thiazolo [5 ,4- c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 -a]pyrazinyl, or imidazo [l ,2-b]pyridazinyl, which are tuted with two R4, and each R4 is independently F.

In one embodiment of Formula (III), X is benzo[d]thiazolyl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (III), X is [Annotation] sak benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (III), X is benzo[d]thiazolyl, which is substituted with one R4. In another embodiment of a (III), X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (111), X is benzo[d]thiazolyl, which is tuted with one R4, and R4 is on12 01‘ halogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is C1, F, 01‘ methoxy. In another embodiment of Formula (III), X is d]thiazolyl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (III), Z1 is selected from the group ting of C(O)OR9, C(O)NR1°R“, C(O)R“, NR1°C(O)R“, NR1°C(O)NR1°R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=N0R1°)NR1°R“, NR10C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, N(R1°)S(O)2R“, =NR“)NR1°R“, C(=S)NR1°R“, °)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N O ,N O HN, , o )LN A I\I‘N flOH )OL HN\ ,N H ‘111‘ 9 9 I111. 9 LL21- 9 H H O O o o o 0 OH 0 ,N \\ // II MOH S, _ _ 14 NJ4 MMO’Rk “a. 0H N Rk E i I11‘." H H O 9 9 9 9 9 O O O O “KAN O9 H ”RANK/OH ”RANN \/\OH ”RAN O Rkz \ H 9 H 9 H 9 H 9 / O 0 o I O\\ //O I )L /\\S /O \ )L \\S’N\Rk ‘ ’ \ .111 N k “a N \\ / N N R “a H O H and 9 9 In another ment of Formula (III), Z1 is 0 R O 0 , O | A HN “LN )L j‘s/O 0\\ ,N\ ”‘11.. “‘11..

\ I N OH \Rk “111‘ S\\ 1,1 N H or E o ’ ’ ’ In another O ,N O HN \\ O\\ 40 A \ ,N )L ,s\ ”to OH “'11 N “L‘L N Rk embodiment of Formula (III), Z1 is ’ ’ H ' In another 0 O o EAOH ”RAN \\ /Os/ or ‘Rk embodiment of Formula (III), Z1 is ’ H In another embodiment of Formula (III), Z1 is [Annotation] sak In one embodiment of Formula (III), 0 is 0. In r embodiment of Formula (III), 0 is 0, 1, or 2. In another embodiment of Formula (III), 0 is 1 or 2; and Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, S, 5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1. In another embodiment of Formula (III), 0 is 1 or 2; and Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (111), o is 1 or 2; and Rx, at each occurrence, is ndently selected from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl. In another embodiment of a (III), 0 is 1 or 2; Rx is R5, C1, or CN; and R5 is CH3. In another embodiment of Formula (III), 0 is 1; and RK is CN. In another embodiment of Formula (III), 0 is 1; and RK is Cl. In another embodiment of Formula (III), 0 is 1; Rx is R5; and R5 is CH3.

In one embodiment of Formula (III), L1 is selected from the group consisting of (CR6R7)q, (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S-C(O)-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)—(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A-(CR6R7)r, and )S-NR6AS(O)2-(CR6R7)r; and Y2 is Cg_14 lkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or C344 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally tuted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, SOzRg, , CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, )R8, NHS(O)2R8, NRgs(O)2R8, OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, R8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, 8802R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In another embodiment of Formula (III), L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl, and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2. In another embodiment of Formula (111), L1 is selected from the group consisting of (CR6R7)s-S(O)2-(CR6R7)I, (CR6R7)s-C(O)NR6A- (CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of Cg.14 cycloalkyl, and Cg.14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

[Annotation] sak In another ment of a (111), X is heteroaryl; Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-S(O)2-(CR6R7)I, (CR6R7)s-C(O)NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is C344 cycloalkyl, or C344 heterocycloalkyl; wherein Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, 0R8, SOZRg, CO(O)R8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of 0 HN’I‘l~ 0 0 N )L s40 LL"!- ,and R , H ; R2, at each occurrence, is ndently C1_6 alkyl; R5, at each occurrence, is ndently C1_6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl and heterocyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR16, SOZRm, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R16, at each occurrence, is independently ed from the group consisting of C1_4 alkyl, aryl, and cycloalkyl; wherein the R16 CM alkyl is optionally substituted with one tuent independently ed from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is l or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, l, or 2; o is 0,1, or 2; and p is 0.

Still another embodiment pertains to a compound having Formula (111) selected from the group consisting of ation] sak 1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - {1 - c10[3.3.1.13’7]decy1methy1]—1H-pyrazolyl}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [3 ,5 - dimethyl- 1 yc10 [3 . 3 . 1 . 13’7]dec-1 -y1methy1)-1 H-pyrazolyl]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 1,3 -benzothiazol-Z-y1carbam0yl)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -[1- (Spiro [3 .5 ]n0ny1methyl)- 1 H-pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]—3-(1-{[3,5 - dimethyltricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazolyl)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - hydroxytricyclo [3 .3 . 1 . 1 3’7]decy1]methy1}- 1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 decy1]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[3-(2- methoxyethoxy)tricyclo[3.3.1.13’7]decy1]methy1}-1H—pyrazo1y1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydrois0quinolin-2(1H)-y1]—3- {1 - [(3 ,5,7-trimethyltricyc10[3.3.1.13’7]decy1)methyl]—1H-pyrazoly1}pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -[1- (tricyclo [3 .3 . 1 . 13’7]decy1methy1)- 1 H-pyrazo1y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - bromotricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -( 1 - { [3 - (propan-Z-yloxy)tricyclo [3 .3 . 1 .13’7]decy1]methy1}-1H-pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -[1-(2 - 0xatricyc10[3.3. 1 . 13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6- [8-(1 ,3 -benzothiazol-Z-y1carbam0yl)-4,4-dimethy1-3 ,4-dihydI0is0quinolin-2( 1 H)- yl]—3- [5 -methy1(tricyc10[3.3.1 .13’7]decy1methyl)-1H-pyrazoly1]pyridine-Z-carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -( 1 - { [3 - (morpholinyl)tricyclo[3.3.1.13’7]decy1]methy1}-1H-pyrazolyl)pyridinecarb0xylic acid; ation] sak 6-[8-(1,3 thiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(1- {[3 - methoxytricyc10[3 .3 . 1 . 13’7] decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridine-2 -carb0xylic acid; N-(1,3-benzothiazolyl) {6- [(methylsulfonyl)carbamoyl] -5 - [5 -methyl (tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; N-(1,3-benzothiazol-2 -y1)-2 - {6-[(cyclopropy1su1f0ny1)carbam0yl] -5 - [5-methy1 (tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridiny1}-1,2,3,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl){5-[5-methyl(tricyc10[3.3.1.13’7]decylmethyl)-1H- pyrazoly1](2H-tetrazol-5 ridiny1} - 1 ,2,3 ,4-tetrahydr0isoquinoline-8 - carboxamide; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)-1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[5 ,4-b]pyridiny1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -[1-({3-[2- (morpholinyl)ethoxy]tricyc10[3.3.1.13’7]decy1}methyl)-1H-pyrazoly1]pyridine carboxylic acid; 1,3-benzothiazoly1carbam0y1)-3,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - {5 -cyan0- 1-[tricyc10[3.3.1.13’7]decy1methy1]—1H-pyrazoly1}pyridinecarb0xylic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methyl)-1H-pyrazoly1]—6-[8- ([1 ,3]thiazolo[4,5 -b]pyridiny1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1]pyridine-2 - carboxylic acid; ethy1(tricyc10[3.3.1.13’7]decy1methyl)-1H-pyrazoly1]—6-[8- ([1 azolo[4,5 -c]pyridiny1carbam0y1)-3,4-dihydI0is0quinolin-2(1 H)-y1]pyridine carboxylic acid; 6-[8-(1,3 -benzothiazoly1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]—3-(1-{[3,5 - dimethyltricyclo [3 .3 . 1 . 1 3’7]decy1]methy1} -5 -methy1-1H-pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 -(1- {[3 - (1 , 1 dothiomorpholiny1)tricyc10 [3 .3 - 1 H-pyrazol . 1 . 13 ’7]decy1]methy1} y1)pyridinecarb0xylic acid; N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyc10[3.3 . 1 . 1 3’7]decy1]methy1}- -methyl- 1 H-pyrazolyl)[(methylsulfonyl)carbamoy1]pyridin-Z-y1}-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; [Annotation] sak 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(1- {[3 - methoxy-S ,7-dimethy1tricyc10[3.3. 1 . 13’7]decy1]methy1} methy1- 1H-pyrazol yl)pyridinecarb0xylic acid; N-(l ,3-benzothiazolyl) { 5-(1 - { [3 -meth0xytricyclo[3.3.1.13’7]decyl]methyl}- -methyl-1H-pyrazoly1)[(morpholiny1su1f0ny1)carbamoyl]pyridin-2 -y1} -1 ,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l,3-benzothiazolyl)[5-(1-{[3-meth0xytricyclo[3.3.1.13’7]decy1]methyl}-5 - methyl-1H-pyrazoly1) {[(trifluoromethyl)sulfonyl]carbam0y1}pyridiny1]-1,2,3 ,4- tetrahydroisoquinolinecarb0xamide; N-(l zothiazolyl) { 6- [(cyclopropylsulfonyl)carbamoyl]-5 -( 1 - { [3 - methoxytricyc10[3 .3 . 1 . 13’7]dec-1 -y1]methy1}-5 -methy1-1H-pyrazolyl)pyridiny1}-1,2 ,3 ,4- tetrahydroisoquinolinecarb0xamide; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ydrois0quinolin-2(1H)-y1]—3- {5 - ch10r0[tricyc10[3.3.1.13’7]decy1methyl]—1H-pyrazoly1}pyridinecarb0xy1ic acid; 1,3 -benzothiazol-Z-y1carbam0y1)methy1-3,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 -methyl(tricyc10 [3 .3 . 1 .13 ’7]decy1methy1)- 1 H-pyrazoly1]pyridine-2 -carb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)(1,1 3,4-dihydI0is0quinolin-2(1H)-yl]—3 - [5 -methyl(tricyc10 [3 .3 . 1 .13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[3-(2- methoxyethoxy)tricyclo [3 .3 . 1 . 1 3’7]decy1]methy1} -5 1-1H-pyrazoly1)pyridine carboxylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ,4-dihydI0is0quinolin-2( 1H)-y1]—3 -(1- {[1-(2- methoxyethyl)cyc100cty1]methy1} methy1-1H-pyrazolyl)pyridinecarb0xy1ic acid; 6-[8-(imidazo[1,2-a]pyridiny1carbam0yl)-3 ,4-dihydI0is0quin01in-2(1 H)-y1]—3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazolyl]pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 -(5 - {[3 -(tetrahydro-ZH-pyrany1meth0xy)tricyclo[3.3.1.13’7]decy1]methyl}-1H- pyrazoly1)pyridinecarb0xylic acid; 6-[8-(1,3-benzothiazoly1carbam0y1)-3 ydI0is0quinolin-2( 1H)-y1]—3 -(1- {[2-(2- yethyl)tricyclo [3 .3 - 1 H-pyrazoly1)pyridinecarb0xy1ic . 1 . 1 3’7]decy1]methyl} acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2( 1 H)-y1] -3 - [5 - methyl-1 -(2-0xatricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0yl)-3 ,4-dihydI0is0quinolin-2(1H)-y1]—3 - [5 - methyl(tricyc10[3.3. 1 . 13’7]decy1methyl)-1H-pyrazoly1]pyridinecarb0xylic acid; [Annotation] sak 6-[8-(1,3-benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2(1H)-y1]—3 -[1-({3-[2- (2-meth0xyethoxy)ethoxy]tricyclo [3 . 3 . 1 .13’7]decy1}methy1)methy1-1H-pyrazol y1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2(1H)-y1]—3 - [5 - methyl({ 1-[2-(methy1su1f0ny1)ethoxy]cyc100cty1}methy1)-1H-pyrazoly1]pyridine carboxylic acid; 3-[5-methy1(2-0xatricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]—6-[8- ([1,3]thia2010[5 ,4-b]pyridiny1carbam0y1)-3 ,4-dihydI0is0quin01in-2( 1 H)-y1]pyridine-2 - carboxylic acid; 6-[8-(imidazo[1,2-a]pyraziny1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]—3 - [5 - methyl(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; 2- {6- [(methylsulfonyl)carbamoyl] -5 - [5 -methy1-1 -(tricyc10 [3 . 3 .1 .13’7]decy1methy1) 1H-pyrazoly1]pyridiny1}-N-([1,3]thiazolo[5,4-b]pyridiny1)-1,2,3 ,4- ydroisoquinolinecarb0xamide; 6- [ 8-(imidazo [1 ,2-b]pyridazin-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 - [5 -methy1(tricyc10 [3 .3 . 1 .13’7]decy1methy1)-1H-pyrazoly1]pyridinecarb0xy1ic acid; 3-[5-methy1(tricyc10[3.3.1.13’7]decy1methy1)-1H-pyrazoly1]—6-[8- ([1,3]thia2010[5 ,4-c]pyridiny1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]pyridine carboxylic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2 ( 1 H)-y1] -3 - {1 -[(5 - methoxyspiro [2 . 5 ]0ct-5 -y1)methy1] -5 1-1H-pyrazoly1}pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 -(1- {[3 - {2-[2-(2-meth0xyethoxy)eth0xy]ethoxy}tricyc10[3.3.1.13’7]decy1]methy1}-5 -methy1-1H- pyrazoly1)pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 -(5 - { [3 -(methy1su1f0ny1)tricyc10[3.3.1.13’7]decy1]methy1}-1H-pyrazoly1)pyridine- 2-carb0xy1ic acid; 1,3-benzothiazol-Z-y1carbam0y1)-3,4-dihydI0is0quin01in-2(1H)-y1]—3 -[1-( { 3,5- dimethy1[2-(methy1amin0)ethoxy]tricyc10 [3 . 3 . 1 .13’7]decy1}methy1)methy1-1H- pyrazoly1]pyridinecarb0xy1ic acid; 6-[8-(1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2( 1 H)-y1] -3 -(5 - {[3-(2-{2-[2-(methy1amin0)ethoxy]ethoxy}ethoxy)tricyc10[3.3.1.13’7]dec y1]methy1}-1H-pyrazoly1)pyridinecarb0xy1ic acid; 1,3 -benzothiazol-Z-y1carbam0y1)-3 ,4-dihydI0is0quin01in-2(1H)-y1]—3 -[1-({8- [(benzyloxy)carbony1] azabicyc10 [3 .2 . 1 ]0ct-3 -y1}methy1)-1H-pyrazoly1]pyridine-2 - carboxylic acid; [Annotation] sak 6-[8-(1 ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]( l - {[3,5 - dimethyl(2- {2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3 .3. l .13’7]dec- l - yl]methyl} -5 -methyl- 1 zolyl)pyridinecarboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present ion provides nds of Formula (IV) (R1)m (R2)n £6mi I (R3)p/ Formula (IV) and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof, n X, L1, Y2, 21, R1, R2, R3, m, n, and p are as described herein for Formula (I); Rx is as described herein for substituents on Y1, and o is 0 or 1.

One embodiment of this ion pertains to compounds, and therapeutically acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (IV) (R1)m (R2)n HNijo:N\E/N: N(RX)0 I (R3)p/ \IJI\Y2 Formula (IV), wherein X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Rx is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, )2R5, NHC(O)OR5, )OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is selected from the group consisting of (CR6R7)q, )S-O-(CR6R7)r, (CR6R7)S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)- [Annotation] sak (CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A- (CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g lkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, 2, R8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(O)NRgsOZR8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR1°C(O)R“, NR1°C(0)NR1°R“, OC(O)NR10R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R1°)S(O)2R“, =NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N O ,N | o HN’N\\ o’N\ O HN ‘ E N RAOH \N'N MOH \N H RXN 9 9 I'LL;- 9 LLLL‘ 9 H O\ 40 O O O OH N ('3' Rk H O I'LLL 9 9 9 9 i O O ,OH OH )1 ,O\ H 9 H 9 H 9 H 9 / o O \\ 40 O I O N O )L \\ / ‘W-LLJLN S\ ’ ‘ Q3: I /S\\ k , R k N ”Li/ N N R .117“ H 0 ,and H H , ; R1, at each ence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R2, at each occurrence, is independently ed from the group consisting of deuterium, halo, C1_6 alkyl, CM alkenyl, CM l, and C1_6 haloalkyl; two R2 that are attached to the same carbon atom, er with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each ence, is independently selected from the group ting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; [Annotation] sak R4, at each occurrence, is ndently selected from the group ting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, 4 and R14; R5, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 kyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, lkyl, and cycloalkenyl; R6A is independently selected from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R”, on”, SR”, S(O)R15, soZR”, C(O)R15, CO(O)R15, 15, OC(O)OR15, NHZ, NHRIS, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, IS, SOZN(R15)2, , C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are optionally tuted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, 802R”, C(O)R16, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, O)NHR16, O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSOZR16, C(O)NR16SOZR16, SOZNHZ, SOZNHRm, SOgN(R16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; R9 is selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)1_4 phenyl; and R10 and R“, at each occurrence, are each ndently ed from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM alkynyl, C3_6 cycloalkyl, C1_6 haloalkyl, phenyl and _4-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; [Annotation] sak Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R12 and R”, at each occurrence, are each independently selected from the group consisting of en, C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl and (CH2)1_4 phenyl; R“, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl and C1_4 haloalkyl; R12 and R”, or R12 and R”, at each occurrence, together with the atom to which each is attached, are optionally ed to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 l, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one, two, or three substituents independently ed from the group consisting of O-(C1_4 alkyl), NHZ, C(O)NH2, SOZNHZ, C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, 3, F, Cl, Br and 1; R16, at each ence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one substituent independently selected from the group consisting of OCH3, ZOCHg, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, l, or 2; mis 0,1, 2, or 3; nis 0,1, 2, 3, 4, 5, or 6; o is 0 or 1; and p is 0, l, or 2.

In one embodiment ofFormula (IV), in is 0, l, 2, or 3; n is 0, l, 2, 3, 4, 5, or 6; and p is 0, l, or 2. In another embodiment of Formula (IV), n is 0, l, or 2. In another embodiment of Formula (IV), n is 0, l, or 2; and each R2 is independently deuterium or C1_6 alkyl. In another embodiment of Formula (IV), m, n, and p are 0.

In one ment of Formula (IV), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (IV), X is aryl, which is unsubstituted. In another ment of Formula (IV), X is heteroaryl, which is tuted with one R4. In another embodiment of Formula (IV), X is heteroaryl, which is —65— [Annotation] sak substituted with two R4. In another embodiment of a (IV), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (IV), X is heteroaryl, which is substituted with two R4, and each R4 is independently on12 or halogen. In another ment of Formula (IV), X is heteroaryl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (IV), X is heteroaryl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (IV), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l yridinyl, lo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l yrazinyl, or imidazo[l ,2- b]pyridazinyl, which are unsubstituted. In r embodiment of Formula (IV), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are tuted with one R4. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2- a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [l ,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 - a]pyrazinyl, or imidazo[l ,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or halogen. In r embodiment of a (IV), X is benzo[d]thiazolyl, thiazolo[5,4- b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[ l ,2-a]pyridinyl, lo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, imidazo [ l ,2 idinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo [5 ,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2-a]pyridinyl, thiazolo [5 ,4- c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 -a]pyrazinyl, or imidazo [l ,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (IV), X is benzo[d]thiazolyl, which is ally substituted with one, two, three or four R4. In r embodiment of Formula (IV), X is benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with one R4. In another embodiment of Formula (IV), [Annotation] sak X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is on12 01‘ halogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is C1, F, 01‘ methoxy. In another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently F.

In one ment of Formula (IV), Z1 is ed from the group consisting of C(O)OR9, C(O)NR1°R“, , NR10C(O)R“, NR10C(O)NR10R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=NOR10)NR1°R“, =NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N’0 O /N HN \\ AN 0 A HN,I‘LN i)—OH )OL \ ’N a, “in OH \ N H \N' '11?— 9 9 .111: 9 “Li-L 9 H O O O OH O O O ,N \\ // II MOHN S\ k "‘11?LN Rk 2_ _OH '11: N4 fi Rk ELMO/R H H O .111“ 9 9 9 9 9 O O O O /OH ,O\ 1.1“ ”EA /\/OH WANN \/\OH .111“ N Rk H 9 H 9 H 9 H 9 / O O I \ /O O 0\\S//0 I \ KANE: )L ,\\S’N\Rk I111—/ \N N Rk "'11 H \\0 , ,and In another embodiment of Formula (IV), Z1 is 0 ,N O\\ ,0 0 o ['8 A HN “N «ELAN/S: \\ ’N\Rk “a OH \N' Rk “LL N 111 H “o ’ ’ ’ H In another )OJ\ ,N O HN 0 “N )L \\S//O ”‘1.“ OH \Nl 1‘1. N/ '1‘"- ‘Rk embodiment of Formula (IV), Z1 is ’ ’ H ' In O 0 )L Q‘s/O It," OH '11:. N’ ‘ or Rk another embodiment of a (IV), Z. 1 . , H is In “axon another embodiment of Formula (IV), Z1 is In one ment of Formula (IV), 0 is 0. In another embodiment of Formula (IV), o is 0 or 1. In another embodiment of Formula (IV), 0 is l; and RK is independently selected —67— [Annotation] sak from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, 5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, 2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, SSOZR5, SOZNHZ, SOZNHRS, 5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and I. In another embodiment of Formula (IV), 0 is 1; and RK is independently selected from the group consisting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (IV), 0 is 1; and RK is independently selected from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl. In another embodiment of Formula (IV), 0 is 1; Rx is R5, C1, or CN; and R5 is CH3. In another embodiment of Formula (IV), 0 is 1; and RK is CN. In another embodiment of Formula (IV), 0 is 1; and RK is Cl. In another embodiment of a (IV), 0 is 1; Rx is R5; and R5 is CH3.

In one embodiment of a (IV), L1 is selected from the group consisting of (CR6R7)q, (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S-C(O)-(CR6R7)r, )S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)—(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, )S-S(O)2NR6A-(CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; and Y2 is Cg_14 cycloalkyl, Cg_14 lkenyl, Cg_14 heterocycloalkyl, or C344 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently ed from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, 8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, )R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, 2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(O)NR8802R8, SOgNHg, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In another embodiment of Formula (IV), L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2. In another ment of Formula (IV), L1 is selected from the group consisting of (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-C(O)NR6A- (CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of Cg.14 cycloalkyl, and Cg_14 heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

In another embodiment of a (IV), X is heteroaryl; Rx is independently selected from the group consisting of R5, CN, F, Cl, Br and I; [Annotation] sak L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-S(O)2-(CR6R7)I, (CR6R7)S-C(O)NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is Cg_14 cycloalkyl or Cg_14 heterocycloalkyl; wherein Y2 is optionally substituted with one, two, or three substituents independently ed from the group consisting of R8, 0R8, SOZRg, CO(O)R8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of O 0 HN(Ii O\\ O EAOH RJQN,N // and EAE/ S\Rk , , ; R2, at each occurrence, is independently C1_6 alkyl; R5, at each occurrence, is independently C1_6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group ting of C1_6 alkyl and heterocyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one substituent independently selected from the group ting of R16, OR16, SOZRm, and NHR16; Rk, at each occurrence, is independently selected from the group ting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, aryl, and heterocycloalkyl; wherein the R16 CM alkyl is ally substituted with one substituent independently selected from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is l or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, l, or 2; o is 0 or 1; and p is 0.

Still another embodiment pertains to a compound having Formula (IV) selected from the group ting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] [5- methyl(tricyclo [3 .3. l . l 3’7]dec-l -ylmethyl)- l H-l ,2,3 -triazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-[5- 3 5 methyl(2 icyclo [3 .3 . l . l 3’7]dec- l -ylmethyl)- l H- l ,2,3 -triazolyl]pyridine [Annotation] sak ylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula (V) (R1)m (R2)n \l /j N N 21 \E /\ /<RX>0 Hi1 0 (R3)! ‘ X / and therapeutically able salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof, wherein X, L1, Y2, 21, R1, R2, R3, m, n, and p are as described herein for a (I); Rx is as described herein for substituents on Y1, and o is 0, l, 2, 3, or 4.

One embodiment of this invention pertains to compounds, and therapeutically acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (V) (R1)m (R2)n | i \ N N\ z T / /<RX>0 Hi1 0 (R3>p/ ‘ X / Formula (V), wherein X is heteroaryl; wherein the aryl ented by X is optionally substituted with one, two, three, or four R4; Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, 2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, SOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is selected from the group consisting of )q, (CR6R7)s-O-(CR6R7)I, (CR6R7)S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)I, (CR6R7)s-NR6AC(O)- (CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, )s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A- (CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; [Annotation] sak Y2 is C344 cycloalkyl, C344 cycloalkenyl, C344 heterocycloalkyl, or C344 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C33 cycloalkane, C33 cycloalkene, benzene, C54 heteroarene, C3_3 heterocycloalkane, and C33 heterocycloalkene; wherein Y2 is optionally tuted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, , sozng, C(O)R8, 8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, OR8, C(O)NHSOZR8, C(0)NR8s02R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR1°C(O)R“, NR1°C(O)NR1°R“, OC(O)NR10R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, °)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of I 0 j: O4 o ,N “a, g “‘21 OH \N'N '11..- EN—0, KAN \ 9 9 9 9 H H O O O O 0 O OH O ,N \\// II N S k _ _ / OH '71../ ‘Nl Rk .111. O KANJLRI‘ E E H H O ‘11.“ 9 9 9 9 O O O O “HA ,OH "RA /\/OH 5%in \/\OH ”RAN,0\Rk H a H a H 9 H a / o O O ' O\ 00 \ I )L 0 \ '11; N \ )L \‘ ’N\Rk ’ x k \\ / N N R “a,“ N ”L‘L H H H , ,and ; R1, at each occurrence, is independently selected from the group consisting of halo, C14 alkyl, C24 alkenyl, C24 alkynyl, and C14 haloalkyl; R2, at each occurrence, is independently selected from the group consisting of deuterium, halo, C14 alkyl, C24 l, C24 alkynyl, and C14 haloalkyl; two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring ed from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group ting of halo, C14 alkyl, C24 alkenyl, C24 alkynyl, and C14 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, S(0)R14 and R14; [Annotation] sak R5, at each occurrence, is independently selected from the group consisting of Ci_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is independently selected from the group consisting of en, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of en, R”, on”, SR”, 5, soZR”, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NHZ, NHRIS, 2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, SOZNHRIS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently ed from the group consisting of R16, OR16, SR16, S(O)R16, SOZR16, 6, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, OH, C(O)NHOR16, C(O)NHSOZR16, 16SOZR16, SOZNHZ, SOZNHRm, SOZN(R16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; n the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently ed from the group consisting of C1_6 alkyl, CM alkenyl, CM l, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; R9 is selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)1_4 phenyl; and R10 and R“, at each occurrence, are each independently ed from the group consisting of hydrogen, C1_6 alkyl, CM alkenyl, CM alkynyl, C3_6 cycloalkyl, C1_6 haloalkyl, phenyl and (CH2)1_4-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is attached are ed to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; [Annotation] sak R12 and R”, at each occurrence, are each independently selected from the group consisting of hydrogen, C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl and (CH2)1_4 phenyl; R14, at each occurrence, is ndently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl and C1_4 haloalkyl; R12 and R”, or R12 and R”, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and lkenyl; wherein the R15 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are ally substituted with one, two, or three substituents independently selected from the group consisting of O-(C1_4 alkyl), NHZ, C(O)NH2, SOZNHZ, C(O)H, , (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and lkenyl; wherein the R16 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 yalkyl are optionally substituted with one substituent ndently selected from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, l, or 2; mis 0,1, 2, or 3; nis 0,1, 2, 3, 4, 5, or 6; o is 0,1, 2, 3, or 4; and p is 0, l, or 2.

In one embodiment ofFormula (V), m is 0, l, 2, or 3; n is 0, l, 2, 3, 4, 5, or 6; and p is 0, l, or 2. In another embodiment of a (V), n is 0, l, or 2. In r ment of Formula (V), n is 0, l, or 2; and each R2 is independently deuterium or C1_6 alkyl. In another embodiment of Formula (V), m, n, and p are 0.

In one embodiment of a (V), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In r embodiment of Formula (V), X is heteroaryl, which is unsubstituted. In another embodiment of Formula (V), X is heteroaryl, which is substituted with one R4. In another embodiment of Formula (V), X is heteroaryl, which is substituted with two R4. In another embodiment of Formula (V), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (V), ation] sak X is heteroaryl, which is substituted with two R4, and each R4 is independently on12 01‘ halogen. In another embodiment of Formula (V), X is heteroaryl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (V), X is heteroaryl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (V), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo[1,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2- b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2- b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (V), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2- a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [1 yrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of a (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5 -c]pyridinyl, imidazo[1,2-a]pyridinyl, lo [5 yridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[1,2 - a]pyrazinyl, or imidazo[l ,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4- b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, o[1,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, imidazo[1,2 idinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo [5 ,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, o [1 ,2-a]pyridinyl, thiazolo [5 ,4- c]pyridinyl, thiazolo [4,5 -b]pyridinyl, o[1,2 -a]pyrazinyl, or imidazo [1 yridazinyl, which are substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (V), X is benzo[d]thiazolyl, which is optionally substituted with one, two, three or four R4. In another ment of Formula (V), X is benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with one R4. In another embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is on12 01‘ halogen. In [Annotation] sak another embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In r embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In r embodiment of Formula (V), X is benzo[d]thiazolyl, which is substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (V), Z1 is selected from the group ting of 9, C(O)NR1°R“, C(O)R“, NR10C(O)R“, NR10C(O)NR10R“, OC(O)NR1°R“, O)OR9, C(=NOR1°)NR1°R“, NR10C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R10)S(O)2R“,NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR10)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of O N ,N O HN \ o HN’ \\ o ‘ “AN ”HgkOH \ IN MOH )\ )QN’N H “.11“ N .111“ .111. 9 9 9 9 £11 9 O O 0 O OH O O O ,N \\ ’/ KANJLRk II N S\ MIRk 2_ _ | OH fi OH / N4 .111“ H H 9 9 9 9 9 O O O O “IRAN,OH QL /\/OH figN/V \/\OH “LAN 0 Rk/ \ H 9 H 9 H 9 H 9 / O O | O I RJLN \\ /O O O\\ // ,S/ \\ / ‘ k /S \N \N \Rk 311%N/ S\\O ”L”!— H H H , ,and In another embodiment of Formula (V), Z1 is In another O ,N o HN «N (iv/0 \ I IS ”a ‘ OH N ”'17. N embodiment of a (V), Z1 is ' In another ' embodiment of Formula (V), Z1 is In r EAOH embodiment of Formula (V), Z1 is In one embodiment of Formula (V), o is 0. In another embodiment of Formula (V), o is 0, l, 2, 3, or 4. In another embodiment of Formula (V), o is l, 2, 3, or 4; and Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, [Annotation] sak NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, )N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1. In another embodiment of Formula (V), o is 1, 2, 3, or 4; and Rx, at each occurrence, is ndently ed from the group ting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (V), o is 1, 2, 3, or 4; and Rx, at each occurrence, is independently ed from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl. In another embodiment of Formula (V), o is 1 or 2; Rx is R5 or CN; and R5 is CH3. In another embodiment of Formula (V), o is 1; and RK is CN. In another embodiment of Formula (V), o is 1; and RK is Cl. In r embodiment of Formula (V), o is 1; Rx is R5; and R5 is CH3.

In one embodiment of Formula (V), L1 is selected from the group consisting of (CR6R7)q, (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S-C(O)-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)—(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A-(CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; and Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or C344 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally tuted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, SOZRg, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, , NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, 8802R8, , SOzNHRg, SOzN(R8)2, , C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In another embodiment of Formula (V), L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl, and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2. In another embodiment of Formula (V), L1 is selected from the group ting of )S-O-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S- S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)SNR6A- )r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of C344 cycloalkyl, and Cg_14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of en, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

In another embodiment of Formula (V), X is heteroaryl; ation] sak Rx, at each ence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; L1 is ed from the group consisting of (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S- S—(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A- (CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is Cg_14 cycloalkyl, or Cg_14 heterocycloalkyl; wherein Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, 0R8, SOZRg, 8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of O HN’N‘ O O\ O ”Ll-LAOH EJQN’N and , D LL‘LJLE/Skk‘ ’/ ; R2, at each occurrence, is independently C1_6 alkyl; R5, at each occurrence, is independently C1_6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each ence, is ndently selected from the group consisting of C1_6 alkyl and heterocyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR”, SOZRM, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R16, at each occurrence, is independently ed from the group consisting of C1_4 alkyl, aryl, and heterocycloalkyl; wherein the R16 C1_4 alkyl is optionally substituted with one substituent independently selected from the group ting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is l or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, l, or 2; o is 0 or 1; and p is 0.

Still another embodiment pertains to a compound having Formula (V) selected from the group consisting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] {2- methyl [tricyclo [3 .3. l . l c- l -ylmethoxy]phenyl}pyridinecarboxylic acid; [Annotation] sak 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 - {2 - methyl-3 - clo [3 .3 . l . l 3’7] decylmethoxy]phenyl } pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 - {3 - clo [3 .3 . l . ec-l -ylmethoxy]phenyl }pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] {2- methyl [tricyclo [3 .3. l . l 3’7]dec- l -yloxy]phenyl}pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 - {2-cyano- 3-[tricyclo[3.3.l .13’7]dec-l-ylamino]phenyl}pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 - {2-cyano- 3 - [tricyclo [3 . 3 . l .13’7]dec-l-ylsulfanyl]phenyl}pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z bamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -(2- methyl-3 - {[tricyclo [3 . 3. l.13’7]dec-l-ylcarbonyl]amino}phenyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 - {2 - methyl [tricyclo [3 .3. l . l 3’7]dec- l -ylsulfamoyl]phenyl}pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. l.13’7]dec-l-ylcarbonyl]amino}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ydroisoquinolin-2( l H)-yl] {2- methyl-3 - [tricyclo [3 .3. l . l 3’7] decylcarbamoyl]phenyl } pyridine-2 -carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. l . l3 ’7]dec- l -ylmethyl]amino } phenyl)pyridinecarboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z-ylcarbamoyl)-3,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [2-cyano(tricyclo [3 . 3 . l .13’7]dec-l-ylsulfonyl)phenyl]pyridine-2 -carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] -3 -(2- methyl-3 - {methyl [(tricyclo [3 .3 . l . l3 -2 -yl] carbamoyl }phenyl)pyridine-2 -carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] {2- methyl-3 yl(2-oxatricyclo [3 .3 . l .13’7]dec-l-ylcarbonyl)amino]phenyl}pyridine carboxylic acid; 6- [8-(1 ,3 -benzothiazol-Z -ylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] -3 -(2- methyl-3 - {methyl [tricyclo [3 . 3. l . l3 ’7]decyl] sulfamoyl } )pyridinecarboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides nds of Formula (VI) [Annotation] sak \E \ (RX)0 0 (R3)p// \/ H171 | l X /N Formula (VI) and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof, wherein X, L1, Y2, 21, R1, R2, R3, m, n, and p are as described herein for Formula (I); Rx is as described herein for substituents on Y1, and o is 0, 1, 2, or 3.

One ment of this invention pertains to compounds, and therapeutically acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-XL proteins, the compounds having Formula (VI) (R1)m (R2)n EECr; I (R3)p/ Formula (VI), wherein X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, )OR5, NHC(O)NH2, NHC(O)NHR5, N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, , SOZNHRS, SOZN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1; L1 is selected from the group consisting of (CR6R7)q, )S-O-(CR6R7)r, )S- C(O)—(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)- (CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, )S-NR6A-(CR6R7)r, )S-S(O)2NR6A- (CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; Y2 is Cg_14 cycloalkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or Cg_14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g lkane, C3_g cycloalkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g ation] sak heterocycloalkene; wherein Y2 is optionally substituted With one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, )2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8, SOZR8, C(0)NR8s02R8, SOZNHZ, SOZNHRg, SOZN(R8)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; z1 is selected from the group consisting of C(O)OR9, C(O)NR1°R“, , NR1°C(O)R“, 0)NR1°R“, OC(O)NR10R“, NR1°C(O)OR9, C(=NOR1°)NR1°R“, NR1°C(=NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R11,N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is selected from the group consisting of N O ,N HN \ | o HN,1\I\ O,N\ O 571' N "LL" OH MOH H \NIN “51ANJQN’ 9 9 '11..- 9 I111. 9 H H o o O O 0 0 OH O ,N \\// KANJL M N S\ KMO’Rk Rk E_ _OH | / OH 'sz N4 E ‘11.“ H H O 9 9 9 9 9 O O O O ”LAN,OH N/\/OH EAN/VOV\OH EAN,0\ “Ln Rk H a H a H 9 H a / O O I O\\//O )L 98:”\ O O I )L :‘ ’N\Rk \N La" N Rk “a,“ N “0 ‘11:,/ ‘N H , ,and § R1, at each occurrence, is independently ed from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R2, at each occurrence, is independently selected from the group ting of deuterium, halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; two R2 that are attached to the same carbon atom, together With said carbon atom, optionally form a ring selected from the group ting of cycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C1_6 alkyl, CM alkenyl, CM alkynyl, and C1_6 haloalkyl; R4, at each occurrence, is independently ed from the group consisting of NRIZRB, 0R”, CN, N02, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13,NRIZS(O)2R14, NR”S(O)R14, S(O)2R14, S(0)R14 and R14; R5, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CM alkynyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; [Annotation] sak R6A is ndently selected from the group consisting of hydrogen, C1_6 alkyl, C2_6 alkenyl, CM alkynyl, and C1_6 haloalkyl; R6 and R7, at each occurrence, are each independently ed from the group consisting of hydrogen, R15, 0R”, SR”, S(O)R15, SOZRIS, C(O)R15, 15, OC(O)R15, OC(O)OR15, NHZ, NHRIS, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NRISS(O)2R15, NHC(O)OR15, NR15C(O)OR15, NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSOZR15, C(O)NRISSOZR15, SOZNHZ, SOZNHRIS, SOZN(R15)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CH alkenyl, CM alkynyl, C1_6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1_6 alkyl, C2_6 l, CM alkynyl, and C1_6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SOZRIG, C(O)R16, CO(O)R16 OC(O)R16, OC(O)OR16, NHZ, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, OR16, O)OR16, NHC(O)NH2, NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSOZR16, C(O)NR16SOZR16, SOZNHZ, SOZNHR16, SOZN(R16)2, CO(O)H, C(O)H, OH, CN, N3, N02, F, Cl, Br and 1; wherein the R8 aryl, heterocyclyl, lkyl, and lkenyl are optionally tuted with one, two, or three substituents independently selected from the group consisting of C1_6 alkyl, CM alkenyl, CH alkynyl, C1_6 haloalkyl, NHZ, C(O)NH2, SOZNHZ, C(O)H, (O), OH, CN, N02, OCF3, OCFZCF3, F, Cl, Br and I; R9 is selected from the group consisting of C1_6 alkyl, CH alkenyl, CM alkynyl, C1_6 haloalkyl, cycloalkyl, phenyl and (CH2)1_4 phenyl; and R10 and R“, at each occurrence, are each independently selected from the group consisting of en, C1_6 alkyl, CH alkenyl, CM alkynyl, C3_6 cycloalkyl, C1_6 haloalkyl, phenyl and (CH2)1_4-phenyl; or R10 and R“, or R10 and R9, together with the atom to which each is ed are combined to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, CH alkenyl, CM alkynyl, C3_7 heterocycloalkyl, C3_7 cycloalkyl and C1_6 haloalkyl; R12 and R”, at each occurrence, are each independently selected from the group consisting of hydrogen, C1_4 alkyl, C24 alkenyl, C24 l, C1_4 haloalkyl and (CH2)1_4 phenyl; R14, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl and C1_4 haloalkyl; [Annotation] sak R12 and R”, or R12 and R14, at each ence, er with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of O-(C1_4 alkyl), NHZ, C(O)NH2, SOZNHZ, C(O)H, C(O)OH, (O), OH, CN, N02, OCF3, OCF2CF3, F, Cl, Br and 1; R16, at each occurrence, is independently selected from the group consisting of C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 kyl, C1_4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1_4 alkyl, C24 alkenyl, C24 alkynyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl are optionally substituted with one tuent independently selected from the group ting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is 1, 2, or 3; sis 0,1, 2, or 3; ris 0,1, 2, or 3; wherein the sum ofs and r is 0, 1, or 2; mis 0,1, 2, or 3; nis 0,1, 2, 3, 4, 5, or 6; o is 0,1, 2, or 3; and p is 0, 1, or 2.

In one embodiment ofFormula (VI), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (VI), n is 0, 1, or 2. In another ment of Formula (VI), n is 0, 1, or 2; and each R2 is independently deuterium or C1_6 alkyl. In another embodiment of Formula (VI), m, n, and p are 0.

In one embodiment of a (VI), X is heteroaryl, which is optionally substituted with one, two, three or four R4. In another embodiment of a (VI), X is heteroaryl, which is unsubstituted. In another embodiment of Formula (VI), X is heteroaryl, which is substituted with one R4. In another ment of Formula (VI), X is heteroaryl, which is substituted with two R4. In another embodiment of Formula (VI), X is heteroaryl, which is substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (VI), X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or halogen. In another ment of a (VI), X is heteroaryl, which is tuted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (VI), X is heteroaryl, which is substituted with two R4, and each R4 is independently F.

[Annotation] sak In one embodiment of Formula (VI), X benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 - b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are optionally substituted with one, two, three or four R4. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are unsubstituted. In another embodiment of a (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[l ,2-a]pyridinyl, lo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[l ,2-a]pyrazinyl, or imidazo[l ,2- b]pyridazinyl, which are substituted with one R4. In another ment of a (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2- a]pyridinyl, thiazolo [5 yridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [l ,2-a]pyrazinyl, or o[l,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 - zinyl, or imidazo[l ,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (VI), X is d]thiazolyl, thiazolo[5,4- b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[ l ,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are substituted with two R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5- c]pyridinyl, imidazo [ l ,2 -a]pyridinyl, thiazolo [5 ,4-c]pyridinyl, thiazolo [4,5 idinyl, o[l,2-a]pyrazinyl, or imidazo[l,2-b]pyridazinyl, which are tuted with one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo [5 ,4-b]pyridinyl, thiazolo [4,5 -c]pyridinyl, imidazo [l ,2-a]pyridinyl, thiazolo [5 ,4- c]pyridinyl, thiazolo [4,5 -b]pyridinyl, imidazo [ l ,2 -a]pyrazinyl, or imidazo [l yridazinyl, which are substituted with two R4, and each R4 is independently F.

In one embodiment of Formula (VI), X is benzo[d]thiazolyl, which is optionally substituted with one, two, three or four R4. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with one R4. In r embodiment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with two R4. In another ment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is on12 01‘ halogen. In another embodiment of Formula (VI), X is d]thiazolyl, which is substituted with two R4, and each R4 is ndently OR12 or halogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is C1, F, 01‘ methoxy. In [Annotation] sak another ment of Formula (VI), X is benzo[d]thiazolyl, which is substituted With two R4, and each R4 is ndently F.

In one embodiment of Formula (VI), Z1 is selected from the group ting of C(O)OR9, C(O)NR1°R“, C(O)R“, NR10C(O)R“, O)NR10R“, OC(O)NR1°R“, NR1°C(O)OR9, C(=N0R1°)NR1°R“, =NCN)NR1°R“, NR1°S(O)2NR1°R“, S(O)2R9, S(O)2NR1°R“, N(R1°)S(O)2R“, NR1°C(=NR“)NR1°R“, C(=S)NR1°R“, C(=NR1°)NR1°R“, halogen, N02, and CN; or Z1 is ed from the group consisting of N »N I >=O i HN’NxN “'11.. .171. OH \ I )O;N>—OH\ )OL HN\ :N\NN H N '11?- 9 9 ‘11}, 9 I171; 9 H 9 O O O OH O O O ,N \\ ’/ 0 II MOHN S\ MMO’R k ”HAN Rk E_ _ “if NA 3 OH .111“ H H O 9 9 9 9 9 O O O O ,OH , \ H 9 H 9 H 9 H 9 / O 0 ll 0 \\ //O O O\\S/: I \ ”IRAN] S\ )L ,\\S: Rk '1'?—/ N N N‘ 3» H and H , , In another embodiment of Formula (VI), Z1 is O ,N O\\ 0 O 0 I A HN ’/ N ”RAN” ‘ \\S’N\Rk ”‘5, \ I k / OH R \ “a, N H “a, N ‘o ’ ’ ’ H In another )OJ\ ,N 0 HN “N )L O\\S//O .111“ OH \Nl ‘11?“ N/ .111- \11k embodiment of Formula (VI), Z1 is ’ ’ H ' In O 0 O\\ ,,o A )L /S\ '111, OH 9'71. N or Rk another embodiment of Formula (VI), Z1 is ’ H EAOH another embodiment of Formula (VI), Z1 is In one embodiment of Formula (VI), 0 is 0. In another embodiment of Formula (VI), o is 0, l, 2, or 3. In another embodiment of Formula (VI), 0 is l, 2, or 3; and Rx, at each occurrence, is independently selected from the group consisting of R5, 0R5, SR5, S(O)R5, SOZRS, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NHZ, NHRS, N(R5)2, R5, NR5C(O)R5, NHS(O)2R5, NRSS(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, )NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSOZR5, C(O)NRSSOZR5, SOZNHZ, [Annotation] sak SOzNHRS, SOzN(R5)2, CO(O)H, C(O)H, OH, CN, N5, N02, F, Cl, Br and 1. In another embodiment of Formula (VI), 0 is l, 2, or 3; and Rx, at each occurrence, is independently selected from the group ting of R5, CN, F, Cl, Br and I. In another embodiment of Formula (VI), 0 is l, 2, or 3; and Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; wherein R5 is C1_6 alkyl. In another embodiment of Formula (VI), 0 is l or 2; Rx is R5 or CN; and R5 is CH3. In another embodiment of Formula (VI), 0 is l; and RK is CN. In another embodiment of Formula (VI), 0 is l; and RK is Cl. In r embodiment of Formula (VI), 0 is l; Rx is R5; and R5 is CH3.

In one embodiment of Formula (VI), L1 is selected from the group consisting of )q, (CR6R7)q, (CR6R7)S-O-(CR6R7)r, (CR6R7)S-C(O)-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, (CR6R7)S-S(O)2-(CR6R7)I, (CR6R7)S-NR6AC(O)—(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, )S-NR6A-(CR6R7)r, (CR6R7)S-S(O)2NR6A-(CR6R7)r, and (CR6R7)S-NR6AS(O)2-(CR6R7)r; and Y2 is Cg_14 lkyl, Cg_14 cycloalkenyl, Cg_14 heterocycloalkyl, or C344 cycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3_g cycloalkane, C3_g lkene, benzene, C5_6 heteroarene, C3_g heterocycloalkane, and C3_g heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, 0R8, SR8, S(O)R8, sozng, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NHZ, NHRg, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NRgs(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSOZR8, C(O)NR8802R8, SOZNHZ, SOZNHRg, SOZN(R8)2, , C(O)H, OH, CN, N3, N02, F, Cl, Br and 1.

In another embodiment of Formula (VI), L1 is (CR6R7)q; and Y2 is selected from the group consisting of C344 cycloalkyl, and C344 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is l or 2. In another embodiment of Formula (VI), L1 is selected from the group consisting of (CR6R7)S-O-(CR6R7)r, (CR6R7)S-S-(CR6R7)r, )S- S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A-(CR6R7)r, (CR6R7)S- NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of C344 cycloalkyl, and Cg_14heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group ting of hydrogen, and C1_6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

In another embodiment of Formula (VI), X is heteroaryl; Rx, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; [Annotation] sak L1 is selected from the group consisting of )q, (CR6R7)s-O-(CR6R7)r, (CR6R7)S- s—(CR6R7)., (CR6R7)S-S(O)2-(CR6R7)r, (CR6R7)S-NR6AC(O)-(CR6R7)r, (CR6R7)S-C(O)NR6A- (CR6R7)r, (CR6R7)S-NR6A-(CR6R7)r, and (CR6R7)S-S(O)2NR6A-(CR6R7)r; Y2 is Cg_14 cycloalkyl, or Cg_14 cycloalkyl; wherein Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, 0R8, SOZRg, CO(O)R8, OH, F, Cl, Br and 1; Z1 is selected from the group consisting of O O HN ’N‘ RAOH HickN’N EA O\\ , O / / S\Rk , , E ; R2, at each occurrence, is independently C1_6 alkyl; R5, at each occurrence, is independently C1_6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1_6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group consisting of C1_6 alkyl and heterocyclyl; wherein the R8 C1_6 alkyl is optionally substituted with one tuent independently selected from the group consisting of R16, OR16, SOZRm, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1_6 alkyl, C3_7 heterocycloalkyl, C3_7 lkyl and C1_6 haloalkyl; R16, at each occurrence, is independently ed from the group consisting of C1_4 alkyl, aryl, and heterocycloalkyl; wherein the R16 CM alkyl is optionally substituted with one substituent independently selected from the group consisting of OCH3, OCHZCHZOCHg, and OCHZCHZNHCHg; q is 1 or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, 1, or 2; o is 0 or 1; and p is 0.

Still another embodiment pertains to a compound having Formula (VI) selected from the group consisting of 1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]—2'— (tricyclo [3 .3 . l . 13’7]dec- l hoxy)-3 pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—3'—methyl- 2'—(tricyclo[3.3.1.13’7]decylmethoxy)-3,4'-bipyridinecarboxylic acid; [Annotation] sak 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]-2'— octyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3'—methyl- 2'—(tricyclo [3 .3. l . 13’7]dec-l -ylsulfonyl)-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3'—methyl- 2'—(tricyclo [3 .3. l . 13’7]dec-l -ylsulfanyl)-3 ,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3'—methyl- 2'—(tricyclo[3.3.l.13’7]dec-l-ylamino)-3,4'-bipyridinecarboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof. ceutical itions, Combination Therapies, Methods of Treatment, and Administration r ment comprises pharmaceutical itions comprising a compound having a (I) and an excipient.

Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmune disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for ng diseases during Which anti-apoptotic Bcl-XL proteins are sed, said compositions comprising an excipient and a eutically effective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in a patient during Which anti-apoptotic Bcl-XL proteins are expressed, said methods sing administering to the patient a therapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, c lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, ma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an ent and a therapeutically effective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic ia, ctal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung , prostate cancer, —87— [Annotation] sak small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseases during Which are expressed anti-apoptotic Bcl-xL ns, said itions comprising an ent and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating disease in a patient during Which are sed anti-apoptotic Bcl-xL proteins, said methods comprising stering to the patient a therapeutically ive amount of a compound having a (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to compositions for ng bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular , lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, n cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate , small cell lung cancer or spleen cancer, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods of treating r cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, ctal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid ancies of T-cell or B-cell origin, melanoma, enous ia, myeloma, oral cancer, ovarian cancer, all cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.

Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated With anti-apoptotic Bcl-xL ns.

Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have y for treating diseases associated With expression of anti-apoptotic Bcl-xL proteins.

[Annotation] sak Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during ion or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the nds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, e, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hloride, hydrobromide, hydroiodide, lactobionate, lactate, e, mesitylenesulfonate, methanesulfonate, ylenesulfonate, nicotinate, oxalate, e, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, anate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds are contemplated as being embraced by this invention. Basic addition salts of the compounds are those d from the reaction of the compounds with the hydroxide, ate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.

The compounds haVing Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrastemally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds haVing Formula (I) depend on the recipient of the treatment, the disorder being treated and the ty thereof, the composition containing the compound, the time of administration, the route of administration, the duration of ent, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (I) used to make a ition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.

Compounds haVing Formula (I) may be administered with or without an excipient.

Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, fiers, extenders, fillers, flavoring agents, ants, lubricants, perfumes, preservatives, propellants, ing agents, sterilizing agents, sweeteners, lizers, wetting agents and mixtures thereof.

Excipients for preparation of compositions sing a compound haVing Formula (I) to be administered orally in solid dosage form include, for e, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, seed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, [Annotation] sak panol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, 's solution, safflower oil, sesame oil, sodium carboxymethyl ose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, n oil, stearic acids, stearyl fumarate, sucrose, tants, talc, anth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene s, propylene glycol, sesame oil, water and mixtures thereof Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.

Excipients for preparation of itions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof. nds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-l) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell r) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, xygenase-2 inhibitors, DVDs, leukemia viral oncogene g ) or inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal ies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), alating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA’s, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs s), poly ADP sine diphosphate)-ribose rase (PARP) inhibitors, um chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, some inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, ation] sak small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with one or more of these agents .

BiTE antibodies are bi-specific antibodies that direct s to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.

Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by , one of the isms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.

SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart sed stability and/or sed cellular potency. Examples of chemical modifications include orothioate groups, 2'-deoxynucleotide, 2'—OCH3-containing ribonucleotides, 2'—F- ribonucleotides, 2'—methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have g s (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or tric ends (overhangs). The overhang of 1-2 tides can be present on the sense and/or the antisense strand, as well as present on the '- and/ or the 3'—ends of a given . For example, siRNAs targeting Mcl-l have been shown to e the activity of ABT-263, (i.e., N-(4-(4-((2-(4-chlorophenyl)—5,5 -dimethyl- l-cyclohexenyl)methyl)piperazin- l -yl)benzoyl)((( l R)—3-(morpholinyl)—l - ((phenylsulfanyl)methyl)propyl)amino)-3 -((trifluoromethyl)sulfonyl)benzenesulfonamide) or ABT-737 (i.e., N-(4-(4-((4'—chloro( l l '-biphenyl)yl)methyl)piperazin-l -yl)benzoyl) ((( l R)—3 -(dimethylamino)- l -((phenylsulfanyl)methyl)propyl)amino)-3 - nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9), 3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are ered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term “multispecific binding protein” means a g protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen g sites. Such DVDs may be monospecific (i.e., e of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a [Annotation] sak light chain variable domain With a total of 6 CDRs involved in antigen binding per antigen binding site.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® ustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine , mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal grth factor receptor (EGFR) tors, insulin grth factor-2 receptor (IGFR-Z) inhibitors, matrix metalloproteinase-2 (MMP-Z) inhibitors, matrix oproteinase-9 (MMP-9) inhibitors, platelet-derived grth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) tors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, 14, MTA), -azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® ibine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflomithine, EICAR (5 -ethynyl-l-B -D-ribofuranosylimidazole carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination With leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, tatin, raltitrexed, rin, ne, trimetrexate, S-l, tiazofurin, tegafur, TS-l , Vidarabine, UFT and the like.

Antivirals e vir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific kinase tors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.

Bcl-2 protein tors include AT-lOl ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcltargeting antisense oligonucleotide)), 4, IPI-565, N-(4-(4-((4'— ( 1 ,1 '-biphenyl)yl)methyl)piperazin-1 -yl)benzoyl)(((1R)-3 -(dimethylamino)-l - ((phenylsulfanyl)methyl)propyl)amino)-3 -nitrobenzenesulfonamide) (ABT-73 7), N-(4-(4-((2- orophenyl)-5 ,5 -dimethylcyclohex-1 -en-1 -yl)methyl)piperazin-1 -yl)benzoyl) (((1R)(morpholinyl)((phenylsulfanyl)methyl)propyl)amino)-3 - ((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® 54825), GLEEVEC® (imatinib) and the like. ation] sak CDK inhibitors include AZD-543 8, BMI-1040, EMS-032, EMS-3 87, 84, flavopyridol, GPC-286l99, MCS-5A, PD0332991, FHA-690509, seliciclib (CYC-202, ovitine), ZK-3 04709 and the like. cox—2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), ® (valdecoxib), BMS347070, CELEBREX® (celecoxib), 9 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl(3,4-dirnethylphenyl)-l-(4- sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-838l, SVT-2016, 8-2474, T-6l4, VIOXX® (rofecoxib) and the like.

EGFR tors include ABX-EGF, GFR immunoliposornes, EGF-Vaccine, EMD-7200, ERBITUX® (cetuxirnab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib 01‘ 051—774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP7l4, CI-1033 tinib), TIN® (trastuzurnab), ® inib), OMNITARG® (204, petuzurnab), TAK-165, GW-572016 (ionafarnib), GW-282974, 9, PI-l66, dHER2 (HER2 vaccine), AFC-8024 (HER-2 vaccine), anti-HEIUZneu bispecific antibody, B7.her21gG3, AS HER2 ctional bispecfic antibodies, mAB AR-209, mAB 2B-l and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.

HSP-90 inhibitors include l7-AAG-nab, l7-AAG, CNF-101, CNF-1010, CNF-2024, l7-DMAG, geldanarnycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HG81029, GDC-0145, GDC- 0152, LCL-l6l, LBW-242 and the like.

Antibody drug conjugates e anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-01 l-VcMMAE, PSMA-ADC, MEDI-547, Am SGN-35, SGN—75 and the like Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apornab, conaturnurnab, ETR2- ST01, GDC0145 (lexatumumab), HGS-1029, LBY- l 35, PRO-1762 and trastuzurnab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors e CEP-701 (lesaurtinib), XL019 and INCB018424 and the like.

MEK inhibitors e ARRY-l42886, ARRY-43 8162 PD-325901, PD-98059 and the like.

[Annotation] sak mTOR inhibitors include AP-23573, 9, everolimus, RAD-001, rapamycin, olimus, ATP-competitive TORCl/TORCZ inhibitors, including PI-103, PP242, PP30, Torin l and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® late), D® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® xen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), ® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, , CP-868596 and the like.

Platinum chemotherapeutics include tin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL- 147, CAL-120, ONO-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZZ35, XL765 and the like.

Thrombospondin analogs include ABT-SlO, ABT-567, ABT-898, TSP-l and the like.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, ABE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis yme Pharmaceuticals (Boulder, CO.) and Chiron, Ville, CA)) axitinib 73 6), AZD-217l, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU- 11248), VEGF trap, ATM (vandetanib, ZD-6474) and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or ® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), cin C, nemorubicin, neocarzinostatin, ycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors e aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), ide, exatecan, lO-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-3 8, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT- 1/B,denosumab, ERBITUX® (cetuximab), HUMAX-CD4® imumab), IGFlR-specific [Annotation] sak antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), N® (rituximab), ticilimumab, zimab, CD20 dies types I and II and the like.

Hormonal therapies e ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, IL® (flutamide), EVISTA® ifene), AFEMATM (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® terol), MIFEPREX® (mifepristone), NILANDRONTM (nilutamide), NOLVADEX® ifen citrate), PLENAXISTM (abarelix), prednisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB l 089, CB 1 093), lexacalcitrol 0), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-5 9436, AZD-228l, AG- 014699, BSI-201, BGP-l 5, IND-1001, ONO-2231 and the like.

Plant ids include, but are not limited to, Vincristine, Vinblastine, Vindesine, Vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-l 71 and the like.

Examples of immunologicals include interferons and other -enhancing agents. Interferons include eron alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, ACTIMMUNE® (interferon lb) or interferon gamma-n1 , combinations thereof and the like. Other agents include ALFAFERONE® ,(IFN- o), BAM-OOZ (oxidized glutathione), BEROMUN® ermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, mod, MDX-Ol 0 (anti-CTLA-4), ma vaccine, mab, molgramostim, MYLOTARGTM (gemtuzumab icin), NEUPOGEN® (filgrastim), OncoVAC-CL, ® (oregoyomab), pemtumomab (Y-muHMFGl), PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-lOO (Specific nce of Maruyama (SSM)), WF-lO (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), [Annotation] sak ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include n, lentinan, sizofiran, picibanil PF- 3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include bine (ara C or oside C), cytosine arabinoside, doxifluridine, A® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYLTM (triacetyluridine itabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL® (mercaptopurine). totic agents include batabulin, epothilone D (KOS-862), N-(2-((4- yphenyl)amino)pyridinyl)methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), Vinflunine, ZK-EPO (synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as ensitizers that enhance the efficacy of radiotherapy. es of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and , unsealed source radiotherapy and the like.

Additionally, compounds haVing Formula (I) may be combined With other chemotherapeutic agents such as ABRAXANETM (ABI-007), ABT-lOO (famesyl transferase inhibitor), ADVEX1N®(Ad5CMV-p53 vaccine), R® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3,17-dione-androsta-1,4- diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), ® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® xydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPATTM (cyproterone e), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused Via a His-Ala linker to human epidermal grth factor) or TransMID-107RTM (diphtheria toxins), dacarbazine, dactinomycin, 5,6- dimethylxanthenoneacetic acid (DMXAA), acil, EVIZONTM (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f can mesylate), enzastaurin, EPO906 (epithilone B), IL® ivalent human papillomavirus ation] sak (Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, NSE®, GMK ioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-l 01 , IL-l 3-PE3 8, IL- 1 3 -PE3 8QQR edekin besudotox), IL-l3-pseudomonas exotoxin, interferon-0t, interferon-y, JUNOVANTM or MEPACTTM (mifamurtide), lonafamib, 5,10-methylenetetrahydrofolate, osine (hexadecylphosphocholine), TAT®(AE-94l), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), SE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine), ORATHECINTM (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEXTM (aglycone saponins from ginseng sing 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, odiol, procarbazine, rebimastat, REMOVAB® axomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), LINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PTlOO), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn- KLH), thymitaq (2-amino-3,4-dihydromethyloxo-5 -(4-pyridylthio)quinazoline dihydrochloride), TNFERADETM (adenovector: DNA carrier containing the gene for tumor necrosis factor-0L), TRACLEER® or ZAVESCA® tan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), n (anti-alphavbeta3 antibody), XCYTR1N® (motexafin gadolinium), XINLAYTM (atrasentan), XYOTAXTM (paclitaxel poliglumex), IS® (trabectedin), ZD-6126, ZINECARD® zoxane), ZOMETA® (zolendronic acid), zorubicin and the like.

Data ination of the utility of compounds having Formula (I) as binders to and inhibitors of anti-apoptotic Bcl-XL proteins was performed using the Time ed- Fluorescence Resonance Energy Transfer (TR-FRET) Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No. PV4216).

Probe Synthesis All reagents were used as obtained from the vendor unless otherwise specified.

Peptide synthesis reagents ing diisopropylethylamine (DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP), 2-(1H-benzotriazole-l-yl)—1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained from Applied Biosystems, Inc. (AB1), Foster City, CA or American Bioanalytical, Natick, MA. Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid cartridges (Fmoc-Ala- [Annotation] sak OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)—OH, Fmoc-Glu(tBu)—OH, Fmoc-Phe-OH, Fmoc- Gly-OH, Fmoc-His(Trt)—OH, Fmoc-Ile-OH, Fmoc-Leu-OH, ys(Boc)—OH, Fmoc-Met- OH, Fmoc-Asn(Trt)—OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, Fmoc-Arg(be)—OH, Fmoc- u)—OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)—OH, Fmoc-Tyr(tBu)—OH) were obtained from ABI or Anaspec, San Jose, CA. The peptide synthesis resin Rink amide MBHA resin) and Fmoc-Lys(Mtt)—OH were ed from Novabiochem, San Diego, CA. Single-isomer 6-carboxyfluorescein imidyl ester (6-FAM-NHS) was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood Products, West Columbia, SC. Thioanisole, phenol, triisopropylsilane (TIS), 3,6-dioxa-l,8-octanedithiol (DODT) and isopropanol were obtained from Aldrich Chemical Co., Milwaukee, WI.

Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO MS). Electrospray mass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp., San Jose, CA) in both positive and negative ion mode.

General Procedure For Solid-Pliase Peptide Synthesis (SPPS) Peptides were synthesized with, at most, 250 umol preloaded Wang resin/vessel on an ABI 433A peptide synthesizer using 250 umol scale FastmocTM coupling cycles. Preloaded cartridges containing 1 mmol standard Fmoc-amino acids, except for the position of attachment of the phore, where 1 mmol ys(Mtt)-OH was placed in the cartridge, were used with conductivity feedback monitoring. N-terminal acetylation was accomplished by using 1 mmol acetic acid in a cartridge under standard coupling ions. l 0f4-Methyltrityl (Mtt) From Lysine The resin from the synthesizer was washed thrice with dichloromethane and kept wet. 150 mL of 95 :4:1 dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed through the resin bed over 30 s. The mixture turned deep yellow then faded to pale yellow. 100 mL ofDMF was flowed through the bed over 15 minutes. The resin was then washed thrice with DMF and filtered. rin tests showed a strong signal for primary amine.

Resin Labeling With 6—Carboxyflaorescein-NHS (6—FAM-NHS) The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF and stirred or shaken at ambient temperature overnight. When complete, the resin was drained, washed thrice with DMF, thrice with (l X dichloromethane and 1X methanol) and dried to provide an orange resin that was negative by ninhydrin test. l Procedure For Cleavage And ection OfResin-Boand Peptide Peptides were cleaved from the resin by shaking for 3 hours at ambient temperature in a ge cocktail consisting of 80% TFA, 5% water, 5% isole, 5% phenol, 2.5% T18, and 2.5% EDT (1 mL/0.l g resin). The resin was removed by filtration and rinsing twice with TFA. The TFA was evaporated from the filtrates, and product was precipitated with ether (10 [Annotation] sak mL/0.1 g resin), red by centrifugation, washed twice with ether (10 mL/0.1 g resin) and dried to give the crude e.

General Procedure For Purification 0fPeptides The crude peptides were purified on a Gilson preparative HPLC system running Unipoint® analysis software n, Inc., Middleton, WI) on a radial compression column containing two 25 X 100 mm segments packed with Delta-PakTM C18 15 um particles with 100 A pore size and eluted with one of the gradient s listed below. One to two milliliters of crude peptide solution (10 mg/mL in 90% DMSO/water) was purified per injection. The peaks containing the product(s) from each run were pooled and lyophilized.

All preparative runs were run at 20 mL/min with eluents as buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure For Analytical HPLC Analytical HPLC was performed on a Hewlett-Packard 1200 series system with a diode-array or and a Hewlett-Packard 1046A fluorescence detector running HPLC 3D ChemStation software version A.03.04 (Hewlett-Packard. Palo Alto, CA) on a 4.6 X 250 mm YMC column packed with ODS-AQ 5 mm particles with a 120 A pore size and eluted with one of the gradient methods listed below after preequilibrating at the starting conditions for 7 minutes. s were buffer A: 0.1% TFA-water and buffer B: itrile. The flow rate for all gradients was 1 .

F-Bak.‘ Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)—(SEQ ID NO: 2)INR-NH2 Fmoc-Rink amide MBHA resin was ed using the general peptide synthesis procedure to provide the protected bound peptide (1.020 g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved and deprotected as described hereinabove to provide the crude product as an orange solid (0.37 g). This product was purified by RP- HPLC. Fractions across the main peak were tested by analytical RP-HPLC, and the pure fractions were isolated and lyophilized, with the major peak providing the title compound (0.0802 g) as a yellow solid; MALDI-MS m/z = 2137.1 [(M+H)+].

Alternative Synthesis ofPeptide Probe F-Bak: -(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)—(SEQ ID NO:2)INR-NH2 The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHA resin (Novabiochem) on an Applied Biosystems 433A ted peptide synthesizer g FastmocTM coupling cycles using pre-loaded 1 mmol amino acid cartridges, except for the fluorescein(6-FAM)—labeled lysine, where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge. The N-terminal acetyl group was incorporated by putting 1 mmol acetic acid in a cartridge and coupling as described hereinabove. Selective removal of the 4- [Annotation] sak methyltrityl group was accomplished with a solution of 95:4:1 DCM:TIS:TFA (V/V/V) flowed through the resin over 15 minutes, followed by quenching with a flow of dimethylformamide.

Single-isomer oxyfluorescein-NHS was reacted with the lysine side-chain in 1% DIEA in DMF and confirmed complete by ninhydrin testing. The peptide was cleaved from the resin and side-chains deprotected by treating with 80:55 5:25:25 TFA/water/phenol/ thioanisole/triisopropylsilane: 3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide was recovered by precipitation with l ether. The crude peptide was purified by reverse- phase high-performance liquid tography, and its purity and identity were ed by analytical reverse-phase high-performance liquid chromatography and matrix-assisted laser- desorption pectrometry (m/z = 2137.1 ((M+H)+).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay The measurement of competition of compounds of the invention with F-Bak for a Bcl- 2 family protein (Bcl-xL) binding site using a Time Resolved Fluorescence nce Energy Transfer (TR-FRET) binding assay: Test compounds were serially diluted in DMSO starting at 50 MM (2x starting concentration; % DMSO) and 10 ML transferred into a 384-well plate. Then 10 ML of a protein/probe/antibody mix is added to each well at final concentrations listed in Table 1.

Table 1 GST-Bcl- F-Bak (GQVGRQLAIIGDK(6- 100 Tb-anti- xL FAM)1NR-amide) GST The s are then mixed on a shaker for 1 minute then incubated for an additional 2 hours at room temperature. For each assay plate, a probe/antibody and protein/antibody/probe mixture were included as a negative and a positive control, respectively. Fluorescence was measured on the Envision (Perkin Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak) and 495/510 nm (Tb-labeled anti-his antibody) emission filters. iation constants (K) were determined using Wang's equation (Wang, Z.X. An exact mathematical expression for describing competitive binding oftwo difi’erent s to a protein molecule. FEBS Lett. 1995 360:111-114). The TR-FRET assay can be performed in the presence of varying concentrations of human serum (HS) or fetal bovine serum (FB S).

TR-FRET assay results (K in lar) for representative compounds of a (I) set forth in Table 2 are provided below in Table 2.

For comparison, the measurement of the competition of compounds of Formula (I) for other Bcl-2 family n binding sites (e.g., Bcl-2) using the TR-FRET binding assay was accomplished by substituting GST-Bcl-xL in the TR-FRET assay with other beled protein, e.g., GST-Bcl-Z, prepared in-house. —100— ation] sak In one embodiment, compounds of Formula (I) selectively inhibit the Bcl-2 family protein, Bcl-xL, over other Bcl-2 family proteins, such as Bcl-2. For ison, data (K in micromolar) from the measurement of the competition by certain compounds of Formula (I) (i.e., Examples 3, 23, 45, 52 and 59 in Table 3) with F-Bak for the Bcl-2 binding site using the TR-FRET binding assay are 0.007, 0.016, 0.010, 0.104, and 0.007 respectively.

FL5.12 Cellular Assay The efficacy of compounds of Formula (I) can also be determined in cell-based killing assays using a variety of cell lines and mouse tumor models. For example, their ty on cell viability can be assessed on a panel of ed tumorigenic and non- tumorigenic cell lines, as well as primary mouse or human cell tions. In one exemplary set of conditions, mouse FL5.12 cells transfected with Bcl-xL were cultured under standard conditions in RPMI with 2 mM glutamine, 1% 100 mM sodium pyruvate, 2% 1 M HEPES, 4 uL/L of B-mercaptoethanol, 1% penicillin—streptomycin, 10% FE S, and 10% WEHI-3B conditioned media (for IL-3). For assaying the compound activity, the cells were exchanged into an ILdepleted deprivation media, which was identical to the growth media except for the absence of FBS and WEHI-3B conditional media, for 2 days. Then the cells were exchanged to 3% FBS assay media (RPMI with 2 mM glutamine, 1% 100 mM sodium pyruvate, 2% 1 M HEPES, 4 uL/L of aptoethanol, 1% penicillin—streptomycin, 3% FB S). Compounds in series dilutions were added, and the cells were cultured for 24 hours.

Compounds in series dilutions were added, and the cells were cultured for 24 hurs. Cell viability was assayed using the the CellTiter-Glo assay (Promega Corp., Madison, WI) according to the manufacturer ctions. Individual determinations were the result of duplicate values. Cell viability assay results (EC50 in nanomolar) for representative Examples are provided below in Table 2.

Table 2. In Vitro Data TR-FRET binding FL5.12 Bcl-xL, T binding FL5.12 Bcl-xL, Bcl-xL Ki (nM) -IL3, EC50 (nM) Bcl-xL Ki (nM) -IL3, EC50 (nM) —101— ation] sak 6 — 7 5 3 11 4 14 - 12 16 0.3 0.8 21 3 22 - 23 1 —102— ation] sak IH 36 3 37 .0 \o 38 H 39 P 40 d. 9.. 41 P9 44 <0.1 0.3 n.d. = no data available Molt-4 Cellular Assay Molt-4 (ATCC, Manassas, VA) human acute lymphoblastic leukemia cells were plated 50,000 cells per well in 96-well tissue culture plates in a total volume of 100 ML tissue culture medium supplemented With 10% human serum (Invitrogen, Carlsbad, CA) and treated With a 3-fold serial dilution of the compounds of interest from 5 MM to 0.020 ML. Each —103— [Annotation] sak concentration was tested in duplicate at least 3 separate times. The number of viable cells following 48 hours of compound treatment was determined using the CellTiter 96® Aqueous non-radioactive cell proliferation MTS assay according to manufacturer's recommendations (Promega Corp., Madison, WI). Molt-4 cell ity results (i. e. EC50 in micromolar) for certain compounds ula (I), i.e., Examples 1, 3, 10, 18, 23, 28, 45, 52, 59, and 72 in Table 2, are 0.201, 0.006, 0.487, 0.024, 0.016, 0.526, 0.004, 0.029, 0.024, and 0.035 respectively.

Single Dose Pharmacokz’netz’cs The single dose cokinetics of select compounds were evaluated in Sprague—Dawley rats (Charles River) after a 5 mg/kg oral dose (n = 3) (10% DMSO in PEG- 400) stered by gavage or by 5 mg/kg IV bolus dose (n = 3) (10% DMSO in PEG-400).

Compound and the al standard were separated from each other and coextracted contaminants on a 50 mm X 3 mm Keystone Betasil CN 5 um column with an acetonitrile/0.1% trifluoroacetic acid mobile phase (50:50, by volume) at a flow rate of 0.7 mL/min. is was performed on a Sciex API3 000 biomolecular mass analyzer with a heated nebulizer interface. Compound and internal standard peak areas were determined using Sciex MacQuan software. The plasma drug concentration of each sample was calculated by least-squares linear regression analysis (nonweighted) of the peak area ratio (parent/intemal standard) of the spiked plasma standards versus concentration. The plasma concentration data were submitted to multiexponential curve fitting using WinNonlin.3. The area under the plasma concentration—time curve was ated using the linear trapezoidal rule for the plasma concentration—time profiles.

In pharmacology, bioavailability (BA) is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By ion, when a medication is administered intravenously, its ilability is 100 % in, J.P. The Textbook of Pharmaceutical Medicine (6th Ed.) New Jersey: BMJ Books). However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) and may vary from t to patient. Bioavailability is one of the essential tools in cokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

One way to calculate bioavailability of a drug or agent is by dividing the plasma concentration following an oral dose by the concentration following an intravenous dose. The oral bioavailability (as represented by % F) in Sprague-Dawley rats for representative compounds of the invention are provided below in Table 3.

In the drug discovery setting, it is generally accepted that Lipinski’s “rule of 5” predicts that poor oral absorption or poor permeation for a drug is likely when two or more of —104— [Annotation] sak the following metrics are satisfied: i) there are more than 5 hydrogen bond donors, ii) the molecular weight is greater than 500, iii) there are greater than 10 hydrogen bond acceptors (expressed as the sum of nitrogen and oxygen atoms), or iv) the calculated Log P (cLogP) is greater than 5 (Lipinski et al. Adv. Drug Del. Rev. 2001, 3-26). Indeed, the combination of high molecular weight (>5 00) and high cLogP (>5) is the best predictor of poor absorption or permeation. nds of the invention lly exceed the recommended ranges pertaining to molecular weight (>500) and cLogP (>5). It is notable, therefore, that compounds of Formula (I) have acceptable oral bioavailability in rats (as defined by % F >1 0, see Martin J. Med. Chem. 2005, 48, 3164.), as illustrated in Table 3.

Table 3. PK Data, Rat p.o. Dose Molecular E cLogP F (%), dose weight g/mol.

Data in Table 2 and cited Molt-4 data show the utility of compounds of the invention to functionally inhibit anti-apoptotic Bcl-xL protein in a cellular t. The ability of compounds to kill FL5. 12 cells over-expressing Bcl-xL or human tumor cell lines that are dependant upon Bcl-xL such as Molt-4 cells is a direct measure of the nd’s ability to inhibit anti-apoptotic Bcl-xL protein function. Compounds of the invention are very ive in killing FL5.12 cells xpressing Bcl-xL or human tumor cell lines that are dependant upon Bcl-xL such as Molt-4 cells as demonstrated by low EC50 values. In addition, as —105— [Annotation] sak demonstrated in Table 3, compounds of the invention have good oral bioavailability in preclinical rodent studies, and therefore may find utility as orally-dosed therapeutics in a clinical setting.

Overexpression of Bcl-XL proteins ates With resistance to chemotherapy, clinical outcome, disease progression, l prognosis or a combination thereof in various s and disorders of the immune . Cancers include, but are not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t- cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer ding estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's ma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, ctal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, geal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, f1brosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophobalstic disease, astoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non- small cell lung cancer), lymphangioendothelio-sarcoma, ngiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin’s ma and non-Hodgkin’s lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, as, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary oma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, rcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian , pancreatic cancer, papillary arcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, us cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer ding germ cell testicular cancer), thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, e cancer, Wilms’ tumor and the like. —106— ation] sak It is also ed that compounds having a (I) would inhibit growth of cells expressing Bcl-xL proteins derived from a pediatric cancer or neoplasm including embryonal myosarcoma, pediatric acute lymphoblastic ia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic moma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing’s family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm’s tumor, pediatric favorable histology Wilm’s tumor, pediatric glioblastoma, pediatric medulloblastoma, ric lastoma, ric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell s (such as leukemia), ric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic , inflammatory diseases, and thrombocytopenia, acute or chronic immune disease associated with organ transplantation, Addison's disease, allergic diseases, ia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, le c arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), mune bullous disease, abetalipoprotemia, acquired immunodeficiency-related diseases, acute immune disease associated With organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, adult (acute) respiratory distress me, AIDS dementia complex, alcoholic cirrhosis, alcohol- d liver injury, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-l- antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis associated lung disease, anterior horn cell degeneration, antibody ed cytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivity ons, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, atrophic autoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmune hepatitis, type-l autoimmune hepatitis (classical autoimmune or lupoid hepatitis), autoimmune mediated hypoglycaemia, mune neutropaenia, autoimmune thrombocytopaenia, autoimmune d disease, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bronchiolitis obliterans, bundle branch block, burns, cachexia, c arrhythmias, cardiac stun syndrome, —107— [Annotation] sak cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, llar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chlamydia, choleosatatis, chronic lism, chronic active hepatitis, chronic fatigue syndrome, chronic immune disease associated With organ transplantation, chronic eosinophilic pneumonia, chronic atory ogies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary e , c late intoxication, common varied immunodeficiency (common variable hypogammaglobulinaemia), conjunctivitis, connective tissue disease associated interstitial lung disease, contact itis, Coombs positive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune tis, cryptogenic fibrosing alveolitis, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Crohn's disease, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, itis, scleroderma, dermatologic conditions, dermatomyositis/polymyositis associated lung disease, diabetes, diabetic osclerotic disease, diabetes mellitus, Diffuse Lewy body disease, dilated cardiomyopathy, d congestive cardiomyopathy, discoid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, Down's Syndrome in middle age, nduced interstitial lung disease, nduced hepatitis, drug-induced movement disorders induced by drugs which block CNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic histiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, female infertility, fibrosis, fibrotic lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis, glomerular nephritis, glomerulonephritides, Goodpasture's syndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty tis, graft rejection of any organ or , graft versus host disease, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, group B streptococci (GB S) infection, Grave's disease, iderosis associated lung disease, hairy cell leukemia, hairy cell leukemia, Hallerrorden-Spatz e, Hashimoto's thyroiditis, hay fever, heart transplant ion, hemachromatosis, poietic malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, Henoch- Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's chorea, hyperkinetic movement disorders, ensitivity reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic leucopaenia, thic pulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver disease, ile spinal muscular atrophy, infectious —108— [Annotation] sak diseases, inflammation of the aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile ious anaemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplant ion, legionella, aniasis, leprosy, lesions of the ospinal system, linear IgA disease, lipidema, liver transplant rejection, Lyme disease, lymphederma, lymphocytic rative lung disease, malaria, male infertility idiopathic or NOS, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, mixed connective tissue disease associated lung disease, monoclonal gammopathy, multiple myeloma, le systems degenerations (Mencel Dej erine-Thomas Shi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease, myasthenia gravis, microscopic vasculitis of the kidneys, mycobacterium aVium intracellulare, mycobacterium ulosis, myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I ar atrophies, neutropenic fever, Non-alcoholic Steatohepatitis, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, organ transplant rejection, is/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian failure, pancreas transplant rejection, parasitic diseases, parathyroid transplant rejection, son's disease, pelvic inflammatory disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, perennial rhinitis, pericardial e, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis carinii nia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin s syndrome), post perfusion me, post pump syndrome, post-MI cardiotomy syndrome, postinfectious interstitial lung disease, premature n failure, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sing cholangitis, primary itis, Progressive supranucleo Palsy, psoriasis, sis type 1, psoriasis type 2, psoriatic arthropathy, pulmonary hypertension secondary to connective tissue disease, pulmonary manifestation of polyarteritis nodosa, post-inflammatory interstitial lung disease, ion fibrosis, radiation therapy, d's phenomenon and disease, d's disease, 's disease, regular narrow QRS tachycardia, Reiter's disease, renal e NOS, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, toid arthritis associated interstitial lung disease, rheumatoid spondylitis, dosis, Schmidt's syndrome, scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell , Sjogren's disease associated lung disease, Sjorgren's —109— [Annotation] sak syndrome, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar degenerations, spondyloarthopathy, ic, polyglandular deficiency type I, sporadic polyglandular deficiency type II, Still's disease, streptococcal myositis, stroke, structural s of the cerebellum, Subacute sclerosing panencephalitis, sympathetic ophthalmia, Syncope, syphilis of the cardiovascular system, ic anaphylaxis, systemic atory response syndrome, systemic onset juvenile rheumatoid arthritis, ic lupus matosus, systemic lupus erythematosus-associated lung disease, systemic sclerosis, systemic sclerosis-associated titial lung disease, T-cell or FAB ALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Type mediated diseases, thromboangitis obliterans, ocytopenia, ditis, toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), type B insulin ance With acanthosis nigricans, type III hypersensitivity reactions, type IV hypersensitivity, ulcerative colitic arthropathy, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins, vasculitis, vasculitic diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, Vitiligo acute liver disease, viral and fungal infections, Vital encephalitis/aseptic meningitis, Vital- associated hemaphagocytic syndrome, Wegener‘s granulomatosis, Wemicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, yersinia and ella-associated arthropathy and the like.

Schemes and Experimentals The following abbreviations have the meanings ted. ADDP means l,l'-(azodicarbonyl)dipiperidine; AD-mix-B means a mixture of (DHQD)2PHAL, K3Fe(CN)6, K2C03, and K2804; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means azabicyclo[5.4.0]undecene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means l,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means l,4-bis(diphenylphosphino)-butane; dppe means 1,2- bis(diphenylphosphino)ethane; dppf means l,l'-bis(diphenylphosphino)ferrocene; dppm means l,l-bis(diphenylphosphino)methane; EDAC-HCl means l-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means O-(7-azabenzotriazol-l -yl)-N,N'N'N'-tetramethyluronium hexafiuorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl l; MP-BH3 means macroporous triethylammonium polystyrene cyanoborohydride; TEA means ylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means —110— [Annotation] sak N—chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine.

The following schemes are ted to provide what is believed to be the most useful and readily understood description of ures and conceptual aspects of this invention. Compounds of this invention may be made by synthetic al ses, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be ted and deprotected, as necessary.

Schemes Scheme 1 (Rum (R2)n (R1)m (R2)n | /j \/ NH2 | fi \ NYC + )'( —> \ NY0 —> O 0 <2 0 WV (2) HI 0 H (1) X (3) J( X3 N z1 \ (R1)m (R2) ( R1 ) 2 :[//I I n m / \/ 5R )n \ j Br /j I (R )p I (5) \ N N Z’I \ NH T \ —» H'?‘ O Br HN o (R3)p// )I( (4) X (6) (R1)m (R2)n \/ I | W N N Z 1 \ As shown in Scheme 1, compounds of formula (1), wherein R1, R2, n, and m are as described herein, can be reacted with compounds of formula (2) wherein X is as described herein, in the presence of a carboxyl activating agent such as but not limited to N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, and a catalyst such but not limited to 4-dimethylaminopyridine, to provide compounds of formula (3). The reaction is typically performed at room temperature in a solvent such as but not limited to dichloromethane. Compounds of formula (4) can be prepared by reacting nds of a (3) with an acid such as but not limited to hydrochloric acid in a solvent such as but —111— [Annotation] sak not limited to 1,4-dioxane. Compounds of formula (4) can be reacted with compounds of formula (5), wherein Z, R3 and p are as described herein and X3 is chloro or fluoro, in the presence of a base such as but not limited to cesium carbonate, to provide nds of formula (6). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to N,N-dimethylacetamide. Compounds of formula (7) can be prepared by reacting compounds of a (6) with 5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran, in the presence of a base such as but not limited to triethylamine, and a catalyst such as but not limited to [l ,l '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane. The reaction is typically performed at elevated temperature and with the addition of a solvent such as but not limited to acetonitrile. Additionally, the on may be med in a microwave reactor.

Scheme2 ( R1 )m 5‘R2)” y Ho’B‘Y1—L1—Y2 (R2)n I l \ N N Z1 (8) \ or (R1)m\\/I HN o E/ Br | (R )p M~ HN Nl/N:[ZY1— L1—Y2 X Y1—L1—Y2 I (R)p3) (6) x (88) (R1)m\ (R2)n 1—Y21 (R1)m “r1: 0 —. \\/I (1)"R2 O / (R3)p NI1::[21 my (R3)p/ Y1—L1—Y2 After preparation as bed in Scheme 1, compounds of formula (6) can be reacted with a boronic acid (or the boronate equivalent) of formula (8) or an organotin or zinc halide compound of a (8a) wherein Y1, L1, and Y2 are as described herein, and M is tributyltin or a zince halide, under Suzuki, Stille, or Negishi coupling conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (1). Alternatively, compounds of formula (7), which can be ed from compounds of formula (6) as described in Scheme 1, can be reacted with compounds of formula (9) n X1 is a triflate or halide, and Y1, L1, and Y2 are as described herein, under Suzuki coupling conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (I). —112— [Annotation] sak RX1 \LLYZ RX1 Rx2_x2 i \\,N (11) | \N (13) ' [<N\ NH NI W “.1 ’ (10) (12) LLYz (15W RXZ NL1~ (15) (R )ngQn1 (Rm/\EE4 %o Ra (6) (17) L~Y2 | \,N x2 N 1.1- 2 As shown in Scheme 3, pyrazoles of formula (10), wherein RXI is hydrogen or a substituent on Y1 as described , can be d with alcohols of formula (1 1), wherein L1 and Y2 are as described herein, and cyanomethylenetributylphosphorane, to e compounds of formula (12). The reaction is typically performed at ambient temperature in a solvent such as but not limited to toluene. Compounds of formula (14) can be prepared by adding compounds of formula (13) wherein R"2 is an appropriate substituent as described herein for substituents on Y1, and X2 is a halide, to a cold solution of compounds of formula (12) treated with n-butyllithium in hexanes. The reaction is typically performed in a solvent such as but not limited to tetrahydrofuran. Compounds of formula (14) can be treated with N- bromosuccinimide or N-iodosuccinimide to provide compounds of formula (15), wherein X4 is bromo or iodo. The reaction is typically performed in a t such as N,N- dimethylformamide. Compounds of a (15) can be d with compounds of formula (7) under Suzuki coupling conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (17), which are representative of compounds of formula (1). Alternatively, compounds of formula (15) can be reacted with propyl borate, in the presence of n-butyllithium in hexanes, followed by pinacol to provide compounds of formula (18). The additions are typically performed at low temperature in a solvent such as but not limited to tetrahydrofuran, toluene, or mixtures thereof. atively, compounds of the a (15) can be d with 4,4,5,5-tetramethyl-l,3,2-dioxaborolane in the presence of a palladium st system such as but not limited to —113— ation] sak bis(acetonitrile)palladium dichloride and SPhos in a solvent such as but not limited to 1,4- dioxane to provide compounds of the formula 18. The reaction is typically performed at elevated temperature. Compounds of formula (18) can be reacted with compounds of formula (6) under Suzuki coupling conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (17), which are representative of compounds of formula (1).

Scheme 4 OL Y1_ 2 RX1 Br 0 \\ R)G I | \ |\ Rx3 Rx3 o—B Rx2 N‘ I RX3 LLYZ 1 (23) (25) L1~v2 es of formula (21) wherein R“, R”, and RX3 are hydrogen or are as described herein for substituents on Y1, can be reacted with alcohols of formula (11), wherein Y2 and L1 are as described herein, and cyanomethylenetributylphosphorane, to provide compounds of formula (22). The reaction is typically performed at ambient temperature in a solvent such as but not limited to toluene. Compounds of formula (22) can be treated with N- bromosuccinimide to provide compounds of formula (23). The reaction is typically performed in a solvent such as methylformamide. Compounds of formula (23) can be reacted with propyl borate, in the presence of n-butyllithium in hexanes, followed by pinacol to provide compounds of formula (24). The additions are typically performed at low temperature in a solvent such as but not limited to tetrahydrofuran, e, or mixtures f. Alternatively, nds of the a (23) can be treated with 4,4,5,5- tetramethyl-l ,3,2-dioxaborolane in the presence of a ium catalyst system such as but not limited to etonitrile)palladium dichloride and SPhos in a solvent such as but not limited to 1,4-dioxane to provide compounds of the formula (24). The reaction is typically performed at an elevated temperature. Compounds of formula (24) can be reacted with compounds of formula (6) under Suzuki coupling conditions known to those skilled in the art and readily available in the ture to provide nds of formula (25), which are representative of —114— [Annotation] sak compounds of formula (1). Alternatively, compounds of formula (23) can be reacted with compounds of a (7) under Suzuki coupling ions known to those skilled in the art and readily ble in the literature to provide compounds of formula (25), which are representative of compounds of formula (1).

Scheme 5 OH Y1 002Rx4 X2 002RX4 Yl-H R X1 RX2 RX2 RX2 z ) (23A) 2 ) z ) (24A) 2 ) L/ n _’ L n _’ n _> n / L/ L/ Rx1 Rx1 Rx1 Rx1 (23B) (24B) (25A) (22A) Compounds of formula (22A), wherein Z is O, a substituted or unsubstituted N, or a substituted or unsubstituted C; RXI is hydrogen or is as described herein for substituents on Y2; RX4 is alkyl; and n is 0, l, or 2; can be added to a cooled solution of lithium diisopropylamide, followed by the addition of compounds of formula (23A); wherein R"2 is an appropriate substituent as described herein for substituents on Y1, and X1 is a halide; to provide compounds of formula (23B). The reaction is lly performed at low temperature before warming to ambient temperature in a solvent such as but not limited to tetrahydrofuran. Compounds of formula (23B) can be reacted with LiAlH4 to provide compounds of formula (24B). The reaction is typically performed at an elevated temperature in a solvent such as but not limited to diethyl ether. Compounds of formula (25A) can be ed by reacting compounds of formula (24B) with compounds of formula (24A) wherein Y1 is as described herein; and ethylenetributylphosphorane. The reaction is typically med at ambient temperature in a solvent such as but not limited to e. nds of formula (25A) can be processed in a manner similar to compounds of formula (12) in Scheme 3 and compounds of formula (22) in Scheme 4 to provide compounds of formula (1).

Scheme 6 Y1 Y1 O Y1'H o OH RXZ-X2 o—Rx2 )n—>RX1_ )n —>(24A) RX1_ )n —>(13) RX1_ )n RX1_ (26) (27) (28) (29) As shown in Scheme 6, compounds of formula (27), wherein RXI is hydrogen or a substituent on Y1 as described herein, can be prepared by reacting nds of formula (26) with hylsulfonium iodide, in the ce of potassium tert-butoxide. The reaction is lly performed at ambient temperature in an anhydrous solvent such as but not limited to dimethylsulfoxide. Compounds of formula (27) can be added to a mixture of compounds of formula (24A) and a base such as but not limited to cesium carbonate, to provide compounds of formula (28). The reaction is typically performed at ed temperature in a solvent such —115— [Annotation] sak as but not limited to N,N-dimethylformamide, and may be performed in a microwave r.

Compounds of formula (28) can be d with sodium hydride, followed by the addition of compounds of formula (13) to provide compounds of formula (29). The reaction is typically performed at ambient temperature in a solvent such as but not limited to tetrahydrofuran, and may involve the use of hexamethylphosphoramide. Compounds of formula (29) can be processed in a manner similar to compounds of formula (12) in Scheme 3 and compounds of formula (22) in Scheme 4 to provide compounds of formula (1).

Scheme 7 (R1)m (R2)n E" “NH M_y1_|_1-y2 (R1)m (R2)n X3 N Z1 X3 N\ Z1 HN o / T): \ (33) )'( (4) | A Z 1 // —> \ Br 3//TI Yl-Ll-YZ —> ( R3 )p (R)p NTN\ (34) HN o IYl-Ll-YZ 3 // (32) )'( (R )p Compounds of formula (33) wherein M is a boronic acid, boronate, or tributlytin attached to Y1 and Y1, L1, and Y2 are as described herein, and X3 is chloro or fluoro; can be reacted with nds of formula (32) wherein 21, R3, and p are as described herein, under Suzuki or Stille ng conditions known to those skilled in the art and readily available in the literature to provide compounds of formula (34). Compounds of formula (34) can be reacted with compounds of formula (4), in the presence of a base such as but not limited to cesium carbonate, to provide compounds of formula (I). The reaction is typically performed at an elevated ature in a solvent such as but not limited to N,N-dimethylacetamide. —ll6— [Annotation] sak Scheme 8 SnBU3 U1 F N 21 RX2 / B”38" I (36A) N\\ (37) \ N, N3_1L-Y —»2 l ,N —> | \IN RXZ N‘ RXZ N\ (35) LLYz LL 2 (36) (38) Y (R1)m\/ (R2)n (39) N\L‘Y2 Triazoles of formula (3 6) can be prepared by reacting azides of formula (35), wherein L1 and Y2 are as described , with compounds of formula (3 6A) wherein RXZ is alkyl, under conditions known to those skilled in the art and readily available in the literature.

Compounds of formula (37), wherein Z1 is as described herein, can be reacted with compounds of formula (3 6) under Stille coupling ions known to those skilled in the art and readily available in the literature to provide compounds of formula (38). nds of a (4), wherein R1, R2, X, m and n are as described herein, can be d with compounds of a (3 8), in the presence of a base such as but not limited to cesium carbonate, to provide compounds of formula (39), which are representative of compounds of formula (I). The reaction is typically med at an elevated temperature in a solvent such as but not limited to N,N-dimethylacetamide.

Scheme 9 Br Z2 Br Y1-H RB-ZZH (30) (32) —> —> Br Y1 Y1 (31 ) (33) As shown in Scheme 9, 1-bromo-3 omethyl)-adamantane can be reacted with compounds of formula (30), wherein Y1 is as described herein, in the presence of sodium hydride to provide compounds of formula (31). The addition is typically performed in a solvent such as but not limited to N,N-dimethylformamide at low temperature, prior to warming to an elevated temperature. Compounds of formula (31) can be reacted with —ll7— [Annotation] sak compounds of formula (32), optionally in the presence of silver sulfate, wherein R8 is as described herein and Z2 is O, NH, or NR8, to provide compounds of formula (33) which are representative of compounds of formula (9). The reaction is lly performed at elevated temperature and may involve an additional solvent. Additionally, the reaction may be med in a microwave reactor. nds of a (33) can be processed in a manner similar to compounds of a (12) in Scheme 3 and compounds of formula (22) in Scheme 4 to e compounds of formula (I).

The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The exemplified compounds were named using ACD/ChemSketch Version 5.06 (05 June 2001, Advanced try Development Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13 May 2009), Advanced try Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

Examples EXAMPLE 1 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3 - { 1 - [tricyclo[3.3. 1 .13’7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid EXAMPLE lA 4-(4,4,5,5 methyl-1,3,2-dioxaborolanyl)—1-(tricyclo[3.3.1.13’7]decylmethyl)-1H- A mixture of 1-(bromomethyl)adamantane (0.458 g) and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-lH-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0°C. To this on was added 60% sodium hydride (0.096 g). The solution was heated at 70°C overnight. The reaction mixture was partitioned n water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 1B tert-butyl 8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a solution of 2-(tert—butoxycarbonyl)—1,2,3,4-tetrahydroisoquinolinecarboxylic acid (6.8 g) and benzo[d]thiazolamine (5.52 g) in dichloromethane (80 mL) was added 1- ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4- dimethylaminopyridine (6 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (400 mL), washed with 5% aqueous HCl, —118— [Annotation] sak water, and brine, and dried over NaZSO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound.

EXAMPLE 1C N—(benzo[d]thiazol-2 -yl)- 1 ,2,3 ,4-tetrahydroisoquinolinecarboxamide dihydrochloride To a solution of EXAMPLE IE (8.5 g) in dichloromethane (80 mL) was added 2N HCl in ether (80 mL). The on mixture was stirred at room ature overnight and concentrated under reduced pressure to provide the title compound.

EXAMPLE 1D tert-butyl 3-bromochloropicolinate Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5 -bromo picolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0°C. The reaction was then d at room temperature for 12 hours. NaHCO3 (aqueous, saturated) was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over NaZSO4. Filration and evaporation of the organic solvent provided the title compound which was used in the next step without further purification.

EXAMPLE 1E tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)—yl) bromopicolinate EXAMPLE 1D (0.736 g), EXAMPLE 1C (1.62 g), and Cs2C03 (4.1 g) were stirred in 12 mL of anhydrous N,N-dimethylacetamide at 120°C for 12 hours. The cooled reaction mixture was then diluted with ethyl e and 10% citric acid. The organic phase was washed three times with citric acid, once with water and brine, and dried over NaZSO4.

Filtration and concentration afforded crude material, which was chromatographed on silica gel using 0-40% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 1F utyl tricyclo[3.3.l.13’7]decylmethyl]-lH-pyrazolyl}[8-(1,3-benzothiazol- 2-ylcarbamoyl)-3 ydroisoquinolin-2( 1 H)-yl]pyridinecarboxylate A mixture ofEXAMPLE 1E (0.100 g), EXAMPLE 1A (0.059 g), tetrakis(triphenylphosphine)palladium(0) (0.022 g) and CsF (0.090 g) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 120°C for 30 minutes under microwave g conditions ge Initiator). The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, d, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to afford the title compound.

EXAMPLE 1G —119— [Annotation] sak 6-[8-(1,3 thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3 - { 1 - [tricyclo[3.3. 1 .13’7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid EXAMPLE 1F (90 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 24 hours. The volatiles were removed under reduced pressure. The residue was purified by Prep HPLC using Gilson system eluting with 20-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-dG) 8 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.43 (s, 1H), 7.46-7.50 (m, 1H), 7.42-7.44 (m, 1H), 7.34- 7.38 (m, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.85-3.88 (m, 2H), 3.77 (s, 2H), 3.00 (t, 2H), 1.92 (m, 3H), 1.52-1.65 (m, 6H), 1.45-1.46 (m, 6H).

EXAMPLE 2 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl][3,5 -dimethyl (tricyclo[3.3.l.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 2A 3,5-dimethyl(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolanyl)—1-(tricyclo[3.3.l .13’7]dec ylmethyl)- 1H-pyrazole To a on of l-adamantanemethanol (0.090 g), methyl(4,4,5,5- ethyl-l,3,2-dioxaborolanyl)—1H-pyrazole (0.160 g) and cyanomethylenetributylphosphorane (0.215 g) were added and stirred together in toluene (2 mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica gel and eluted using a gradient of 2% to 20% ethyl acetate/hexanes to provide the title compound.

EXAMPLE 2B tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 —3- [3,5- yl(tricyclo[3.3 .1 .13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylate E 1E (0.150 g), EXAMPLE 2A (0.121 g), tetrakis(triphenylphosphine)palladium(0) (14 mg) and cesium carbonate (0.260 g) were stirred together in N,N-dimethylformamide (1 mL), dioxane (0.7 mL), and water (0.4 mL) and the reaction degassed with nitrogen and heated at 100°C for 1 hour. The reaction was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and trated. Silica gel chromatography eluting with a gradient of 2% to 50% ethyl acetate/hexanes provided the title compound.

E 2C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)—yl] [3 ,5 -dimethyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid —120— ation] sak To EXAMPLE 2B (0.070 g) in dichloromethane (1 mL) was added TFA (1 mL) and the reaction was stirred overnight. The reaction was concentrated, dissolved in dichloromethane and loaded onto silica gel and eluted using a gradient of 0.5% to 5% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 13.04 (s, 1H), 12.84 (s, 1H), 8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (t, 2H), 7.54 - 7.32 (m, 5H), 7.22 - 7.14 (m, 2H), 7.11 - 7.01 (m, 2H), 6.93 (d, 1H), 4.94 (s, 2H), 4.30 (t, 2H), 3.86 (t, 2H), 3.08 (t, 2H), 3.00 (t, 2H).

EXAMPLE 3 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl clo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 3A 1-(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazole The title compound was prepared by tuting pyrazole for methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 2A.

EXAMPLE 3B 1-(tricyclo[3.3.1.13’7]decylmethyl)methyl-1H-pyrazole A solution of EXAMPLE 3A (869 mg) in tetrahydrofuran (10 mL) was chilled to - 45°C. n-Butyllithium (2.3 M solution in hexanes, 2.10 mL) was added dropwise over 5 minutes. The reaction was stirred for 1.5 hours, during which time the temperature increased to -20°C. Iodomethane (0.305 mL) was added dropwise over 3 minutes. The on was stirred for 30 minutes n -20 and -15°C. Water (25 mL) was added and the mixture was ted with ethyl acetate (3 x 25 mL). The extracts were dried (NaZSO4), filtered, and concentrated to provide the title compound.

EXAMPLE 3C 1-(tricyclo [3 .3 .1 . 1 3’7]dec- 1 hyl)bromo-5 l-1H-pyrazole EXAMPLE 3B (865 mg) was dissolved in N,N-dimethylformamide (7 mL) and N- bromosuccinimide (334 mg) was added. The reaction was stirred at room temperature for 1 hour. Water (25 mL) was added and the product was obtained by ion.

EXAMPLE 3D 1-( tricyclo [3.3 .1 .13’7]decylmethyl)methyl(4,4,5,5-tetramethyl-1 ,3 ,2-dioxaborolan yl)-1H-pyrazole EXAMPLE 3C (250 mg) was placed into a flask, and was degassed with N2.

Tetrahydrofuran (2.5 mL) and toluene (2.500 mL) were added and the solution was chilled to -78°C. Triisopropyl borate (0.243 mL) was added, followed by dropwise addition of n- butyllithium (2.3 M in hexanes, 0.6 mL) over 5 minutes. The mixture was stirred for 15 minutes at -78°C and then a degassed solution of pinacol (143 mg) in tetrahydrofuran (1 mL) was added over 2 minutes. After stirring for 10 minutes at -78°C, the reaction was warmed to —121— ation] sak room temperature and stirred for 45 minutes. Water (0.073 mL) was then added and the mixture was stirred for 2 hours. The crude reaction mixture was concentrated to dryness to provide the title compound.

EXAMPLE 3E tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)—3 ,4-dihydroisoquinolin-2( 1 H)-yl)-3 -[1- (tricyclo [3 .3 . 1 . ec-1 -ylmethyl)-5 -methyl-1H-pyrazolyl]picolinate The title compound was prepared by substituting EXAMPLE 3D for EXAMPLE 2A in EXAMPLE 2B.

EXAMPLE 3F 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 3E for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, ylsulfoxide-d6) 8 ppm 12.84 (s, 1H), 12.74 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 - 7.53 (m, 3H), 7.31 - 7.39 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.70 (s, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.89 - 1.95 (m, 3H), 1.48 - 1.69 (m, 12H).

EXAMPLE 4 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)—yl][1-(spiro[3.5]non- 7-ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 4A 4-bromo(spiro [3 . 5 ylmethyl)— 1 H-pyrazole The title compound was prepared by substituting 4-bromo-1H-pyrazole for 3,5-dimethyl (4,4,5 ,5 -tetramethyl-1,3 ,2 -dioxaborolanyl)-1H-pyrazole and 7-hydroxymethyl-spiro [3 .5]nonane for 1-adamantanemethanol in E 2A.

EXAMPLE 4B tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3 -(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)picolinate A mixture of E 1E (1.2 g), 1.0 M 5-tetramethyl-1,3,2-dioxaborolane in ydrofuran (4.24 mL), triethylamine (0.92 mL), and [1,1'— bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.087 g) in CH3CN (15 mL) was heated at 100‘rC under microwave conditions (Biotage) for 30 minutes. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The e was purified by flash column chromatography on silica gel to provide the title compound. —122— [Annotation] sak EXAMPLE 4C tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)—3 ,4-dihydroisoquinolin-2( l H)-yl)( l - (spiro[3.5]nonanylmethyl)-lH-pyrazolyl)picolinate A suspension ofEXAMPLE 4B (50 mg), EXAMPLE 4A (23.12 mg), tris(dibenzylideneacetone)dipalladium(0) (7 mg), l,3,5,7-tetramethylphenyl-2,4,8-trioxa phosphaadamantane (12 mg) and potassium phosphate (52.0 mg) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was heated under microwave conditions (Biotage) at 140°C for 5 minutes.

The reaction mixture was d with ethyl acetate, separated, and d by chromatography on silica gel using 10-60% ethyl acetate/hexanes as eluent to provide the title compound.

EXAMPLE 4D 6- [8-(l ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl] [ l -(spiro[3.5 ]non- 7-ylmethyl)- l H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 4C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 5 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.74 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.52 (s, 1H), 7.45 - 7.51 (m, 1H), 7.40 - 7.44 (m, 1H), 7.36 (t, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.83 - 3.93 (m, 3H), 3.00 (t, 2H), 1.73 - 1.85 (m, 2H), 1.55 - 1.75 (m, 8H), 1.35 (d, 2H), 1.09 - 1.23 (m, 2H), 0.88 - 1.04 (m, 2H).

EXAMPLE 5 6-[8-(l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl] -3 -(l - { [3 ,5 - dimethyltricyclo [3 .3 - l H-pyrazolyl)pyridinecarboxylic acid . l . 13’7]dec- l -yl]methyl} EXAMPLE 5A 4-bromo-l - { [3 ethyltricyclo[3.3.l.13’7]dec-l-yl]methyl}-lH—pyrazole The title compound was ed by substituting 4-bromo-lH-pyrazole for 3,5- dimethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole and methyl-l- adamantanemethanol for l-adamantanemethanol in EXAMPLE 2A.

EXAMPLE 5B tert-butyl l ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]( l - {[3,5 -dimethyltricyclo[3.3.l.13’7]dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylate The title compound was prepared by substituting E 5A for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 5C 6-[8-(l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl] -3 -(l - { [3 ,5 - yltricyclo [3 .3 - l H-pyrazolyl)pyridinecarboxylic acid . l . 13’7]dec- l -yl]methyl} —123— [Annotation] sak The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 5 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.44 - 7.51 (m, 1H), 7.40 - 7.45 (m, 1H), 7.36 (t, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.87 (t, 2H), 3.80 (s, 2H), 3.00 (t, 2H), 1.96 - 2.05 (m, 1H), 1.26 (d, 6H), 0.96 - 1.17 (m, 6H), 0.77 (s, 6H).

EXAMPLE 6 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - hydroxytricyclo[3.3.1.13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 6A 3-[(4-bromo-1H—pyrazolyl)methyl]tricyclo[3.3.1.13’7]decan-l-ol The title nd was prepared by substituting 4-bromo-1H-pyrazole for 3,5- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and 3-hydroxy tanemethanol for 1-adamantylmethanol in EXAMPLE 2A.

EXAMPLE 6B tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - hydroxytricyclo[3.3. 1 ecyl]methyl}-1H-pyrazolyl)pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 6C 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - hydroxytricyclo[3.3.1.13’7decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid The title nd was prepared by substituting EXAMPLE 6B for EXAMPLE 2B in E 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 5 ppm 13.06 (s, 1H), 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.68 (s, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.44 - 7.51 (m, 1H), 7.40 - 7.44 (m, 1H), 7.35 (t, 2H), 6.93 (d, 1H), 4.94 (s, 2H), 4.35 (s, 1H), 3.87 (t, 2H), 3.82 (s, 2H), 3.00 (t, 2H), 2.08 (s, 2H), 1.36 - 1.56 (m, 6H), 1.33 (s, 6H). 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - methoxytricyclo[3.3. 1 .13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 7A l-[(3 -bromotricyclo[3 .3. l . 13’7] decyl)methyl]iodo- 1H-pyrazole A mixture of 1-bromo(bromomethyl)-adamantane (1.0 g) and 4-iodopyrazole (0.63 g) in N,N-dimethylformamide (10 mL) was cooled to 0 0C. To this solution was added 60% sodium hydride (0.20 g). The solution was stirred at 65°C overnight. The reaction e was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed three times with —124— [Annotation] sak water, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel g with 10% ethyl acetate in s to provide the title compound.

EXAMPLE 7B 4-iodo[(3-methoxytricyclo[3.3.1.13’7]decyl)methyl]-1H-pyrazole EXAMPLE 7A (5 g), silver sulfate (6 g) and methanol (15 mL) were heated at 110 0C under microwave conditions ge, Initiator) for 60 minutes. After cooling to room temperature, the suspension was filtered. The solid residue was washed by ethyl acetate (3x 5mL) and filtered. The combined solution was dried under vacuum. The residue was taken up into dichloromethane and purified by flash chromatography (Varian, Superflash 00 g column), eluting with 0-70% ethyl acetate/hexane, to provide the title compound.

EXAMPLE 7C tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - methoxytricyclo [3 .3. 1 .13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylate The title compound was prepared by substituting E 7B for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 7D 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - methoxytricyclo[3.3. 1 .13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 7C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, ylsulfoxide-d6) 8 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (m, 2H), 7.61 (d, 1H), 7.54 (s, 1H), 7.41 (m, 4H), 6.94 (d, 1H), 4.94 (s, 2H), 3.87 (m, 4H), 3.07 (s, 3H), 3.00 (t, 2H), 2.14 (m, 2H), 1.46 (m, 12H).

EXAMPLE 8 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl] -3 -(1- {[3-(2- methoxyethoxy)tricyclo [3.3 .1 decyl]methyl}-1H—pyrazolyl)pyridinecarboxylic acid EXAMPLE 8A 4-iodo{[3-(2-methoxyethoxy)tricyclo[3.3.1.13’7]decyl]methyl}-1H—pyrazole The title compound was prepared by substituting 2-methoxyethanol for methanol in EXAMPLE 7B.

EXAMPLE 8B utyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - (2-methoxyethoxy)tricyclo[3.3. 1 .13’7]decyl]methyl }-1H-pyrazolyl)pyridine carboxylate The title nd was prepared by substituting EXAMPLE 8A for EXAMPLE 4A in EXAMPLE 4C. —125— [Annotation] sak EXAMPLE 8C 6- [8-( l zothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl] -3 -( l - { [3-(2- methoxyethoxy)tricyclo [3.3 .l .13’7]dec-l-yl]methyl}-lH—pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 8B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, ylsulfoxide-dé) 8 ppm 12.85 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.70 (m, 2H), 7.61 (d, 1H), 7.54 (s, 1H), 7.40 (m, 5H), 6.94 (d, 1H), 4.94 (s, 2H), 3.86 (m, 4H), 3.42 (m, 2H), 3.35 (m, 2H), 3.21 (s, 3H), 3.00 (t, 2H), 2.13 (m, 2H), 1.46 0n,12H) E 9 6- [8-(1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3 - { l -[(3 ,5,7- trimethyltricyclo [3 .3 . l . l 3’7]dec- l -yl)methyl]- l H-pyrazolyl}pyridinecarboxylic acid E 9A 3 ,5 -adamantanemethanol , 8-trimethyl-l To a solution of 3,5,8-trimethyl-l-adamantane carboxylic acid (0.5 g) in tetrahydrofuran (3 mL) was se added BH3.tetrahydrofuran (4.50 mL) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with methanol (3 mL), concentrated and purified by chromatography on silica gel using 0-30% ethyl acetate/hexanes as eluent to provide the title compound.

EXAMPLE 9B 4-iodo- l - { [3,5 ,7-trimethyltricyclo[3.3.l .13’7]dec-l-yl]methyl}-lH—pyrazole The title compound was prepared by substituting EXAMPLE 9A for l- adamantanemethanol and 4-iodopyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2 -yl)- l zole in EXAMPLE 2A.

EXAMPLE 9C tert-butyl 6- [8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 - { l - [(3,5,7-trimethyltricyclo [3.3 .l .13’7]dec-l-yl)methyl]-lH-pyrazolyl}picolinate The title compound was prepared by substituting EXAMPLE 9B for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 9D 6- [8-(1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3 - { l -[(3 ,5,7- trimethyltricyclo [3 .3 . l . l 3’7]dec- l -yl)methyl]- l H-pyrazolyl}pyridinecarboxylic acid The title compound was prepared by tuting EXAMPLE 9C for E 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.48 (t, 1H), 7.40 - —126— ation] sak 7.44 (m, 1H), 7.36 (t, 2H), 6.95 (d, 1H), 3.87 (t, 1H), 3.82 (s, 2H), 3.00 (t, 2H), 1.03 (s, 6H), 0.92 - 1.01 (m, 6H), 0.78 (s, 9H).

EXAMPLE 10 6-[8-(1,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][1- (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 10A 2-adamantanemethanol The title compound was prepared by substituting 2-adamantane carboxylic acid for 3,5,8-trimethyladamantane carboxylic acid in E 9A.

EXAMPLE 10B 1-(tricyclo[3.3.1.13’7]decylmethyl)iodo-1H-pyrazole The title compound was prepared by substituting E 10A for 1- adamantanemethanol and 4-iodopyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-pyrazole in EXAMPLE 2A.

EXAMPLE 10C utyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][1- clo [3 . 3 . 1 .13’7]decylmethyl)-1H-pyrazolyl]pyridine-2 -carboxylate The title compound was prepared by substituting E 10B for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 10D 6-[8-(1,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][1- (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 10C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.74 - 7.84 (m, 2H), 7.69 (d, 1H), 7.61 (d, 1H), 7.52 (s, 1H), 7.40 - 7.51 (m, 2H), 7.36 (t, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 4.21 (d, 2H), 3.86 (t, 2H), 3.17 (s, 2H), 3.00 (t, 2H), 2.13 - 2.24 (m, 1H), 1.98 (d, 2H), 1.44 - 1.89 (m, 12H), 1.07 (s, 1H).

EXAMPLE 11 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - bromotricyclo[3.3 .1 .13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 11A tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - bromotricyclo[3.3 .1 .13’7]decyl]methyl }-1H-pyrazolyl)pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 7A for EXAMPLE 4A in EXAMPLE 4C. —127— [Annotation] sak E 11B 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 -(l - { [3 - bromotricyclo[3.3. 1 .13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 11A for E 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (d, 2H), 7.61 (d, 1H), 7.56 (s, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 6.95 (d, 1H), 4.94 (s, 2H), 3.87 (m, 4H), 3.00 (t, 2H), 2.25 (m, 2H), 2.12 (m, 6H), 1.54 (m, 6H).

EXAMPLE 12 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]-3 -( l - ropan yloxy)tricyclo[3.3 .l .13’7]dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylic acid EXAMPLE 12A 4-iodo-l- {[3-(propanyloxy)tricyclo[3.3. l . 13’7]dec-l-yl]methyl}-lH—pyrazole The title compound was prepared by substituting propanol for methanol in EXAMPLE 7B.

EXAMPLE 12B tert-butyl 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl] -3 -(l - { [3 - (propanyloxy)tricyclo[3.3.1.13’7]dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylate The title compound was ed by substituting EXAMPLE 12A for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 12C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]-3 -( l - {[3-(propan yloxy)tricyclo[3.3 .l .13’7]dec-l-yl]methyl}-lH-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by tuting EXAMPLE 12B for E 2B in E 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.70 (m, 2H), 7.61 (d, 1H), 7.53 (s, 1H), 7.41 (m, 4H), 6.94 (d, 2H), 4.94 (s, 2H), 3.86 (m, 4H), 3.00 (t, 2H), 2.11 (m, 2H), 1.62 (m, 2H), 1.49 (m, 3H), 1.37 (m, 7H), 0.98 (d, 6H).

EXAMPLE 13 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] [ l -(2- oxatricyclo[3.3.l.13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid EXAMPLE 13A 2-oxatricyclo[3.3.1.13’7]decylmethanol To a solution of (oxatricyclo[3.3.1.13’7]decyl)carboxylic acid (0.32 g) in diethyl ether (5 mL) was added lithium aluminum hydride (1.0M in tetrahydrofuran, 2.1 mL) at 0°C.

The reaction was allowed to warm to room temperature and was stirred for 2 hours. The reaction was cooled to 0°C and quenched with water (0.24 mL). 15% Aqueous NaOH (0.24 —128— [Annotation] sak mL) was added followed by more water (0.72 mL). The reaction was stirred for 1 hour, and magnesium sulfate was added. The mixture was filtered and concentrated to provide the title compound.

EXAMPLE 13B l-(2-oxatricyclo [3 .3 . l . 13’7]dec-l -ylmethyl)(4,4,5,5 -tetramethyl- l ,3,2-dioxaborolanyl)- azole The title compound was prepared by substituting EXAMPLE 13A for 1- adamantanemethanol and ,5,5-tetramethyl- l ioxaborolan-2 -yl)- l H-pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole in EXAMPLE 2A.

EXAMPLE 13C tert-butyl 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] [l -(2- oxatricyclo[3 .3 . l . 13’7]dec-l -ylmethyl)- l H-pyrazolyl]pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 13B for EXAMPLE 2A in EXAMPLE 2B.

EXAMPLE 13D 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] [ l -(2- oxatricyclo[3.3.l.13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid The title nd was prepared by substituting EXAMPLE 13C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.72 (t, 2H), 7.61 (d, 1H), 7.52 (s, 1H), 7.42 (m, 4H), 6.94 (d, 1H), 4.94 (s, 2H), 3.99 (s, 1H), 3.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.07 (s, 2H), 1.74 (m, 4H), 1.55 (m, 6H).

EXAMPLE l4 1,3-benzothiazolylcarbamoyl)-4,4-dimethyl-3 ,4-dihydroisoquinolin-2(lH)-yl] [5- methyl-l -(tricyclo[3 .3. l .13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid EXAMPLE 14A methyl 2 -(5 -bromo(tert-butoxycarbonyl)pyridinyl)-4,4-dimethyl-1,2 ,3 ,4- tetrahydroisoquinolinecarboxylate Methyl 4,4-dimethyl-l ,2,3,4-tetrahydroisoquinolinecarboxylate (500 mg), EXAMPLE ID (572 mg), and triethylamine (0.545 mL) in anhydrous ylsulfoxide (6.5 mL) was heated to 100°C oyemight, and the mixture was then cooled to room temperature.

The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2x 15 mL). The combined organics were dried with ous sodium sulfate, d and concentrated under d pressure. The residue was purified by chromatography on silica gel with 0-40% ethyl acetate/hexanes to provide the title product. —129— [Annotation] sak EXAMPLE 14B 2-(5-bromo(tert-butoxycarbonyl)pyridinyl)-4,4-dimethyl- l ,2 ,3 ,4- tetrahydroisoquinolinecarboxylic acid To an ambient solution of EXAMPLE 14A (245 mg) in tetrahydrofuran (2.1 mL) was added a on of LiOH (30.9 mg) in water (0.52 mL). The reaction was stirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, and acidified to pH ~3 with 10% aqueous HCl solution. The layers were separated, and the s layer was extracted with additional ethyl acetate (2 x 8 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title nd.

EXAMPLE 14C tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin- 2( l -3 -bromopicolinate An ambient solution of EXAMPLE 14B (182 mg), benzo[d]thiazolamine (71.1 mg), l-ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (113 mg), l-hydroxybenzotriazole hydrate (91 mg), and N-methylmorpholine (0.065 mL) was stirred overnight. An additional 1 equivalent each of l-ethyl[3-(dimethylamino)propyl]- carbodiimide hydrochloride, N-methylmorpholine, l-hydroxybenzotriazole e, and 2- aminobenzothiazole were added, and the reaction was heated to 40 0C for 4 hours. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous bicarbonate solution and ethyl e. The layers were separated, and the s was extracted with additional 2x ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under d pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title product.

EXAMPLE 14D tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin- 2( l H)—yl)—3- [5 -methyl-l yclo[3 .3. l . l 3’7]dec- l -ylmethyl)- l H-pyrazolyl]picolinate A mixture ofEXAMPLE 14C (70 mg), EXAMPLE 3D (63 mg), K3PO4 (87 mg), Pd2(dba)3 (2.7 mg), and l,3,5,7-tetramethyltetradecyl-2,4,8-trioxaphosphaadamantane (4.9 mg) in a on vial equipped with a magnetic stir bar was degassed with nitrogen. In a separate vial a 1:1 mixture of 1,4-dioxane and water (0.2 M total concentration) was degassed by a stream of nitrogen for 20 min. The solvent was erred by syringe to the reaction vial containing the solid reactants. The reaction was heated to 90 0C for 4 hours. The reaction was ed by the addition of saturated aqueous bicarbonate solution (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2x 5 mL). The combined cs were dried with ous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by —130— [Annotation] sak chromatography on silica gel (12 g) with 0-50% ethyl e/hexanes to provide the title product.

EXAMPLE 14E 6-[8-(1,3-benzothiazolylcarbamoyl)-4,4-dimethyl-3 ,4-dihydroisoquinolin-2(1H)-yl] [5- methyl(tricyclo[3.3.l . 13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 14D for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 5 ppm 12.82 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.42 (m, 5H), 7.27 (s, 1H), 7.00 (d, 1H), 4.93 (s, 2H), 3.71 (s, 2H), 2.11 (s, 2H), 1.93 (s, 3H), 1.60 (m, 15H), 1.34 (s, 6H).

EXAMPLE 15 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - (morpholinyl)tricyclo[3.3.1. 13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid E 15A 4-{3-[(4-iodo-1H—pyrazol-l-yl)methyl]tricyclo[3.3.1.13’7]decyl}morpholine The title compound was ed by substituting morpholine for methanol in EXAMPLE 7B.

EXAMPLE 15B tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - (morpholinyl)tricyclo[3.3.1.13’7]decyl]methyl }-1H-pyrazolyl)pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 15A for EXAMPLE 4A in E 4C.

EXAMPLE 15C 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - (morpholinyl)tricyclo[3.3.1. 13’7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 15B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.85 (s, 1H), 9.15 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (m, 2H), 7.62 (d, 1H), 7.57 (s, 1H), 7.41 (m, 4H), 6.96 (d, 1H), 4.95 (s, 2H), 3.94 (m, 6H), 3.40 (m, 2H), 3.05 (m, 4H), 2.25 (m, 4H), 1.86 (m, 2H), 1.70 (m, 4H), 1.38 (m, 6H).

EXAMPLE l6 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 - methoxytricyclo[3.3.1.13’7]decyl]methyl}-5 l-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 16A (3-bromotricyclo[3.3. 1 . 13’7]decyl)methanol —131— [Annotation] sak In a 250 ml round-bottomed flask, 3-bromoadamantanecarboxylic acid (7.89 g) was dissolved in tetrahydrofuran (30 mL). Borane tetrahydrofuran complex (1M in , 60 mL) was added slowly. The mixture was stirred at room temperature overnight. Methanol (20 mL) was added to the solution slowly. After removal of the solvents, methanol (5 mL) was added to the oily e. Removal of the solvent provided the title nd.

EXAMPLE 16B 1-[(3-bromotricyclo[3.3.1.13’7]decyl)methyl]-1H—pyrazole The title compound was prepared by substituting EXAMPLE 16A for 1- adamantanemethanol and pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2 -yl)- 1 H-pyrazole in EXAMPLE 2A.

EXAMPLE 16C methoxytricyclo [3 .3 . 1 . 13’7]dec-1 -yl)methyl] -1H—pyrazole The title nd was prepared by substituting E 16B for EXAMPLE 7A in EXAMPLE 7B.

EXAMPLE 16D l-[(3-methoxytricyclo[3.3. 1 .13’7]decyl)methyl]methyl-1H—pyrazole The title compound was prepared by substituting EXAMPLE 16C for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 16E 4-iodo- l -[(3 -methoxytricyclo[3.3.1.13’7]decyl)methyl]-5 -methyl-1H—pyrazole A mixture ofEXAMPLE 16D (0.116 g) and N-iodosuccinimide (0.11 g) in 1 mL DMF was stirred overnight. The mixture was taken up in ethyl acetate, and the resulting solution was washed three times with water, and brine, then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title compound.

EXAMPLE 16F tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3 -( 1 - { [3 - methoxytricyclo[3.3.1.13’7]decyl]methyl}-5 -methyl-1H-pyrazolyl)pyridine carboxylate The title compound was prepared by substituting EXAMPLE 16E for E 4A in EXAMPLE 4C.

EXAMPLE 16G 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3 -(1 - { [3 - methoxytricyclo [3 .3 . 1 . 13’7]dec-1 -yl]methyl} -5 -methyl-1H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by tuting E 16F for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHZ, dimethylsulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.03 (d, —132— [Annotation] sak 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.27 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.79 (s, 2H), 3.08 (s, 3H), 3.01 (t, 2H), 2.12 (m, 5H), 1.49 (m, 12H).

EXAMPLE 17 N-(1 ,3-benzothiazolyl)—2- { 6- [(methylsulfonyl)carbamoyl][5-methyl-1 - (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide E 3F (220 mg), methanesulfonamide (40 mg), imethylaminopropyl) N’ -ethylcarbodiimide hloride (100 mg), and 4-(dimethylamino)pyiridine (80 mg) were dissolved in dichloromethane (2.5 mL) and stirred at room temperature over the weekend.

The reaction mixture was concentrated and purified by Prep HPLC using Gilson system eluting with 20-80% itrile in 0.1% water. 1H NMR (400MHz, dimethylsulfoxide-dG) 8 ppm 12.84 (br s, 1H), 11.83 (s, 1H), 8.01 (d, 1H), 7.77 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.26 (s, 1H), 6.96 (d, 1H), 4.95 (s, 2H), 3.92 (t, 2H), 3.69 (s, 2H), 3.10 (s, 3H), 3.02 (t, 2H), 2.10 (s, 3H), 1.90 (br s, 3H), 1.61 (br m, 3H), 1.50 (br m, 9H).

EXAMPLE 18 N—( 1 , 3 -benzothiazolyl)—2 - {6- [(cyclopropylsulfonyl)carbamoyl] -5 - [5 -methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide The title compound was ed by substituting ropanesulfonamide for methanesulfonamide in EXAMPLE 17. 1H NMR (400MHz, dimethylsulfoxide-dg) 5 ppm 12.85 (br s, 1H), 11.74 (s, 1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.46 (m, 2H), 7.36 (m, 2H), 7.28 (s, 1H), 7.00 (d, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.77 (m, 1H), 2.11 (s, 3H), 1.91 (br s, 3H), 1.62 (br m, 3H), 1.51 (br m, 9H), 1.00 (m, 2H), 0.90 (m, 2H).

EXAMPLE 19 N-( 1 ,3-benzothiazolyl)—2- {5 -[5 -methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazol- 4-yl] (2H-tetrazol-5 -yl)pyridinyl}-1,2 ,3 ,4-tetrahydroisoquinolinecarboxamide EXAMPLE 19A N-(benzo[d]thiazolyl)(5-bromocyanopyridinyl)-1,2 ,3,4-tetrahydroisoquinoline- 8- carboxamide The title compound was prepared by substituting 3-bromochloropicolinonitrile for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 1 9B N-( 1 ,3-benzothiazolyl)—2- {5 -[5 -methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazol- 4-yl] [(cyano)-pyridin-2 -yl]-1,2,3 ,4-tetrahydroisoquinolinecarboxamide —133— [Annotation] sak A mixture ofEXAMPLE 19A (0.245 g), E 3D (0.220 g), 1,3,5,7- tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.021 g), potassium phosphate (0.375 g) and tris(dibenzylideneacetone)dipalladium(0) (0.011 g) were added to dioxane (1.3 mL) and water (1.3 mL). The reaction was degassed with nitrogen, sealed and heated to 90°C. After 2 hours the reaction was cooled, diluted with chloroform (40 mL) and washed with brine (30 mL). The reaction was dried over sodium e, filtered, and concentrated.

Silica gel chromatography eluting with a gradient of 5% to 45% ethyl acetate/hexanes over 30 minutes provided the title nd.

EXAMPLE 19C N-( 1 ,3-benzothiazolyl)—2- {5 -[5 -methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazol- 4-yl] (2H-tetrazol-5 -yl)pyridinyl}-1,2 ,3 rahydroisoquinolinecarboxamide EXAMPLE 19B (100 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and sodium azide (96 mg) and triethylamine hydrochloride (196 mg) were added. The reaction was heated at 110°C overnight. The reaction mixture was cooled, filtered, and purified by Prep HPLC using Gilson system eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid. 1H NMR (400 MHZ, dimethylsulfoxide-d6) 5 ppm 12.84 (br s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (m, 2H), 7.46 (m, 2H), 7.36 (m, 2H), 7.20 (s, 1H), 7.05 (d, 1H), 4.99 (s, 2H), 4.01 (t, 2H), 3.67 (s, 2H), 3.03 (t, 2H), 1.92 (br s, 3H), 1.83 (s, 3H), 1.60 (br m, 6H), 1.48 (br m, 6H).

EXAMPLE 20 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-methyl [tricyclo[3.3.1.13’7]decylmethoxy]phenyl}pyridinecarboxylic acid EXAMPLE 20A 1-[(4-bromomethylphenoxy)methyl]tricyclo[3.3.1.13’7]decane The title compound was prepared by substituting 4-bromo-3 -methylphenol for 3,5- yl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 2A.

EXAMPLE 20B 3 -{2-methyl[tricyclo[3.3.1.13’7]decylmethoxy]phenyl}[8-(1,3-benzothiazol amoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid tert-butyl ester EXAMPLE 4B (120 mg), EXAMPLE 20A (90 mg), trans- dichlorobis(triphenylphosphine)palladium (II) (30 mg), and cesium carbonate (280 mg) were added to a microwave vial. N,N-dimethylformamide (1.0 mL), oxane (0.7 mL), and water (0.4 mL) were added. The vial was placed in a microwave reactor and subjected to 120°C for 15 minutes. The solution was then added to water and extracted with 30% ethyl acetate in hexanes. The extract was washed with brine and dried over ous sodium sulfate. The solution was filtered, trated and purified on silica gel using 30% ethyl acetate in hexanes. —134— ation] sak [Annotation] sak EXAMPLE 20C 6-[8-(1,3 -benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 - {2-methy1 [tricyclo[3.3.1.13’7]decy1methoxy]pheny1}pyridinecarboxy1ic acid The title compound was prepared by substituting EXAMPLE 20B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, y1su1foxide-d 6) 8 ppm 12.85 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.31 (m, 5H), 6.95 (d, 1H), 6.91 (d, 1H), 6.79 (d, 1H), 6.70 (dd, 1H), 4.97 (s, 2H), 3.91 (t, 2H), 3.51 (s, 2H), 3.03 (t, 2H), 2.02 (s, 3H), 1.98 (bs, 3H), 1.78-1.58 (m, 12H).

EXAMPLE 21 6-[8-(1,3 -benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 - hy1-3 - [tricyclo[3.3.1.13’7]decy1methoxy]pheny1}pyridinecarboxy1ic acid EXAMPLE 21A 1-[(3 -bromomethy1phenoxy)methy1]tricyclo[3.3.1.13’7]decane The title compound was prepared by tuting 3-bromomethy1phenol for 3,5- dimethy1(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)-1H-pyrazole in EXAMPLE 2A.

EXAMPLE 21B 3 -{2-methy1[tricyclo[3.3.1.13’7]decy1methoxy]pheny1}[8-(1,3-benzothiazol y1carbamoy1)-3 ,4-dihydroisoquinolin-2(1H)-y1]pyridinecarboxy1ic acid tert-buty1 ester The title compound was prepared by substituting EXAMPLE 21A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 21C 6-[8-(1,3 -benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 - {2-methy1-3 - [tricyclo[3.3.1.13’7]decy1methoxy]pheny1}pyridinecarboxy1ic acid The title compound was prepared by tuting EXAMPLE 21B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethy1su1foxide-d 6) 8 ppm 12.85 (bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.31 (m, 5H), 7.08 (t, 1H), 6.98 (d, 1H), 6.84 (d, 1H), 6.62 (d, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.52 (s, 2H), 3.03 (t, 2H), 1.99 (s, 3H), 1.92 (bs, 3H), 1.78-1.59 (m, 12H).

EXAMPLE 22 6-[8-(1,3 -benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 - { 3- [tricyclo[3.3.1.13’7]decy1methoxy]pheny1}pyridinecarboxy1ic acid EXAMPLE 22A 1-[(3-bromophenoxy)methy1]tricyclo[3.3.1. 13’7]decane The title compound was prepared by substituting 3-bromophenol for 3,5-dimethy1—4- (4,4,5 ,5 -tetramethy1-1,3 ,2 -dioxaborolany1)—1H-pyrazole in EXAMPLE 2A. —135— [Annotation] sak EXAMPLE 22B 3 -{3-[tricyclo[3.3.l.13’7]dec-l-ylmethoxy]phenyl}[8-(l,3-benzothiazolylcarbamoyl)- 3,4-dihydroisoquinolin-2(lH)—yl]pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting E 22A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 22C 1 ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 - { 3- [tricyclo[3.3.l.13’7]dec-l-ylmethoxy]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 22B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.50-7.43 (m, 2H), 7.39-7.33 (m, 2H), 7.29-7.23 (m, 1H), 6.97 (d, 1H), 6.90-6.83 (m, 3H), 4.98 (s, 2H), 3.90 (t, 2H), 3.52 (s, 2H), 3.02 (t, 2H), 1.98 (bs, 3H), 1.78-1.59 (m, 12H).

EXAMPLE 23 6-[8-( l ,3 -benzothiazol-2 -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 -[5-cyano methyl-l-(tricyclo[3.3. l . 13’7]dec-l-ylmethyl)-lH-pyrrolyl]pyridinecarboxylic acid EXAMPLE 23A ethyl 4-iodo-5 l- 1 H-pyrrolecarboxylate The title compound was prepared by following the procedure described for EXAMPLE 16E and replacing EXAMPLE 16D with ethyl 5-methyl-lH-pyrrole carboxylate.

EXAMPLE 23B 4-iodomethyl- l H-pyrrolecarboxylic acid EXAMPLE 23A (1 g) in tetrahydrofuran (30 mL) and methanol (10 mL) was d with 2 N NaOH (20 mL) overnight. The reaction mixture was cooled to 0°C, ed to pH , diluted with water (30 mL) and trated to remove the organic solvent. The precipitates were collected by filtration, washed with water and dried over sodium sulfate to provide the title compound.

EXAMPLE 23C 4-iodomethyl-lH-pyrrolecarboxamide To a solution of EXAMPLE 23B (7.7 g) in tetrahydrofuran (20 mL) at 0°C was added carbonyldiimidazole (14.9 g). The resulting mixture was d at room temperature for 2 hours. The on mixture was cooled to 0°C and ammonium ide (3 mL) was added.

The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title compound.

EXAMPLE 23D 4-iodo-5 -methyl- 1 H-pyrrolecarbonitrile —136— [Annotation] sak To a solution of EXAMPLE 23C (7.89 g) in DMF (80 mL) and pyridine (5 mL) at 0°C was added dropwise oxalyl chloride (5.52 mL). The e was stirred at 0°C for 30 minutes and ice-water was added to quench the reaction. The resulting mixture was diluted with ethyl acetate and washed with aqueous NaHC03 and water extensively. The organic layer was dried over , filtered, and concentrated. The residue was purified by flash column, eluting with dichloromethane to provide the title compound.

EXAMPLE 23E -cyanomethyliodo(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrrole EXAMPLE 23D (170 mg), l-bromomethyladamantane (840 mg) and tetrabutylammonium bromide (171 mg) in N,N-dimethylformamide (20 mL) was treated with sodium hydride (147 mg) at 80°C overnight. The reaction mixture was cooled, diluted with ethyl e and washed with brine. The organic layer was concentrated. The residue was purified by flash chromatography (40% dichloromethane in hexanes) to provide the title compound.

EXAMPLE 23F 3-[5-cyanomethyl-l-(tricyclo[3.3.1.13’7]decylmethyl)-lH-pyrrolyl]—6-[8- (benzothiazolylcarbamoyl)-3,4-dihydro-1H-isoquinolinyl]-pyridinecarboxylic acid tert-butyl ester The title nd was prepared by tuting EXAMPLE 23E for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 23G 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 ano methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrrolyl]pyridinecarboxylic acid The title compound was prepared by tuting EXAMPLE 23F for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 - 7.53 (m, 3H), 7.33 - 7.39 (m, 2H), 6.95 (d, 1H), 6.82 (s, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.74 (s, 2H), 3.01 (t, 2H), 2.09 (s, 3H), 1.96 (s, 3H), 1.62 - 1.69 (m, 3H), 1.53 - 1.60 (m, 9H).

EXAMPLE 24 3-[5-methyl-l-(tricyclo[3.3.1 .13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([l,3]thiazolo[5 ,4- b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid EXAMPLE 24A 3-[5-methyl-l-(tricyclo[3.3.1 .13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([l,3]thiazolo[5 ,4- b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid tert- butyl ester The title nd was prepared by substituting thiazolo[5,4-b]pyridinamine for thiazolo[4,5-b]pyridineamine in EXAMPLE 30D. —137— [Annotation] sak EXAMPLE 24B 3-[5-methyl-l-(tricyclo[3.3.l .13’7]dec-l-ylmethyl)-lH-pyrazolyl]—6-[8-([l,3]thiazolo[5,4- b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 12.98 (s, 2H), 8.57 — 8.47 (m, 1H), 8.16 (d, 1H), 7.63 (d, 1H), 7.56 — 7.47 (m, 2H), 7.45 (d, 1H), 7.38 (t, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.88 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (s, 3H), 42 (m, 12H).

EXAMPLE 25 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)—yl] -2'- (tricyclo[3.3.l.13’7]dec-l-ylmethoxy)-3,4'-bipyridinecarboxylic acid EXAMPLE 25A 2-(tricyclo [3 .3. l . l c- l -ylmethoxy)iodo-pyridine l-Adamantanemethanol (0.820 g) and roiodopyridine (0.22 g) in tetrahydrofuran (5 mL) was treated with sodium hydride (60% in mineral oil) (0.05 7) at room temperature for 6 hours. The reaction was ed with ice-water and extracted with ethyl acetate (3x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether/ethyl acetate (20/1) to provide the title compound.

EXAMPLE 25B 2'—(tricyclo[3.3.l .13’7]dec-l-ylmethoxy)—6-[8-(benzothiazolylcarbamoyl)-3,4-dihydro-lH- nolinyl]-[3,4']bipyridinylcarboxylic acid tert-butyl ester The title compound was prepared by tuting EXAMPLE 25A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 25C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)—yl] -2'- (tricyclo[3.3.l.13’7]dec-l-ylmethoxy)-3,4'-bipyridinecarboxylic acid The title compound was synthesized by substituting EXAMPLE 25B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 5 ppm 12.89 (s, 1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.63 (d, 1H), 7.44-7.49 (m, 2H), .39 (m, 2H), 7.00 (d, 1H), 6.90 (dd, 1H), 6.72 (s, 1H), 5.01 (s, 2H), 3.92 (t, 2H), 3.86 (s, 2H), 3.02 (t, 2H), 1.97 (s, 3H), 1.61-1.72 (m, 12H).

EXAMPLE 26 6-[8-( l ,3 thiazol-2 -ylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 -[ l -( { 3- [2- (morpholinyl)ethoxy]tricyclo[3.3. l .13’7]dec- l -yl}methyl)- l H-pyrazolyl]pyridine carboxylic acid —138— [Annotation] sak EXAMPLE 26A 3-bromotricyclo[3.3.l.13’7]decylmethyl-1H-pyrazole The title compound was prepared by substituting pyrazole for 3,5-dimethyl (4,4,5 ,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and 3 -bromo adamantanemethanol for 1-adamantanemethanol in EXAMPLE 2A.

EXAMPLE 26B morpholinyl)ethoxy]tricyclo[3.3.1.13’7]decylmethyl-1H-pyrazole The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE 7A and 2-morpholinoethanol for methanol in EXAMPLE 7B.

EXAMPLE 26C 4-iodo{[2-(morpholinyl)ethoxy]tricyclo[3.3.1.13’7]decylmethyl}-1H-pyrazole The title nd was prepared by tuting EXAMPLE 26B for EXAMPLE 3B and N-iodosuccinimide for N-bromosuccinimide in EXAMPLE 3C.

EXAMPLE 26D tert-butyl benzo [d]thiazolylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)-yl)-3 -(1-((3-[2- (morpholinyl)ethoxy]tricyclo[3.3. 1.13’7]decyl)methyl)-1H-pyrazolyl)picolinate The title compound was ed by substituting E 26C for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 26E 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[1-({3-[2- (morpholinyl)ethoxy]tricyclo[3.3. 1 .13’7]decyl}methyl)-1H-pyrazolyl]pyridine carboxylic acid The title compound was prepared by substituting EXAMPLE 26D for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 5 ppm 12.86 (br. s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.71 (m, 2H), 7.61 (d, 1H), 7.55 (s, 1H), 7.41 (m, 4H), 6.95 (d, 1H), 4.95 (s, 2H), 3.90 (m, 6H), 3.66 (m, 4H), 3.09 (m, 8H), 2.17 (m, 2H), 1.69 (m, 2H), 1.47 (m, 1 0H).

EXAMPLE 27 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]-3'-methyl-2'- (tricyclo[3.3.l.13’7]dec-l-ylmethoxy)-3,4'-bipyridinecarboxylic acid EXAMPLE 27A 2-(tricyclo[3 .3. l . l 3’7]dec- l -ylmethoxy)iodomethyl-pyridine 1-Hydroxylmethyladamantane (249 mg) was dissolved in tetrahydrofuran (3.5 mL) and NaH (24 mg) was added. After the gas evolution ceased, 2-fluoroiodo methylpyridine (237 mg) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours, quenched with H20 and extracted with ethyl —139— [Annotation] sak acetate. The combined c layers were washed with brine and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether to provide the title compound.

EXAMPLE 27B 2'—( tricyclo [3 .3. l .13’7]dec- l -ylmethoxy) [8-(benzothiazol-2 -ylcarbamoyl)-3 ,4-dihydro-1H- isoquinolinyl] -3 '-methyl-[3 ,4']bipyridinylcarboxylic acid utyl ester The title compound was sized by substituting EXAMPLE 27A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 27C 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)—yl]—3'—methyl-2'— (tricyclo[3.3.l.13’7]dec-l-ylmethoxy)-3,4'-bipyridinecarboxylic acid The title compound was synthesized by substituting EXAMPLE 27B for EXAMPLE 213 in EXAMPLE 20. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 7.88 (d, 1H), 7.71— 7.73 (m, 1H), 7.44-7.47 (m, 1H), .35 (m, 3H), 7.17-7.25 (m, 3H), 6.95 (d, 1H), 6.52 (d, 1H), 5.07-5.16 (m, 2H), 3.81-3.84 (m, 4H), 3.04-3.05 (m, 2H), 1.89-1.93 (m, 6H), 1.61-1.69 (m, 12H).

EXAMPLE 28 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 - {2-methyl-3 - clo[3.3.l.13’7]dec-l-yloxy]phenyl}pyridinecarboxylic acid EXAMPLE 28A l-(3-bromomethylphenoxy)tricyclo[3.3.1.13’7]decane 3-Bromomethylphenol (1000 mg) and l-bromoadamantane (2013 mg) were added to hexamethylphosphoramide (8 mL) and the mixture was heated in a microwave r (Biotage) at 250 0C for 35 minutes. The solution was taken up in diethyl ether, washed with water two times, washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated. The crude al was purified by flash column chromatography on silica gel using 2% ethyl acetate (hexanes) increasing to 5% ethyl e (hexanes) to yield the title compound.

EXAMPLE 28B 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 - {2-methyl-3 - [tricyclo[3.3.1.13’7]dec-l -yloxy]phenyl}pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting E 28A for E 20A in EXAMPLE 20B.

EXAMPLE 28C 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 - {2-methyl-3 - [tricyclo[3.3.l.13’7]dec-l-yloxy]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 28B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.85 (bs, 1H), 12.55 —140— [Annotation] sak (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (m, 2H), 7.50-7.32 (m, 4H), 7.08-6.95 (m, 3H), 6.73 (d, 1H), 4.98 (bs, 2H), 3.91 (m, 2H), 3.03 (t, 2H), 2.13 (bs, 3H), 1.93 (s, 3H), 1.86 (m, 6H), 1.59 (m, 6H).

EXAMPLE 29 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl]-3 - {5-cyano- l - [tricyclo[3.3. l .13’7]dec-l-ylmethyl]-lH-pyrazolyl}pyridinecarboxylic acid EXAMPLE 29A 4-bromocyano[tricyclo[3.3.1.13’7]decylmethyl]-1H-pyrazole The title compound was ed by substituting 4-bromo-3 -cyano-lH-pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole in E 2A.

EXAMPLE 29B 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl]-3 - {5-cyano- l - [tricyclo[3 .3 . l . 13’7]dec-l -ylmethyl]-lH-pyrazolyl}pyridinecarboxylic acid tert-butyl ester The title compound was prepared by tuting EXAMPLE 29A for E 20A in EXAMPLE 20B.

EXAMPLE 29C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl]-3 - {5-cyano- l - [tricyclo[3.3. l .13’7]dec-l-ylmethyl]-lH-pyrazolyl}pyridinecarboxylic acid The title compound was ed by substituting EXAMPLE 29B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-dG) 8 ppm 12.86 (bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.68 (t, 2H), 7.63 (d, 1H), 7.50-7.38 (m, 4H), 7.06 (d, 1H), 5.01 (bs, 2H), 3.97 (s, 2H), 3.93 (t, 2H), 3.02 (t, 2H), 1.95 (bs, 3H), 1.68-1.50 (m, 12H).

EXAMPLE 30 3-[5-methyl-l-(tricyclo[3.3.l .13’7]dec-l-ylmethyl)-lH-pyrazolyl]—6-[8-([l,3]thiazolo[4,5- b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]pyridinecarboxylic acid EXAMPLE 30A methyl 2 -(5 -bromo(tert-butoxycarbonyl)pyridin-2 -yl)- l ,2,3 ,4-tetrahydroisoquinoline-8 - carboxylate The title compound was prepared by substituting methyl 1,2,3,4- tetrahydroisoquinolinecarboxylate for EXAMPLE 1C in E 1E.

EXAMPLE 30B 2-[6-tert-butoxycarbonyl(1-tricyclo[3.3.l.13’7]decanylmethyl-1pyrazolyl)- pyridinyl]-l ,2,3,4-tetrahydro-isoquinolinecarboxylic acid methyl ester The title compound was prepared by substituting EXAMPLE 30A for EXAMPLE 14C in EXAMPLE 14D. —141— [Annotation] sak EXAMPLE 30C 2-[6-carboxy-5 -(1-tricyclo[3.3.1.13’7]decanylmethyl-1pyrazolyl)—pyridinyl]- 1,2,3,4-tetrahydro-isoquinolinecarboxylic acid methyl ester EXAMPLE 30B (2.3 g) was dissolved in tetrahydrofuran (4.0 mL) and methanol (8.0 mL), and 1N LiOH (5.3 mL) was added. The mixture was stirred at room temperature for six days. The reaction mixture was diluted with water (50 mL), 2N aqueous HCl (2.65 mL) was added, and the mixture was stirred for a few minutes. The mixture was filtered, and the solid was washed with water, and dried under high vacuum in the presence of P205 overnight to provide the title nd.

EXAMPLE 30D 3 -(5 ltricyclo[3.3.1.13’7]decanylmethyl-1H-pyrazolyl)—6-[8-(thiazolo[4,5 - b]pyridinylcarbamoyl)-3,4-dihydro-1H-isoquinolinyl]-pyridinecarboxylic acid tert- butyl ester To a solution of EXAMPLE 30C (80 mg) and lo[4,5-b]pyridineamine (21 mg) in romethane (1.5 mL) was added 1-ethyl[3 -(dimethylamino)propyl]— carbodiimide hydrochloride (40 mg) and 4-(dimethylamino)pyridine (26 mg). The mixture was d at room temperature overnight. The reaction mixture was then concentrated and purified by chromatography on silica gel using 1/4 hexanes/ethyl acetate to provide the title compound.

EXAMPLE 30E 3-[5-methyl(tricyclo[3.3.1.13’7]decanylmethyl)-1H-pyrazolyl]—6-[8-(thiazolo[4,5- b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid EXAMPLE 30D (37 mg) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After stirring at room temperature overnight, the reaction mixture was concentrated and triturated with diethyl ether (5 mL) to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) 5 ppm 13.20 (br s, 1H), 8.61 (dd, 1H), 8.56 (dd, 1H), 7.65 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.39 (m, 2H), 7.27 (s, 1H), 6.96 (d, 1H), 4.97 (s, 2H), 3.89 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

E 31 3-[5-methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([1,3]thiazolo[4,5- c]pyridinylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid EXAMPLE 31A 3 -(5 ltricyclo[3.3.1.13’7]decanylmethyl-1H-pyrazolyl)—6-[8-(thiazolo[4,5 - c]pyridinylcarbamoyl)—3,4-dihydro-1H-isoquinolinyl]-pyridinecarboxylic acid tert- butyl ester —142— [Annotation] sak The title compound was prepared by substituting thiazolo[4,5-c]pyridineamine for lo[4,5-b]pyridineamine in EXAMPLE 30D.

EXAMPLE 3 lB 3-[5-methyl(tricyclo[3.3.1.13’7]decanylmethyl)-1H-pyrazolyl]—6-[8-(thiazolo[4,5- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 31A for EXAMPLE 30D in EXAMPLE 30E. 1H NMR (500 MHZ, dimethylsulfoxide-d6) 5 ppm 13.34 (br s, 1H), 9.30 (s, 1H), 8.59 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.47 (d, 1H), 7.40 (t, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 4.97 (s, 2H), 3.89 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

EXAMPLE 32 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -(1 - { [3 ,5 - dimethyltricyclo [3 .3. 1 decyl]methyl}-5 -methyl-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 32A l-((3 ,5-dimethyltricyclo[3.3.1.13’7]decyl)methyl)-1H-pyrazole The title nd was prepared by substituting (3,5 -dimethyladamantan-1 - yl)methanol for l-adamantanemethanol and pyrazole for 3,5-dimethyl(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolanyl)-1H-pyrazole in E 2A.

EXAMPLE 32B l-((3,5-dimethyltricyclo[3.3.1.13’7]decyl)methyl)methyl-lH-pyrazole To a solution of EXAMPLE 32A (2.44 g) in tetrahydrofuran (25 mL) / toluene (25 mL) was added n-butyllithium (7.49 mL) at -40 oC. The reaction mixture was stirred for 60 minutes when CH31 (1.873 mL) was added and the stirring was continued for 2 hours at -40 oC. The reaction e was ed with saturated ammonium chloride solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and purified by flash chromotography a gel, 0% - 15% ethyl acetate/hexanes).

EXAMPLE 32C 3-bromo-l -((3,5 -dimethyltricyclo[3.3. 1 .13’7]decyl)methyl)methyl-1H-pyrazole The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 32D tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3 -(l -((3,5 - dimethyltricyclo[3.3.1.13’7]decyl]methyl)methyl-1H-pyrazolyl)picolinate The title compound was prepared by tuting EXAMPLE 32C for EXAMPLE 4A in EXAMPLE 4C. —143— [Annotation] sak EXAMPLE 32E 6-[8-(1,3-benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 -(1 - { [3 ,5 - dimethy1tricyclo [3 .3. 1 .13’7]decy1]methy1}-5 -methy1-1H-pyrazoly1)pyridinecarboxy1ic acid The title compound was prepared by substituting EXAMPLE 32D for E 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethy1su1foxide-d6) 5 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48 (m, 3H), 7.40 — 7.31 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.88 (d, 2H), 3.74 (s, 2H), 3.01 (t, 2H), 2.09 (s, 3H), 2.04 — 1.97 (m, 1H), 1.33 (s, 2H), 1.24 (s, 4H), 1.21 — 0.98 (m, 6H), 0.78 (s, 7H).

EXAMPLE 33 6-[8-(1,3-benzothiazoly1carbamoy1)-3 ,4-dihydroisoquinolin-2(1H)-y1] -3 3-(1,1- dioxidothiomorpholiny1)tricyclo [3 .3 - 1 H-pyrazoly1)pyridine . 1 . 13’7]decy1]methy1} carboxy1ic acid E 33A 4-(3-((4-iodo-1H-pyrazoly1)methy1)tricyclo[3.3. 1 .13’7]decy1)-1,1-dioxidothiomorpholine The title compound was prepared by substituting rpholine-l ,1-dioxide for methanol in EXAMPLE 7B.

EXAMPLE 33B tert-buyt1 6-[8-(1,3-benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1]-3 -(1 - { [3 - (1,1-dioxidothiomorpholiny1)tricyclo[3.3.1.13’7]decy1]methy1}-1H-pyrazol y1)picolinate The title compound was prepared by tuting EXAMPLE 33A for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 33C 6-[8-(1,3-benzothiazoly1carbamoy1)-3,4-dihydroisoquinolin-2(1H)-y1](1-{3-(1,1- dioxidothiomorpholiny1)tricyclo [3 .3 - 1 H-pyrazoly1)pyridine . 1 . 13 ’7]decy1]methy1} carboxy1ic acid The title compound was prepared by substituting EXAMPLE 33B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethy1su1foxide-d6) 5 ppm 12.85 (br.s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.71 (m, 2H), 7.59 (m, 2H), 7.41 (m, 4H), 6.95 (d, 1H), 4.95 (s, 2H), 3.88 (m, 4H), 3.01 (m, 2H), 2.72 (m, 2H), 2.43 (m, 2H), 2.21 (m, 4H), 1.61 (m, 12H) EXAMPLE 34 6-[8-(1,3-benzothiazoly1carbamoy1)-3 ,4-dihydroisoquinolin-2(1H)-y1]-3 - {5-cyano methy1 [2-(tricyclo [3 .3 . 1 .13’7]decy1)ethy1]—1H-pyrrol-3 ridinecarboxy1ic acid EXAMPLE 34A -cyanomethy1[2-(tricyclo[3.3.1.13’7]decy1)ethy1]-1H—pyrrole —144— [Annotation] sak The title nd was synthesized by substituting EXAMPLE 23D for 3,5- dimethyl(4,4,5 ramethyl- 1 ,3,2-dioxaborolanyl)— 1 H-pyrazole and adamantane ethanol for 1-adamantanemethanol in EXAMPLE 2A.

EXAMPLE 34B 3-[5 -cyanomethyl- l -[2-(tricyclo[3 .3 . l .13’7]dec-l hyl]-lH-pyrrolyl]—6-[8- (benzothiazolylcarbamoyl)-3,4-dihydro-1H-isoquinolinyl]-pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting EXAMPLE 34A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 34C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {5-cyano methyl-1 -[2-(tricyclo [3 .3 . 1 .13’7]decyl)ethyl]-1H-pyrrol-3 -yl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 34B for EXAMPLE 2B in E 2C. 1H NMR (400 MHz, dimethylsulfoxide-dé) 5 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 - 7.51 (m, 3H), 7.33 - 7.39 (m, 2H), 6.95 (d, 1H), 6.78 (s, 1H), 4.96 (s, 2H), 3.96 - 4.04 (m, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.95 (s, 3H), 1.53 - 1.73 (m, 12H), 1.33 - 1.44 (m, 2H).

EXAMPLE 35 N-( l ,3 -benzothiazolyl) { 5- [5 -cyanomethyl-l -(tricyclo[3 .3 . l . l 3’7]dec- l hyl)- 1H- pyrrol-3 -yl] ylsulfonyl)carbamoyl]pyridin-2 ,2,3,4-tetrahydroisoquinoline- 8- carboxamide The title compound was prepared by substituting EXAMPLE 23G for EXAMPLE 3F in EXAMPLE 17. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 12.86 (s, 1H), 11.82 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.42 - 7.50 (m, 2H), 7.32 - 7.40 (m, 2H), 7.00 (d, 1H), 6.82 (s, 1H), 4.96 (s, 2H), 3.94 (t, 2H), 3.73 (s, 2H), 3.13 (s, 3H), 3.03 (t, 2H), 2.10 (s, 3H), 1.95 (s, 3H), 1.50 - 1.70 (m, 12H).

EXAMPLE 36 N-( l ,3 -benzothiazolyl) { 5- [5 -cyanomethyl-l -(tricyclo[3 .3 . l . l 3’7]dec- l -ylmethyl)- 1H- pyrrol-3 -yl] [(cyclopropylsulfonyl)carbamoyl]pyridin-2 -yl}-1,2,3 ,4-tetrahydroisoquinoline- 8-carboxamide The title compound was prepared by substituting EXAMPLE 23G for EXAMPLE 3F and cyclopropanesulfonamide for methanesulfonamide in EXAMPLE 17. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 12.86 (s, 1H), 11.74 (s, 1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.42 - 7.50 (m, 2H), 7.32 - 7.40 (m, 2H), 7.01 (d, 1H), 6.82 (s, 1H), 4.99 (s, 2H), 3.93 (t, 2H), 3.73 (s, 2H), 3.03 (t, 2H), 2.74 - 2.84 (m, 1H), 2.11 (s, 3H), 1.94 (s, 3H), 1.52 - 1.68 (m, 12H), 0.99 - 1.05 (m, 2H), 0.87 - 0.95 (m, 2H). —145— [Annotation] sak EXAMPLE 37 N-( l ,3 thiazol-2 -yl) {5 -( l - { [3 -methoxytricyclo[3.3.l.13’7]dec-l-yl]methyl}methyllH-pyrazolyl ) [(methylsulfonyl)carbamoyl]pyridinyl } - l ,2 ,3 ,4-tetrahydroisoquinoline- 8-carboxamide The title compound was prepared by tuting EXAMPLE 16G for EXAMPLE 3F in EXAMPLE 17. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 12.86 (br. s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.46 (m, 2H), 7.36 (m, 2H), 7.28 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 3.93 (m, 2H), 3.80 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H), 3.02 (m, 2H), 2.13 (m, 4H), 1.49 (m, 12H).

E 3 8 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl](l- {[3 -methoxy- ,7-dimethyltricyclo[3 .3. l .13’7]dec-l-yl]methyl}methyl-lH-pyrazolyl)pyridine carboxylic acid EXAMPLE 38A 5-bromo-3,7-dimethyltricyclo [3 .3. l .13’7]decane- l -carboxylic acid In a 50 mL round-bottomed flask, bromine (3 mL) was cooled to 0 °C and iron (0.56 g) was added. The mixture was stirred at 0 °C for 30 minutes. 3,5 -dimethyladamantane-1 - carboxylic acid (0.5 g) was added. The mixture was stirred at room temperature ght.

After adding ice and 6N aqueous HC1 (10 mL), ethyl acetate (20 mL), and saturated aqueous NaZSO3 were added. The aqueous layer was ted twice with ethyl acetate. The combined organic layers were washed with saturated Na2803 (50 mL, 3x) and dried over NaZSO4. After filtraion and removal of the solvent, the product was used directly in the next step.

EXAMPLE 38B o-3,7-dimethyltricyclo[3.3.1.13’7]decylmethanol The title compound was prepared by substituting EXAMPLE 38A for 3,5,8-trimethyl- l-adamantane carboxylic acid in EXAMPLE 9A.

EXAMPLE 38C romo-3,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl)-lH-pyrazole The title compound was prepared by substituting pyrazole for 3,5-dimethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole and EXAMPLE 38B for l- adamantanemethanol in EXAMPLE 2A.

EXAMPLE 38D l-(5-methoxy-3 ethyltricyclo[3.3.l.13’7]dec-l-yl)-lH-pyrazole The title compound was prepared by substituting EXAMPLE 38C for EXAMPLE 7A in EXAMPLE 7B. —146— [Annotation] sak EXAMPLE 38E 1-(5-methoxy-3 ,7-dimethyltricyclo[3.3.1.13’7]decyl)-5 -methyl-1H-pyrazole The title nd was prepared by substituting EXAMPLE 38C for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 38F 4-bromo(5 -methoxy-3,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl-1H-pyrazole The title compound was ed by substituting EXAMPLE 38E for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 38G tert-buytl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-(5 - methoxy-3,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl-1H -pyrazolyl)picolinate The title compound was prepared by substituting EXAMPLE 38F for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 38H 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl](1-(5-methoxy- 3,7-dimethyltricyclo[3.3 .1 .13’7]decyl)-5 -methyl-1H--pyrazolyl)pyridinecarboxylic acid The title compound was ed by substituting EXAMPLE 38G for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.84 (br.s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.82 (s, 2H), 3.08 (s, 3H), 3.01 (t, 2H), 2.09 (s, 3H), 1.34 (s, 2H), 1.12 (m, 10H), 0.85 (s, 6H).

EXAMPLE 39 N-(1,3 -benzothiazol-2 - {5 -(1 - { [3 -methoxytricyclo[3.3.1.13’7]decyl]methyl}methyl- 1H-pyrazolyl)[(morpholinylsulfonyl)carbamoyl]pyridinyl}-1,2 ,3 ,4- tetrahydroisoquinolinecarboxamide The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE 3F and morpholinesulfonamide for methanesulfonamide in EXAMPLE 17. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.85 (br.s, 1H), 11.64 (s, 1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.44 (m, 5H), 7.27 (s, 1H), 7.01 (d, 1H), 4.99 (s, 2H), 3.91 (t, 2H), 3.79 (s, 2H), 3.12 (m, 4H), 3.08 (s, 3H), 3.02 (t, 2H), 2.12 (m, 5H), 1.48 (m, 12H).

EXAMPLE 40 N-(1,3 thiazolyl)—2- [5 3-methoxytricyclo[3.3.1.13’7]decyl]methyl}methyl- 1H-pyrazolyl)—6- {[(trifluoromethyl)sulfonyl]carbamoyl}pyridinyl]-1,2 ,3 ,4- tetrahydroisoquinolinecarboxamide —147— [Annotation] sak The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE 3F and trifluoromethanesulfonamide for methanesulfonamide in EXAMPLE 17. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 12.84 (br.s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 7.47 (m, 2H), 7.35 (m, 3H), 6.98 (d, 1H), 4.95 (s, 2H), 3.92 (t, 2H), 3.05 (m, 5H), 2.13 (m, 5H), 1.48 (m, 12H).

EXAMPLE 41 N-(1,3 -benzothiazolyl) {6-[(cyclopropylsulfonyl)carbamoyl](1-{[3- methoxytricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide The title nd was prepared by substituting EXAMPLE 16G for EXAMPLE 3F and cyclopropanesulfonamide for esulfonamide in EXAMPLE 17. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 12.86 (br.s, 1H), 11.74 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.46 (m, 2H), 7.36 (m, 2H), 7.29 (s, 1H), 7.01 (d, 1H), 4.98 (s, 2H), 3.93 (t, 2H), 3.79 (s, 3H), 3.08 (s, 3H), 3.03 (t, 2H), 2.11 (m, 5H), 1.50 (m, 12H), 0.96 (m, 4H).

EXAMPLE 42 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -{5-chloro [tricyclo[3.3. 1 .13’7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid EXAMPLE 42A 5-chloro-l-[tricyclo[3.3.l.l3’7]decylmethyl]-1H-pyrazole The title compound was prepared by substituting hexachloroethane for iodomethane in EXAMPLE 3B.

EXAMPLE 42B 4-bromochloro-l-[tricyclo[3.3.1.13’7]decylmethyl]-1H-pyrazole The title compound was prepared by substituting EXAMPLE 42A for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 42C 1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 loro [tricyclo[3 .3 . l . 13’7]dec-l hyl]—lH-pyrazolyl}pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting EXAMPLE 42B for EXAMPLE 20A in EXAMPLE 20B.

E 42D 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -{5-chloro [tricyclo[3.3. 1 .13’7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid —148— [Annotation] sak The title compound was prepared by substituting EXAMPLE 42C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHZ, dimethylsulfoxide-d 6) 5 ppm 12.85 (bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.59 (d, 1H), 7.51-7.43 (m, 3H), 7.37 (m, 2H), 7.00 (d, 1H), 4.98 (bs, 2H), 3.93 (t, 2H), 3.81 (s, 2H), 3.02 (t, 2H), 1.93 (bs, 3H), 1.68-1.50 (m, 12H).

EXAMPLE 43 6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl][5 - methyl(tricyclo[3.3.1 .13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 43A 2-(tert-butoxycarbonyl)methyl-1,2,3 ,4-tetrahydroisoquinolinecarboxylic acid To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolinecarboxylic acid (2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran (40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at -78 oC. The e was stirred at -78 0C for 40 minutes. To the resulting mixture was added thane (5.07 mL) dropwise and the mixture was stirred at -78 0C for 3 hours, ed by stirring at room temperature overnight.

The reaction mixture was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL), washed with brine (40 mL x 3), dried over NaZSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 10% methanol / dichloromethane).

EXAMPLE 43B tert-butyl 8-(benzo[d]thiazolylcarbamoyl)methyl-3,4-dihydroisoquinoline-2(1H)- carboxylate A mixture ofEXAMPLE 43A (400 mg), PyBOP (benzotriazol-l- yloxytripyrrolidinophosphonium hexafluorophosphate, 714 mg), triethylamine (0.383 mL) and benzo[d]thiazolamine (247 mg) in dichloromethane (10 mL) was stirred overnight at room temperature. The e was diluted with ethyl acetate (100 mL), washed with brine (30 mL x 3), dried over NaZSO4, filtered, concentrated and purified by flash chromatography (silica gel, petroleum ether/ethyl acetate=1/ 1).

EXAMPLE 43C N-(benzo [d]thiazol-2 -yl)-1 -methyl-1 ,2,3 ,4-tetrahydroisoquinolinecarboxamide A solution of E 43B ) in dichloromethane (10 mL) was treated with TFA (1 mL). The reaction e was stirred for 2 hours at 30 oC. The reaction mixture was d with ethyl acetate (100 mL), washed with saturated , brine, dried over , filtered and concentrated. The crude product was purified by flash chromotography (silica gel, dichloromethane/methanol=10/1).

E 43D methyl 6-(8-(benzo[d]thiazolylcarbamoyl)methyl-1,2,3,4-tetrahydroisoquinolin-2(1H)- yl)bromopicolinate —149— [Annotation] sak A solution of EXAMPLE 43C (1 g), methyl 3-bromof1uoropicolinate (0.715 g) and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70 oC overnight followed by heating at 105 0C for 4 hours. The reaction mixture was d with ethyl acetate, washed 3 times with water, washed with brine, dried over NaZSO4, filtered, and concentrated. The crude al was purified by flash chromotography (silica gel, 5-25% ethyl acetate/hexanes).

EXAMPLE 43E methyl 6-(8-(benzo[d]thiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-3 -(1-(tricyclo[3.3.1.13’7]decylmethyl)-5 -methyl-1H-pyrazolyl)picolinate The title compound was prepared by substituting EXAMPLE 43D for EXAMPLE 4A and EXAMPLE 3D for EXAMPLE 4B in EXAMPLE 4C.

EXAMPLE 43F 6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl][5 - methyl(tricyclo[3.3.1 .13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 43E for EXAMPLE 14A in EXAMPLE 14B. 1H NMR (dimethylsulfoxide-d6) 8 ppm 12.67 (s, 1H), 8.01 (d, 1H), 7.78 (d, 1H), 7.55 (d, 1H), 7.51 — 7.39 (m, 3H), 7.34 (dt, 3H), 6.77 (d, 1H), 6.13 (d, 1H), 4.11 — 3.96 (m, 1H), 3.70 (s, 2H), 3.66 — 3.54 (m, 2H), 3.06 (t, 2H), 2.13 (s, 3H), 1.93 (s, 3H), 1.67 (s, 1H), 1.63 (s, 2H), 1.58 (s, 2H), 1.53 (s, 6H), 1.41 (d, 3H).

EXAMPLE 44 6-[8-(1,3-benzothiazolylcarbamoyl)-1,1-dideutero-3 ,4-dihydroisoquinolin-2(1H)-yl][5- methyl(tricyclo[3.3.1 .13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 44A 2-(tert-butoxycarbonyl)-1,1 -dideutero-1 ,2,3,4-tetrahydroisoquinolinecarboxylic acid To a ydrofuran (40 mL) on of 2-(tert-butoxycarbonyl)-1,2,3,4- tetrahydroisoquinolinecarboxylic acid (5 g) and tetramethylethylenediamine (2.99 mL) was added dropwise t-butyllithium (1.7 M, 39.4 mL) at -78 °C. The e was stirred at -78 0C for 3 hours. To the resulting mixture, D20 (0.979 mL) was added dropwise and the reaction e was stirred at - 78 0C for 2 hours. The mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over NaZSO4, filtered, and concentrated. The crude product was used in next step without r purification. This procedure was repeated on the same material 5 times.

EXAMPLE 44B tert-butyl 8-(benzo[d]thiazolylcarbamoyl)—1,1-dideutero-1 ,2 etrahydroisoquinoline- carboxylate A mixture of triethylamine (1.753 g), (1H-benzo[d][1,2,3]triazol yloxy)tripyrrolidinylphosphonium hexafiuorophosphate(V) (4.51 g), EXAMPLE 44A —150— ation] sak (2.42 g) and benzo[d]thiazolamine (1.952 g) in romethane (50 mL) was stirred overnight at 30 oC. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine, dried over NaZSO4, filtered, and concentrated. The crude product was purified by flash chromotography (silica gel, 30%-~50% ethyl acetate / petroleum ether).

EXAMPLE 44C N-(benzo[d]thiazolyl)—1,1-dideutero-1,2,3 ,4-tetrahydroisoquinolinecarboxamide The title compound was prepared by substituting EXAMPLE 44B for EXAMPLE 43B in EXAMPLE 43C.

EXAMPLE 44D methyl 6-(8-(benzo azolylcarbamoyl)-1 ,1 -dideutero-1 ,2 ,3 ,4-tetrahydroisoquinolin-yl)— 3-bromopicolinate The title compound was prepared by tuting EXAMPLE 44C for EXAMPLE 43C in EXAMPLE 43D.

EXAMPLE 44E 1 5 methyl 6- [ 8-(1 ,3 -benzothiazolylcarbamoyl)(1 ,1 -diduetero-1 ,2 ,3 ,4-tetrahydroisoquinolin- yl]-3 - [5 -methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridine carboxylate The title compound was prepared by substituting EXAMPLE 44D for EXAMPLE 4A and EXAMPLE 3D for EXAMPLE 4B in EXAMPLE 4C.

EXAMPLE 44F 6-[8-(1,3-benzothiazolylcarbamoyl)(1,1-2H2)-3 ,4-dihydroisoquinolin-2(1H)-yl] [5-methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H—pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE 14A in EXAMPLE 14B. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 12.79 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 — 7.40 (m, 3H), 7.36 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.02 (s, 1H), 3.89 (dd, 2H), 3.70 (s, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.92 (s, 3H), 1.67 (s, 1H), 1.63 (s, 2H), 1.57 (s, 2H), 1.52 (s, 6H).

EXAMPLE 45 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl] -3 -(1- {[3-(2- 3 0 methoxyethoxy)tricyclo[3.3.1.13’7]decyl]methyl}-5 -methyl-1H-pyrazolyl)pyridine carboxylic acid E 45A 1-(5-(2-methoxyethoxy)—3 ,7-dimethyltricyclo[3.3. 1 .13’7]decyl)-1H-pyrazole The title compound was prepared by substituting E 26A for EXAMPLE 7A and 2-methoxyethanol for ol in EXAMPLE 7B. —151— [Annotation] sak E 45B l-((5methoxyethoxy)-3,7-dimethyltricyclo[3.3.l .13’7]dec-l-yl)methyl-lH- pyrazole The title compound was prepared by tuting EXAMPLE 45A for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 45C 4-bromo-l -((5 methoxyethoxy)-3 ethyltricyclo[3.3. l .13’7]dec-l-yl)-5 -methyl- 1 H-pyrazole The title compound was prepared by tuting EXAMPLE 45B for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 45D tert-buytl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-(5 - (2-methoxyethoxy)-3,7-dimethyltricyclo[3.3. l .13’7]dec-l-yl)-5 -methyl- 1H -pyrazol yl)picolinate The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 45E 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]( l -(5 -(2- methoxyethoxy)-3,7-dimethyltricyclo[3.3. l . 13’7]dec- l -yl)methyl- lH -pyrazol yl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 45D for EXAMPLE 2B in E 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.86 (br. s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 5H), 7.28 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78 (s, 2H), 3.21 (s, 3H), 3.01 (t, 2H), 2.11 (m, 5H), 1.50 (m, 12H).

EXAMPLE 46 6- [8-( l ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl] -3 -(l- {[1-(2- methoxyethyl)cyclooctyl]methyl} -5 -methyl- 1 H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 46A methyl cyclooctanecarboxylate To a on of cyclooctanecarbaldehyde (5.0 g) in methanol (300 mL) was added Oxone (22 g). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum and the e was d with ethyl acetate (300 mL) and washed with 1N aqueous HCl, water, and brine, dried over NaZSO4, filtered, and concentrated under reduced pressure to give the crude product.

EXAMPLE 46B methyl l-(2-methoxyethyl)cyclooctanecarboxylate —152— [Annotation] sak To a cooled (-78°C) solution of lithium diisopropylamide (2.0M, 20 mL) in tetrahydrofuran (20 mL) was added EXAMPLE 46A (5.27 g) in tetrahydrofuran (20 mL).

The mixture was stirred at -78°C for 30 minutes and a solution of 1-bromo-3 -methoxypropane (4.3 g) in tetrahydrofuran (10 mL) was added to the mixture. The mixture was stirred overnight and the temperature was allowed to warm up to room temperature. The mixture was ed with aqueous NH4C1 and extracted with ethyl acetate (3 00 mL) and washed with water (3x) and brine and dried over NaZSO4. Filtration and concentration of the solvent gave the crude t which was used in the next reaction without further purification.

EXAMPLE 46C (l-(2-methoxyethyl)cyclooctyl)methanol A solution of E 46B (6.5 g) in ether (50 mL) was added dropwise to a suspension of LiAlH4 (1.2 g) in ether (60 mL). Once the addition was finished, the mixture was refluxed for 90 minutes, cooled to 0°C and 2N aqueous NaOH (50 mL) was added slowly. The mixture was then extracted with ethyl acetate (3 00 mL) and the organic layer was washed with brine and dried over NaZSO4. Filtration and evaporation of the solvent provided the title compound.

EXAMPLE 46D l-((l -(2 xyethyl)cyclooctyl)methyl)- l H-pyrazole The title nd was prepared by substituting EXAMPLE 46C for 1- adamantanemethanol and 1H-pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2 -yl)- 1 H-pyrazole in EXAMPLE 2A.

EXAMPLE 46E l-(( l -(2-methoxyethyl)cyclooctyl)methyl)methyl- l H-pyrazole The title compound was prepared by substituting E 46D for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 46F 4-iodo- l -((l -(2-methoxyethyl)cyclooctyl)methyl)-5 -methyl- 1 H-pyrazole The title nd was prepared by tuting EXAMPLE 46E for EXAMPLE 16D in EXAMPLE 16E.

EXAMPLE 46G 6- [8-( l ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)—yl] -3 -(l- {[1-(2- methoxyethyl)cyclooctyl]methyl} -5 -methyl- 1 H-pyrazolyl)pyridinecarboxylic acid The title nd was ed by substituting EXAMPLE 46F for EXAMPLE 4A in EXAMPLE 4B, then substituting that product for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dé) 5: ppm 12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 6 H), 7.29 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.80 (s, 3H), 3.44 (t, 2H), 3.21 (s, 3H), 3.00 (t, 2H), 2.10 (s, 3H), 1.34 (m, 16H). —153— [Annotation] sak EXAMPLE 47 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano [tricyclo[3.3.1.13’7]decylamino]phenyl}pyridinecarboxylic acid EXAMPLE 47A 2-(tricyclo[3.3. 1 .13’7]decylamino)bromo-benzonitrile 2-Bromofluorobenzonitrile (300 mg) and 1-adamantane (295 mg) were added to dimethyl sulfoxide (5 mL). The on was stirred until reactants had dissolved. The solution was then heated in a ave reactor (Biotage) at 180°C for 20 minutes. The solution was added to ethyl ether, and washed with 1 M s HCl three times, and washed with brine. The combined organic layers were dried on anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 5% ethyl acetate (hexanes) to yield the product.

E 47B 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano [tricyclo[3 .3. 1 .13’7]decylamino]phenyl}pyridinecarboxylic acid utyl ester The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 47C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano [tricyclo[3.3.1.13’7]decylamino]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 47B for EXAMPLE 2B in EXAMPLE zc. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 8.03 (d, 1H), 7.79 (d, 1H), .58 (m, 2H), .29 (m, 6H), 7.06 (dd, 1H), 7.02 (d, 1H), 6.52 (d, 1H), 5.01 (bs, 2H), 3.91 (m, 2H), 3.03 (m, 2H), 2.10 (bs, 3H), 1.98 (bs, 6H), 1.68 (m, 6H).

EXAMPLE 48 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano clo[3.3. 1 .13’7]decylsulfanyl]phenyl}pyridinecarboxylic acid EXAMPLE 48A 2-(tricyclo[3.3.1.13’7]decylsulfanyl)bromo-benzonitrile 1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. ofluorobenzonitrile (3 00 mg) was added and the solution was heated to 130 °C for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound. —154— [Annotation] sak EXAMPLE 48B 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano [tricyclo[3.3.1.13’7]decylsulfanyl]phenyl}pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 48C 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-cyano [tricyclo[3.3. 1 .13’7]decylsulfanyl]phenyl}pyridinecarboxylic acid The title nd was ed by substituting EXAMPLE 48B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, ylsulfoxide-d 6) 8 ppm 12.86 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.68-7.60 (m, 3H), .32 (m, 6H), 7.08 (d, 1H), 5.04 (bs, 2H), 3.98 (t, 2H), 3.05 (t, 2H), 2.00 (bs, 3H), 1.83 (bs, 4H), 1.79-1.72 (m, 2H), 1.60 (m, 6H).

EXAMPLE 49 6-[8-(imidazo [1 ,2-a]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][5 -methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 49A 6-[8-(imidazo [1 ,2-a]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][5 -methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester The title compound was ed by substituting imidazo[1,2-a]pyridineamine for thiazolo[4,5-b]pyridineamine in EXAMPLE 30D.

EXAMPLE 49B 6-[8-(imidazo [1 ,2-a]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][5 -methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was ed by substituting EXAMPLE 49A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 11.66 (br s, 1H), 8.76 (d, 1H), 8.36 (s, 1H), 7.72 (d, 1H), 7.60 (dd, 1H), 7.55 (dd, 1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.37 (t, 1H), 7.27 (s, 1H), 7.24 (t, 1H), 6.93 (d, 1H), 4.96 (s, 2H), 3.88 (t, 2H), 3.71 (s, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.93 (br s, 3H), 1.65 (br d, 3H), 1.54 (br m, 9H).

EXAMPLE 50 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] (2-methyl-3 - {[tricyclo[3.3. 1 .13’7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid EXAMPLE 50A N—(3-bromomethylphenyl)tricyclo[3.3.1.13’7]decanecarboxamide 3-Bromomethylaniline (800 mg) and diisopropylethylamine (1667 mg) were added to dichloromethane (12 mL). 1-Adamantanecarbonyl de (940 mg) was added and the solution was stirred at room temperature for 16 hours. The solution was diluted with 50% —155— [Annotation] sak ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent volume was partially reduced under , and the solid material precipitated out of on, which was isolated by filtration to provide the title compound.

EXAMPLE 50B 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] (2-methyl-3 - {[tricyclo[3.3.1.13’7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid tert-butyl ester The title compound was ed by substituting EXAMPLE 50A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 50C 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] methyl-3 - {[tricyclo[3.3.1 .13’7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid The title compound was prepared by tuting EXAMPLE 50B for E 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (bs, 1H), 8.82 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.49-7.32 (m, 5H), 7.17-7.09 (m, 2H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.99 (bs, 2H), 3.96 (t, 2H), 3.03 (t, 2H), 2.00 (bs, 3H), 1.90 (bs, 9H), 1.69 (bs, 6H).

EXAMPLE 51 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-methyl-3 - [tricyclo[3.3.1.13’7]decylsulfamoyl]phenyl}pyridinecarboxylic acid EXAMPLE 51A 3-bromomethyl-N—(tricyclo[3.3.1.13’7]decyl)benzenesulfonamide 3-Bronu»24neflndbenzeneJrsuhbnylchknide(3001ng)andlradanuunanannne(l85 mg) were dissolved in dichloromethane (4 mL). Diisopropylethylamine (432 mg) was added, and the solution was stirred at room temperature for 16 hours. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to yield the product.

EXAMPLE 51B 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] (2-methyl-3 - {[tricyclo[3.3.1.13’7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid tert-butyl ester The title nd was prepared by substituting EXAMPLE 51A for EXAMPLE 20A in EXAMPLE 20B. —156— [Annotation] sak EXAMPLE 51C 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]—3 - {2-methyl-3 - [tricyclo[3.3.l.13’7]dec-l-ylsulfamoyl]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 51B for EXAMPLE 2B in E 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (bs, 1H), 12.58 (bs, 1H), 8.03 (d, 1H), 7.89 (dd, 1H), 7.79 (d, 1H), 7.66-7.58 (m, 1H), .30 (m, 6H), 7.24 (dd, 1H), 7.03 (d, 1H), 5.01 (bs, 2H), 3.95 (t, 2H), 3.04 (t, 2H), 2.32 (bs, 3H), 1.91 (m, 3H), 1.70 (m, 6H), 1.58-1.44 (m, 6H).

EXAMPLE 52 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3.3 . l . 13’7]dec- l -ylcarbonyl]amino}phenyl)pyridinecarboxylic acid EXAMPLE 52A N—(3-bromomethylphenyl)-N—methyltricyclo[3 .3. l .13’7]decane-l-carboxamide 3-Bromo-N,2-dimethylaniline (300 mg) and diisopropylethylamine (581 mg) were added to l,2-dichloroethane (5 mL). l-Adamantanecarbonyl chloride (328 mg) was added and the solution was heated at 50°C for three days. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 10% ethyl acetate (hexanes) to yield the title compound.

EXAMPLE 52B 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo[3.3. l .13’7]dec- l -ylcarbonyl]amino}phenyl)pyridinecarboxylic acid tertbutyl ester The title compound was prepared by substituting EXAMPLE 52A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 52C 1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3.3 . l . 13’7]dec- l -ylcarbonyl]amino}phenyl)pyridinecarboxylic acid The title nd was prepared by tuting EXAMPLE 52B for EXAMPLE 2B in E zc. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.24-7.14 (m, 2H), 7.04 (dd, 1H), 7.01 (d, 1H), 5.00 (bs, 2H), 3.93 (t, 2H), 3.04 (t, 2H), 2.98 (s, 3H), 1.91 (s, 3H), 1.82-1.71 (m, 6H), 1.61-1.41 (m, 9H). —157— [Annotation] sak EXAMPLE 53 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5 -methyl { [3 - (tetrahydro-2H-pyranylmethoxy)tricyclo[3.3. 1 .13’7]decyl]methyl}-1H-pyrazol yl)pyridinecarboxylic acid EXAMPLE 53A 1-(5 -(tetrahydropyranylmethoxy)-3,7-dimethyltricyclo [3.3. 1 .13’7]decyl)-1H-pyrazole The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE 7A and (tetrahydro-2H-pyranyl)methanol for methanol in E 7B.

EXAMPLE 53B 1-(5 -(tetrahydropyranylmethoxy)-3,7-dimethyltricyclo[3.3. 1 .13’7]decyl) -1H-pyrazole The title compound was prepared by substituting EXAMPLE 53A for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 53C 4-bromo(5 -(tetrahydropyranylmethoxy)-3,7-dimethyltricyclo [3.3 .1 - . 13’7]dec- 1 yl)methyl-1H-pyrazole The title compound was prepared by substituting EXAMPLE 53B for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 53D tert-buytl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-(5 - hydropyranylmethoxy)-3 ,7-dimethyltricyclo [3 .3 . 1 . 13 ’7]dec-1 -yl)-5 l-1H- pyrazolyl)picolinate The title compound was prepared by substituting EXAMPLE 53C for EXAMPLE 4A in EXAMPLE 4C.

E 53E 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5 -methyl { [3 - (tetrahydro-2H-pyranylmethoxy)tricyclo[3.3. 1 .13’7]decyl]methyl}-1H-pyrazol yl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 53D for E 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.84 (br. s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.47 (m, 3H), 7.35 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.80 (m, 4H), 3.22 (m, 6H), 3.01 (t, 2H), 2.11 (m, 5H), 1.51 (m, J=4.00 Hz, 15H).

EXAMPLE 54 1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-methyl-3 - [tricyclo[3.3.1.13’7]decylcarbamoyl]phenyl}pyridinecarboxylic acid —158— [Annotation] sak EXAMPLE 54A omethyl-benzoyl chloride 3-Bromomethylbenzoic acid (2000 mg) was added to dichloromethane (50 mL) and N,N-dimethylformamide (1 mL). Oxalyl chloride (649 mg) was added and the solution was stirred for three minutes. The mixture was washed with l M aqueous HCl three times, washed with brine, and dried on anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the product.

EXAMPLE 54B 3-bromomethyl-N—(tricyclo [3 .3 . l . l 3’7]dec-l -yl)benzamide The title compound was prepared by substituting l-adamananamine for o methylaniline and EXAMPLE 54A for l-adamantanecarbonyl chloride in EXAMPLE 50A.

EXAMPLE 54C tert-butyl 1 ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 - {2- methyl[tricyclo[3.3.l.13’7]dec-l-ylcarbamoyl]phenyl}pyridinecarboxylate The title nd was prepared by substituting E 54B for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 54D 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 - {2-methyl-3 - clo [3 .3. l . l 3’7]dec-1 -ylcarbamoyl]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 54C for EXAMPLE 2B in EXAMPLE zc. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 8.03 (d, 1H), 7.79 (d, 1H), 7.69 (s, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.17-7.14 (m, 2H), 7.05 (t, 1H), 6.99 (d, 1H), 4.99 (bs, 2H), 3.93 (t, 2H), 3.03 (t, 2H), 2.04 (bs, 12H), 1.64 (bs, 6H).

EXAMPLE 55 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo[3.3. l.13’7]dec-l-ylmethyl]amino}phenyl)pyridinecarboxylic acid EXAMPLE 55A 3-bromo-N,2-dimethyl-N—(tricyclo[3.3. 1 . 13’7]decylmethyl)aniline EXAMPLE 52A (232 mg) was dissolved in tetrahydrofuran (3 mL) and borane (l M in tetrahydrofuran, 2.6 mL) was added. The solution was stirred at room ature for 16 hours and was quenched slowly with methanol. s HCl (4M, 6 mL) was added and the solution was stirred at room temperature for four hours. The pH was adjusted to 9 using sodium carbonate and the solution was extracted with diethyl ether. The extract was washed with brine and dried on ous sodium sulfate. After filtration the solvent was removed under vacuum to yield the product. —159— [Annotation] sak EXAMPLE 55B 6- [ 8-( l 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] methyl-3 - {methyl[tricyclo [3 .3 3’7]dec- l -ylmethyl]amino}phenyl)pyridinecarboxylic acid . l . l tert- butyl ester The title compound was prepared by substituting EXAMPLE 55A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 55C 6- [ 8-( l 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo[3.3. l.13’7]dec-l-ylmethyl]amino}phenyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 55B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 5 ppm 12.89 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.20-7.05 (m, 2H), 6.98 (d, 1H), 6.70 (d, 1H), 4.98 (bs, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 2.77 (bs, 2H), 2.61 (bs, 3H), 2.07 (bs, 3H), 1.87 (bs, 3H), 1.66-1.50 (m, 6H), 1.43 (bs, 6H).

EXAMPLE 56 6- [8-( l ,3-benzothiazolylcarbamoyl)-3 ydroisoquinolin-2(lH)-yl] -3 -( l - { [2-(2- methoxyethyl)tricyclo [3 .3. l .13’7]dec-2 -yl]methyl} - l zolyl)pyridinecarboxylic acid EXAMPLE 56A methyl tricyclo [3 .3 . l . l 3’7]decanecarboxylate To a solution of adamantanecarboxylic acid 1 (0.486 g, 2.70 mmol) in ethyl acetate (10 mL) / ol (5 mL) was dropwise added (trimethylsilyl)diazomethane (1.348 ml, 2.70 mmol) and the mixture was stirred at room temperature for 14 hours. The on mixture was concentrated and purified by flash chromotography (silica 40 g, 0% - 30% ethyl acetate/hexanes).

E 56B methyl 2-(2-methoxyethyl)tricyclo [3.3. 1.13’7]decanecarboxylate To a solution of E 56A (0.314 g) in tetrahydrofilran (5 mL) was added dropwise lithium diisopropylamide (1.401 mL) at -78 oC. The reaction mixture was stirred for 60 minutes and 2-bromoethyl methyl ether (0.562 g) was added. The reaction mixture was slowly warmed up to room temperature, d at room temperature overnight, quenched with saturated aqueous NH4Cl solution (2 mL), and extracted with ether. The combined organic layer was dried over , filtered, concentrated and purified by flash chromotography (silica 40 g, 0% - 30% ethyl acetate/hexanes).

EXAMPLE 56C [2-(2-methoxyethyl)tricyclo[3.3.1.13’7]decyl]methanol —160— ation] sak To a solution of EXAMPLE 56B (135 mg) in tetrahydrofuran (5 mL) was added dropwise lithium aluminum hydride (0.535 mL) at room temperature. The reaction mixture was stirred for for 14 hours and sodium hydroxide (0.324 mL) was carefully added. The reaction mixture was stirred at room temperature for 60 minutes, filtered and concentrated.

E 56D 1-{[2-(2-methoxyethyl)tricyclo[3.3.1.13’7]decyl]methyl}-lH-pyrazole The title compound was prepared by substituting EXAMPLE 56C for 1- adamantanemethanol and pyrazole for 3,5-dimethyl(4,4,5,5 -tetramethyl-1 ,3,2- dioxaborolan-2 -yl)- 1 H-pyrazole in EXAMPLE 2A.

EXAMPLE 56E 4-bromo{[2-(2-methoxyethyl)tricyclo[3.3.1.13’7]decyl]methyl}-1H-pyrazole The title nd was prepared by substituting EXAMPLE 56D for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 56F utyl 6-(8-(benzo[d]thiazolylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)—yl)(l - { [2- (2-methoxyethyl)tricyclo [3 .3 . 1 . 13’7]decyl]methyl}- 1 H-pyrazolyl)picolinate The title compound was prepared by substituting EXAMPLE 56E for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 56G 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)—yl] -3 -(1- - methoxyethyl)tricyclo [3 .3. 1 .13’7]dec-2 -yl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 56F for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-dg) 5 ppm 8.04 (d, 1H), 7.80 (d, 1H), 7.69 (d, 2H), 7.61 (d, 1H), 7.54 (s, 1H), 7.51 — 7.45 (m, 1H), 7.43 (d, 1H), 7.35 (dd, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 4.33 (s, 2H), 3.86 (t, 2H), 3.47 (d, 2H), 3.29 — 3.22 (m, 2H), 3.19 (s, 3H), 3.00 (t, 2H), 2.33 — 2.24 (m, 2H), 2.01 (d, 2H), 1.90 (s, 1H), 1.82 (s, 1H), 1.67 (s, 2H), 1.56 (dd, 8H).

EXAMPLE 57 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl][5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-1,2,3 -triazolyl]pyridinecarboxylic acid EXAMPLE 57A 1-(azidomethyl)tricyclo[3.3.1.13’7]decane l-Adamantanemethanol (500 mg) was ved in dichloromethane (15 mL). The solution was d in an ice bath and triethylamine (0.587 mL) was added, followed by methanesulfonyl chloride (0.258 mL). The on e was stirred for 4 hours at 0°C, then transferred to a separatory funnel and rinsed with 1N aqueous HCl (15 mL), saturated —161— [Annotation] sak aqueous NaHC03 (15 mL) and brine (15 mL). The organic extracts were dried (NagsO4), filtered, and concentrated. A portion of the resulting crude mesylate (293 mg) and sodium azide (390 mg) were combined in N,N-dimethylformamide (1.2 mL) and the reaction mixture was heated to 120°C overnight, then cooled to room temperature and partitioned between ethyl acetate (3 x 15 mL) and water (20 mL). The organic extracts were dried (NaZSO4), filtered, and trated to provide the title compound, which was used in the next step without further purification.

EXAMPLE 57B 1-(tricyclo[3.3. l .13’7]decylmethyl)methyl(tributylstannyl)-1H-1,2,3 -triazole EXAMPLE 57A (224 mg), tributyl-n-propynyltin (390 mg) and toluene (2 mL) were combined in a sealed reaction vessel and heated to 130°C overnight. The reaction mixture was placed atop a column and purified by flash chromatography on silica gel eluting with 0- % ethyl acetate in s to provide the title compound.

EXAMPLE 57C methyl 6-aminobromopicolinate To a solution of 6-aminobromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the on mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (5 00 mL) and washed with aqueous Na2C03 solution (twice), then washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.

EXAMPLE 57D methyl 3-bromofluoropicolinate To a solution of nitrosonium uoroborate (17.8 g) in dichloromethane (100 mL) at 5°C was added E 57C (26.1 g) in dichloromethane (250 mL) over 1 hour. The reaction mixture was stirred an additional 30 minutes at 5°C, and allowed to warm to room temperature overnight. The reaction mixture was ed with pH 7 buffer (100 mL), and neutralized with solid potassium ate. The resulting mixture was ted with ether (twice), and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 1-10% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 57E methyl 3 -(tricyclo[3.3.1.13’7]decylmethyl)methyl-1H-1,2,3 -triazolyl)—6- fluoropicolinate EXAMPLE 57B (333 mg), EXAMPLE 57D (178 mg) and PPh3)2 (22 mg) were combined in a sealed tube with N,N-dimethylformamide (1.3 mL) and the mixture was sparged with nitrogen and then heated to 100°C overnight. ted aqueous KF (2 mL) and ethyl acetate (2 mL) were added and the e was d for 1 hour, and filtered through —162— [Annotation] sak diatomaceous earth, rinsing the filter cake with ethyl acetate (20 mL). The filtrate was placed into a separatory funnel and the layers were ted. The aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were dried (NaZSO4), filtered, concentrated, and purified by flash chromatography on silica gel using 0 to 50% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 57F methyl 6-(8-(benzo [d]thiazolylcarbamoyl)—3 ydroisoquinolin-2(1H)-yl)(1- clo[3.3.1.13’7]decylmethyl)methyl-1H-1,2,3-triazolyl)picolinate EXAMPLE 1C (110 mg), EXAMPLE 57E (93 mg) and cesium carbonate (394 mg) were combined in DMSO (1.2 mL) and the mixture was heated to 65°C overnight. The reaction e was then partitioned between ethyl acetate (3 x 10 mL) and water (10 mL).

The organic extracts were dried (NaZSO4), filtered, and concentrated, then purified by flash chromatography using 0 to 70% ethyl e in s to provide the title compound.

EXAMPLE 57G 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-1,2,3 -triazolyl]pyridinecarboxylic acid EXAMPLE 57F (83 mg) was dissolved in e (1 mL) and LiOH (1M in water, 0.616 mL) was added. The mixture was heated to 60°C for 3 hours, then cooled to room temperature and diluted with 1N NaHZPO4 (25 mL) and extracted with ethyl acetate (three times). The organic extracts were dried (NaZSO4), filtered, and concentrated. The residue was purified by flash tography on silica gel eluting with 0 to 10% methanol in romethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 12.68 - 12.90 (br m, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.42 - 7.51 (m, 2H), 7.31 - 7.41 (m, 2H), 7.00 (d, 1H), 5.00 (s, 2H), 3.89 - 3.97 (m, 4H), 3.02 (t, 2H), 2.16 (s, 3H), 1.94 (s, 3H), 1.53 - 1.69 (m, 6H), 1.52 (s, 6H).

EXAMPLE 5 8 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[3- methoxytricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid EXAMPLE 58A 3-iodocyano{[3-methoxytricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrrole The title compound was prepared by substituting 3-methoxyadamantanemethanol for adamantaneethanol and EXAMPLE 23D for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-pyrazole in EXAMPLE 2A. —163— [Annotation] sak EXAMPLE 58B 6-[8-(Benzothiazolylcarbamoyl)-3 ,4-dihydro- l H-isoquinolin-2 -yl] [5-cyano- l -(3 - methoxy-adamantan- l hyl)methyl- 1 H-pyrrolyl] -pyridinecarboxylic acid tertbutyl ester The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE 20A in E 20B.

EXAMPLE 58C 6- [8-(1 ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl](5-cyano-l - { [3- methoxytricyclo[3.3.l.13’7]dec-l-yl]methyl}methyl-lH-pyrrolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE 2B in E 2C. 1H NMR (400 MHz, dimethylsulfoxide-dG) 5 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51 (d, 1H), 7.42 - 7.50 (m, 2H), 7.33 - 7.39 (m, 2H), 6.95 (d, 1H), 6.83 (s, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.82 (s, 2H), 3.10 (s, 3H), 3.01 (t, 2H), 2.18 (s, 2H), 2.09 (s, 3H), 1.40 - 1.65 (m, 12H).

EXAMPLE 59 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(lH)-yl] methyl-l -(2- oxatricyclo[3.3.l.13’7]dec-l-ylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid EXAMPLE 59A l-(2 -oxatricyclo [3 .3 . l . l 3’7]dec- l hyl)chloro- lH-pyrazole The title nd was prepared by substituting EXAMPLE 13A for 1- adamantanemethanol and 4-chloro-lH-pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2 -yl)- l zole in EXAMPLE 2A.

EXAMPLE 59B l-(2-oxatricyclo[3.3.l dec-l-ylmethyl)chloro-5 -methyl- lH-pyrazole A solution of EXAMPLE 59A (0.25 g) in tetrahydrofuran (3 mL) was cooled to - 78°C butyllithium was (0.48 mL) added dropwise. Additional tetrahydrofuran (2 mL) was added and the reaction mixture was stirred for 1 hour at -78°C. To the reaction mixture was added iodomethane (0.08 mL) in one n and the reaction was allowed to warm to 0°C.

After 30 minutes, the reaction was diluted with ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 20% ethyl acetate/hexanes provided the title compound.

EXAMPLE 59C l-(2-oxatricyclo [3 .3. l .13’7]dec- l -ylmethyl)(4,4,5 ,5-tetramethyl-l ,3,2-dioxaborolan methylyl)-lH—pyrazole —164— [Annotation] sak A solution of EXAMPLE 59B (0.13 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 mL), triethylamine (0.20 mL), dicyclohexyl(2',6'-dimethoxybiphenylyl)phosphine (0.04 g) and bis(benzonitrile)palladium(H) chloride (6 mg) was heated in dioxane (2.5 mL) at 105°C.

After 2 hours, the reaction mixture was diluted with ethyl e and washed with water and dried over magnesium sulfate. After filtration and concentration, silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl e/hexanes provided the title compound.

EXAMPLE 59D 6-[8-(1,3 thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl] [5-methyl-1 -(2- oxatricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid A solution of a 1:1 ratio of dioxane and water was degassed with nitrogen for 45 minutes. This solution (5 mL) was added to EXAMPLE 1E (0.31 g), EXAMPLE 59C (0.22 g), potassium phosphate (0.41 g), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.014 g) and 7-tetramethyltetradecane-2,4,8-trioxaphosphaadamantane (0.023 g). The mixture was degassed and heated to 90°C under nitrogen ght. The reaction mixture was , diluted with ethyl acetate (100 mL) and washed with water (three x 50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate/hexanes gave the d ester. The ester was dissolved in dichloromethane (0.5 mL), and TFA (0.5 mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated, loaded onto silica gel and eluted with a gradient of 1% to 4% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8: ppm 12.84 (s, 1H), 8.07 - 7.99 (m, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53 - 7.40 (m, 3H), 7.40 - 7.31 (m, 2H), 7.26 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.96 (s, 1H), 3.93 - 3.82 (m, 4H), 3.01 (t, 2H), 2.14 (s, 3H), 2.08 (s, 2H), 1.86 - 1.65 (m, 4H), 1.56 (m, 6H).

EXAMPLE 60 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[2-cyano clo[3.3.1 .13’7]decylsulfonyl)phenyl]pyridinecarboxylic acid EXAMPLE 60A 2-bromo(tricyclo [3 .3. 1 .13’7]decylthio)benzonitrile To a solution of adamantanethiol (1.01 g) in methylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in l oil) and the reaction was stirred for 10 minutes. 2-Fluorobromobenzonitrile (1 g) was added and the mixture was heated to 80°C for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification. —165— ation] sak EXAMPLE 60B 2-bromo(tricyclo [3.3. 1.13’7]decylsulfonyl)benzonitrile A mixture of EXAMPLE 60A (1.73 g) and m-chloroperoxybenzoic acid (2.46 g) in chloroethane (50 mL) was stirred overnight. The on was diluted with ether (3 00 mL), washed twice with Na2C03 on, and brine, then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 2-50% ethyl acetate in s to give the desired product.

EXAMPLE 60C tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)—3 ,4-dihydroisoquinolin-2( 1 H)-yl)-3 -(2- cyano( tricyclo[3.3.1.13’7]decylsulfonyl)phenyl)picolinate The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE 19A and EXAMPLE 4B for EXAMPLE 3D in EXAMPLE 19B.

EXAMPLE 60D 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[2-cyano (tricyclo[3.3. 1 .13’7]decylsulfonyl)phenyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 60C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.65 (br s, 1H), 8.03 (d, 1H), 7.94 (d, 2H), 7.77 (m, 2H), 7.70 (d, 1H), 7.62 (m, 1H), 7.44 (m, 2H), 7.30 (m, 2H), 7.12 (d, 1H), 5.06 (s, 2H), 4.02 (t, 2H), 3.05 (m, 2H), 2.10 (m, 3H), 1.88 (s, 6H), 1.61 (m, 6H).

E 61 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl] -2'- [cyclooctyl(methyl)amino] -3 '-methyl-3 ,4'-bipyridinecarboxylic acid EXAMPLE 61A N-cyclooctyliodomethylpyridinamine 2-Fluoroiodomethylpyridine (700 mg) in cyclooctanamine (3.8 g) was heated at 130°C overnight, cooled and diluted with dichloromethane. The resulting mixture was loaded onto a silica gel cartridge, eluting with 0 — 100% dichloromethane in hexanes to provide the title compound.

EXAMPLE 61B N-cyclooctyliodo-N,3-dimethylpyridinamine EXAMPLE 61A (150 mg), Cs2C03 (142 mg) and CH31 (0.027 mL) in N,N- dimethylacetamide (2 mL) was stirred at 38 OC ght. More CH31 (0.5 mL) and sodium hydride (52.3 mg, 60% in mineral oil) were added. The resulting mixture was stirred at 39°C for 2 days, quenched with water and diluted with ethyl acetate. The organic layer was washed with brine and concentrated. The e was purified by Prep HPLC using Gilson system eluting with 20-80% acetonitrile in 0.1% TFA/water to provide the title compound. —l66— [Annotation] sak EXAMPLE 61C tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'— (cyclooctyl(methyl)amino)-3'-methyl-3,4'-bipyridinecarboxylate The title compound was ed by substituting E 61B for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 61D 6-( 8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'— (cyclooctyl(methyl)amino)-3 '-methyl-3 ,4'-bipyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 61C for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-dG) 5 ppm 12.88 (s, 2H), 8.01 - 8.07 (m, 2H), 7.79 (d, 1H), 7.63 (d, 1H), 7.59 (d, 1H), 7.43 - 7.50 (m, 2H), 7.32 - 7.41 (m, 2H), 7.07 (d, 1H), 6.88 (s, 1H), 5.03 (s, 2H), 3.96 (t, 2H), 3.04 (t, 2H), 2.82 (s, 3H), 2.02 (s, 3H), 1.36 - 1.87 (m, 15 H).

EXAMPLE 62 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—3-[5-methyl-1 - (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 62A l-(tricyclo[3.3.l.13’7]decylmethyl)-1H—pyrazole The title nd was prepared by substituting EXAMPLE 10A for 1- adamantanemethanol and pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2 -yl)- 1 H-pyrazole in EXAMPLE 2A.

EXAMPLE 62B -methyl-1 -(tricyclo [3 .3 . 1 . 13’7]decylmethyl)-1H—pyrazole To a solution of EXAMPLE 62A (0.192 g, 0.888 mmol) in tetrahydrofuran (1 mL) / toluene (1 mL) was added n-butyllithium (1.6 M, 0.721 mL) at 0 oC. The reaction e was stirred for 60 minutes. Then CH3I (0.166 mL) was added and stirring continued for 3 hours at 0 oC. The on mixture was quenched with water, extracted with diethyl ether, dried over , filtered, and concentrated.

EXAMPLE 62C 4-bromo-5 -methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazole The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE 3B in EXAMPLE 3C.

EXAMPLE 62D tert—butyl 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—3-[5 1 -(tricyclo [3 .3. l .13’7]decylmethyl)- 1H-pyrazolyl]pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 62C for EXAMPLE 4A in EXAMPLE 4C. —167— [Annotation] sak EXAMPLE 62E 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-[5-methyl-l - (tricyclo[3.3.l.13’7]decylmethyl)-lH-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by tuting EXAMPLE 62D for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, ylsulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53 — 7.40 (m, 3H), 7.40 — 7.31 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 4.13 (d, 2H), 3.91 — 3.85 (m, 2H), 3.02 (t, 2H), 2.18 (t, 1H), 2.13 (s, 3H), 2.00 (d, 2H), 1.90 — 1.73 (m, 4H), 1.74 — 1.59 (m, 6H), 1.53 (d, 2H).

EXAMPLE 63 6-[8-( l ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(l H)-yl] [l -( {3 -[2-(2- methoxyethoxy)ethoxy]tricyclo[3.3. l .13’7]dec- l -yl}methyl)-5 -methyl- 1 H-pyrazol yl]pyridinecarboxylic acid EXAMPLE 63A l-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)-lH-pyrazole The title compound was prepared by tuting EXAMPLE 26A for EXAMPLE 7A and 2-(2-methoxyethoxy)ethanol for methanol in EXAMPLE 7B.

EXAMPLE 63B l-( {3 -[2-(2-methoxyethoxy)ethoxy]tricyclo [3 .3. l . l 3’7]dec- l -yl}methyl)-5 -methyl- 1H- pyrazole The title compound was prepared by substituting EXAMPLE 63A for EXAMPLE 3A in EXAMPLE 3B.

E 63C 4-bromo-l-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.l .13’7]dec-l-yl}methyl) methyl- 1 H-pyrazole The title compound was prepared by substituting EXAMPLE 63B for EXAMPLE 3B in EXAMPLE 3C, with the modification that the title compound was purified by RP-HPLC on a Gilson system, eluting with a gradient of 20% to 100% acetonitrile in water containing 0.1% V/V oroacetic acid.

EXAMPLE 63D utyl 6-(8-(benzo [d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl)-3 - [l -( {3 -[2-(2 -methoxyethoxy)ethoxy]tricyclo [3 .3 . l . l 3’7]dec- l -yl}methyl)methyl- l H- pyrazolyl]picolinate The title compound was ed by substituting EXAMPLE 63C for EXAMPLE 4A in EXAMPLE 4C. —168— [Annotation] sak EXAMPLE 63E 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(l H)-yl] [l -( {3 -[2-(2- methoxyethoxy)ethoxy]tricyclo[3.3. l dec- l -yl}methyl)-5 -methyl- 1 H-pyrazol yl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 63D for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 5 ppm 12.84 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.36 (m, 2H), 7.27 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78 (s, 2H), 3.48 (m, 2H), 3.44 (s, 3H), 3.22 (s, 3H), 3.02 (t, 2H), 2.10 (m, 5H), 1.54 (m, 12H).

EXAMPLE 64 1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[(tricyclo[3.3. l . 13’7]decyl] carbamoyl}phenyl)pyridinecarboxylic acid EXAMPLE 64A 3-bromo-N,2-dimethyl-N—(tricyclo[3.3.l.13’7]decyl)benzamide The title compound was prepared by tuting antanyl-N-methyl-amine for l-adamantanamine and 3-bromomethylbenzolyl chloride for l-adamantanecarbonyl chloride in EXAMPLE 50A.

EXAMPLE 64B 1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo[3.3. l . l 3’7]decyl]carbamoyl}phenyl)pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting E 64A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 64C 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3 .3 3’7]dec-2 -yl]carbamoyl}phenyl)pyridinecarboxylic acid . l . l The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE 2B in EXAMPLE zc. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.50-7.32 (m, 6H), 7.20 (t, 1H), 7.08-6.95 (m, 2H), 4.99 (bs, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 2.94 (bs, 3H), 2.22 (bs, 3H), 2.05-1.60 (m, 15H).

EXAMPLE 65 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl] [5 -methyl( { l - [2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)- 1 H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 65A l-((5 -methyl- 1 H-pyrazol- l -yl)methyl)cyclooctanol To a cold (-78°C) solution of llithium (10 mL, 2.5M) in tetrahydrofuran (20 mL) was added 1,5-dimethyl-lH-pyrazole (2.0 g) in tetrahydrofuran (10 mL) dropwise Via —169— [Annotation] sak syringe. After 1 hour, cyclooctanone (2.63 g) in tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with additional ethyl acetate.

The combined organics were dried over NaZSO4, filtered, and concentrated to provide the title compound.

EXAMPLE 65B yl((1 -(2-(methylsulfonyl)ethoxy)cyclooctyl)methyl)- 1 zole Sodium hydride (60% dispersion in mineral oil, 200 mg) was added to a stirred solution of EXAMPLE 65A (667 mg) in tetrahydrofuran (10 mL) and the e was stirred at room temperature for 30 minutes before the addition of methyl Vinyl sulfone (1.27 g). The mixture was stirred at room temperature for 3 hours. Aqueous NH4C1 was added to quench the reaction and the mixture was extracted with ethyl acetate (three times) and the combined organic layers were washed with water and brine, dried over NaZSO4, and filtered. The filtrate was concentrated to provide the crude product.

EXAMPLE 65C 4-iodo-5 -methyl((1 -(2-(methylsulfonyl)ethoxy)cyclooctyl)methyl)- 1 H-pyrazole The title compound was prepared by tuting EXAMPLE 65B for EXAMPLE 16D in EXAMPLE 16E.

EXAMPLE 65D 6-[8-( 1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl] [5 -methyl( {1 - [2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting E 65C for EXAMPLE 4A in EXAMPLE 4B, then substituting that product for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 6 H), 7.31 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.07 (s, 3H), 3.89 (t, 2H), 3.74 (t, 2H), 3.26 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 2.15 (m, 3H), 1.58 (m, 14 H).

EXAMPLE 66 1,3 thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl][5-methyl(2- cyclo[3.3.1.13’7]decylmethyl)-1H-1,2,3 -triazolyl]pyridinecarboxylic acid EXAMPLE 66A 1-(azidomethyl)oxatricyclo [3 .3 . 1 . ecane The title compound was prepared by substituting 1-(2-oxatricyclo[3.3.1.13’7]decyl)- methanol for l-adamantanemethanol in EXAMPLE 57A.

EXAMPLE 66B 1-(2 -oxatricyclo[3 .3. 1 .13’7]dec- 1 hyl)methyl(tributylstannyl)— 1 H-l ,2,3 -triazole —170— [Annotation] sak The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE 57A in EXAMPLE 57B.

EXAMPLE 66C tert-butylbromof1uoropicolinate The title nd was prepared by substituting 3-bromofluoropicolinic acid for 3-bromochloropicolinic acid in EXAMPLE 1D.

EXAMPLE 66D utyl 3 -(1-(2-oxatricyclo[3.3.1.13’7]decylmethyl)methyl-1H-1,2,3 -triazolyl) fluoropicolinate The title nd was prepared by substituting EXAMPLE 66B for E 57B and EXAMPLE 66C for EXAMPLE 57D in EXAMPLE 57E.

EXAMPLE 66E tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)-3 -(1-(2- oxatricyclo[3.3.1.13’7]decylmethyl)methyl-1H-1,2,3-triazolyl)picolinate The title compound was prepared by substituting EXAMPLE 66D for EXAMPLE 57E in EXAMPLE 57F.

EXAMPLE 66F 6-(8-(benzo [d]thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)(1-(2- oxatricyclo[3.3.1.13’7]decylmethyl)methyl-1H-1,2,3-triazolyl)picolinate The title compound was ed by tuting EXAMPLE 66E for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.85 (s, 1H), 12.72 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59 - 7.67 (m, 2H), 7.41 - 7.51 (m, 2H), 7.32 - 7.40 (m, 2H), 7.00 (d, 1H), 4.99 (s, 2H), 4.16 (s, 2H), 3.96 (s, 1H), 3.93 (t, 2H), 3.03 (t, 2H), 2.19 (s, 3H), 2.10 (s, 2H), 1.68 - 1.84 (m, 4H), 1.51 - 1.66 (m, 6H).

EXAMPLE 67 3- [5 -methyl(2-oxatricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8- ([ 1 ,3]thiazolo [5 ,4-b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl]pyridine carboxylic acid EXAMPLE 67A 2 -(5 -bromo(tert-butoxycarbonyl)pyridin-2 -yl)-1,2 ,3,4-tetrahydroisoquinolinecarboxylic acid A solution of methyl 1,2,3,4-tetrahydroisoquinolinecarboxylate, hydrochloric acid (13.6 g), tert-butyl 3-bromochloropicolinate (17.4 g) and cesium carbonate (39 g) were stirred together in N,N-dimethylacetamide (1 10 mL) and heated at 120°C under nitrogen overnight. The on mixture was cooled, d with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried over sodium —171— [Annotation] sak sulfate, filtered and concentrated. Silica gel tography using 20-100% ethyl acetate in hexanes provided the title compound.

E 67B tert-butyl 3-bromo(8-(thiazolo [5 ,4-b]pyridinylcarbamoyl)-3 ,4-dihydroisoquinolin- 2(1H)—yl)picolinate The title compound was prepared by tuting thiazolo[5,4-b]pyridinamine for benzo[d]thiazolamine and EXAMPLE 67A for 2-(tert—butoxycarbonyl)—1,2,3,4- tetrahydroisoquinolinecarboxylic acid in EXAMPLE 1B.

EXAMPLE 67C 3-[5-methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([1,3]thiazolo[5 ,4- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 67B for EXAMPLE 1E in EXAMPLE 59D. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 12.98 (s, 1H), 12.76 (s, 1H), 8.52 (dd, 1H), 8.16 (d, 1H), 7.62 (d, 1H), 7.57 — 7.42 (m, 3H), 7.37 (t, 1H), 7.26 (s, 1H), 6.96 (d, 1H), 4.95 (s, 2H), 3.96 (s, 1H), 3.92 — 3.82 (m, 4H), 3.02 (t, 2H), 2.14 (s, 3H), 2.08 (s, 2H), 1.73 (m, 4H), 1.56 (m, 6H).

EXAMPLE 68 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-methyl-3 - [methyl(2-oxatricyclo[3.3. 1 decylcarbonyl)amino]phenyl}pyridinecarboxylic acid EXAMPLE 68A N-(3-bromomethylphenyl)-N-methyloxatricyclo[3.3.1.13’7]decylcarboxamide A mixture of oxatricyclo[3.3.1.13’7]decyl)carboxylic acid (137 mg) and oxalyl chloride (0.132 mL) in dichloromethane (3 mL) was d for 4 days. 3-Bromo-N,2- dimethylaniline (451 mg) and triethylamine (0.2 mL) were added, and the reaction mixture was stirred for 24 hours. The mixture was chromatographed on silica gel using 1-10% ethyl acetate in hexanes to give the desired product.

E 68B tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)—3 ,4-dihydroisoquinolin-2( 1 H)-yl)-3 -(2- methyl(N-methyl oxatricyclo[3 3.3.1.13’7]decylcarboxamido)phenyl)picolinate The title compound was prepared by tuting EXAMPLE 68A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 68C 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 - {2-methyl-3 - l(2-oxatricyclo[3.3. 1 .13’7]decylcarbonyl)amino]phenyl}pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 68B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.65 (br s, 1H), 8.02 (d, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.40 (m, 5H), 7.09 (m, 2H), 6.96 (m, 3H), 4.99 (s, 2H), —172— [Annotation] sak 3.91 (t, 2H), 3.48 (m, 2H), 3.00 (s, 3H), 2.18 (m, 2H), 1.75-2.01 (m, 9H), 1.69 (m, 2H), 1.51 (m, 1H), 1.33 (m, 2H).

EXAMPLE 69 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3 .3 . l . l3’7]decyl]sulfamoyl}phenyl)pyridinecarboxylic acid EXAMPLE 69A 3 -bromo-N,2-dimethyl-N—(tricyclo[3.3 . 1 . 13’7]decyl)benzenesulfonamide The title compound was prepared by substituting N-methyladamantylamine for l- adamantanamine in EXAMPLE 51A.

EXAMPLE 69B 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3.3 . l . 13’7]dec-2 -yl] sulfamoyl}phenyl)pyridinecarboxylic acid ter-butyl ester The title compound was prepared by substituting EXAMPLE 69A for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 69C 6-[8-(1, 3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] (2-methyl-3 - {methyl[tricyclo [3 .3 . l . ecyl]sulfamoyl}phenyl)pyridinecarboxylic acid The title compound was ed by substituting E 69B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 5 ppm 12.85 (bs, 1H), 12.63 (bs, 1H), 8.03 (d, 1H), 7.78 (m, 2H), 7.63 (d, 1H), 7.49-7.34 (m, 6H), 7.31 (td, 1H), 7.03 (d, 1H), 5.01 (bs, 2H), 3.94 (t, 2H), 3.04 (t, 2H), 2.92 (s, 3H), 2.26 (s, 3H), 2.17 (bs, 2H), 1.81- 1.69 (m, 9H), 1.63 (bs, 2H), 1.45 (d, 2H).

EXAMPLE 70 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3'-methyl-2'- clo[3.3. 1 . 13’7]decylsulfonyl)-3,4'-bipyridinecarboxylic acid To a cooled (0°C) solution of E 74B (150 mg) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (100 mg, 77%). The mixture was stirred at 00 C for minutes. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous Na28203, aqueous NaHC03, water, and brine and dried over NaZSO4. After filtration, the mixture was concentrated and the crude product was loaded on a column and eluted with 20% ethyl acetate in dichloromethane to give the expected product. The pure ester was then dissolved in dichloromethane/TFA (1:1, 10 mL) and stirred at room temperature overnight.

After filtration, the mixture was concentrated and the residue was dissolved in romethane and loaded on a column and eluted with 5% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (s, 1H), —173— [Annotation] sak 8.56 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 7.40 (m, 6 H), 7.09 (d, 1H), 5.03 (s, 3H), 3.96 (t, 2H), 3.04 (t, 2H), 2.34 (s, 3H), 2.07 (m, 4H), 1.97 (m, 6 H), 1.60 (m, 6 H).

EXAMPLE 71 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]-3 -[5-cyano methyl-l -(2-oxatricyclo [3.3 .1 .13’7]dec-l-ylmethyl)-lH-pyrrolyl]pyridinecarboxylic acid EXAMPLE 71A -methyl- l -(2-oxa-tricyclo[3.3 .1 .13’7]dec-l-ylmethyl)-lH-pyrrolecarbonitrile The title nd was prepared by substituting l-hydroxymethyloxadamantane for l-adamantanemethanol and omethylpyrrole for 3,5-dimethyl(4,4,5,5- tetramethyl-l ,3,2-dioxaborolanyl)—lH-pyrazole in EXAMPLE 2A.

EXAMPLE 71B 4-bromo-5 -methyl-l-(2-oxa-tricyclo[3.3.l.13’7]dec-l-ylmethyl)-lH-pyrrolecarbonitrile The title compound was prepared by substituting E 71A for E 3B in EXAMPLE 3C.

EXAMPLE 71C methyl 6-(8-(benzo [d]thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl)-3 - bromopicolinate The title compound was prepared by substituting methyl 3-bromofluoropicolinate for EXAMPLE 1D in EXAMPLE 1E.

EXAMPLE 71D methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)(4,4,5,5- tetramethyl- l ,3 ,2-dioxaborolanyl)picolinate To a solution of EXAMPLE 71C (500 mg), [l,l'— phenylphosphino)ferrocene]dichloropalladium(H) romethane (46.8 mg) and triethylamine (0.399 mL) in acetonitrile (7 mL) and tetrahydrofuran (3.5 mL) was added 4,4,5,5-tetramethyl-l ioxaborolane (0.416 mL). The mixture was heated at 100°C in a Biotage Initiator microwave reactor for 30 minutes, cooled, diluted with ethyl e, and washed with brine. The organic layer was concentrated. The e was purified by flash chromatography, eluting with 0 - 17% ethyl acetate in dichloromethane to provide the title compound.

EXAMPLE 71E 6- [ 8-(B enzothiazolylcarbamoyl)-3 ,4-dihydro- l H-isoquinolin-2 -yl] -3 - [5-cyanomethyl- l - (2-oxa-tricyclo[3.3.l .13’7]dec-l-ylmethyl)-lH-pyrrolyl]-pyridinecarboxylic acid methyl ester The title compound was prepared by substituting EXAMPLE 71D for EXAMPLE 4B and EXAMPLE 71B for EXAMPLE 20A in EXAMPLE 20B. —174— [Annotation] sak EXAMPLE 71F 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[5-cyano methyl-1 atricyclo [3.3 .1 .13’7]decylmethyl)-1H-pyrrolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 71E for EXAMPLE 72C in EXAMPLE 72D. 1H NMR (500 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 - 7.50 (m, 3H), 7.33 - 7.39 (m, 2H), 6.95 (d, 1H), 6.78 (s, 1H), 4.96 (s, 2H), 3.97 (s, 1H), 3.85 - 3.92 (m, 4H), 3.01 (t, 2H), 2.12 (s, 5 H), 1.69 - 1.85 (m, 4H), 1.52 - 1.65 (m, 6 H).

E 72 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1 H)-yl]-3 - {5-cyano methyl[(3 -methyloxatricyclo[3.3.1.13’7]decyl)methyl]-1H-pyrrolyl}pyridine ylic acid EXAMPLE 72A -methyl(3 -methyloxa-tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrrolecarbonitrile The title compound was prepared by substituting 1-hydroxymethylmethyl oxadamantane for l-adamantanemethanol and 2-cyanomethylpyrrole for 3,5-dimethyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole in EXAMPLE 2A.

EXAMPLE 72B omethyl(3 -methyloxa-tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrrole carbonitrile The title compound was prepared by substituting E 72A for EXAMPLE 3B in EXAMPLE 3C.

E 72C 6- [8 -(benzothiazolylcarbamoyl)-3,4-dihydro- 1 H-isoquinolinyl] -3 - [5 methyl (3 -methyloxa-tricyclo [3 . 3 . 1 3’7] dec- . 1 1 -ylmethyl)- 1 H-pyrrol-3 -yl] -pyridine-2 -carboxylic acid methyl ester The title compound was prepared by substituting EXAMPLE 71D for EXAMPLE 4B and EXAMPLE 72B for EXAMPLE 20A in EXAMPLE 20B.

EXAMPLE 72D 3 0 6- [8 -(benzothiazolylcarbamoyl)-3,4-dihydro- 1 H-isoquinolinyl] -3 - [5 -cyanomethyl (3-methyloxa-tricyclo[3.3. 1 .13’7]decylmethyl)-1H-pyrrolyl]pyridinecarboxylic acid EXAMPLE 72C (80 mg) in tetrahydrofuran (8 mL) and methanol (3 mL) was treated with 2N aqueous NaOH (3 mL) overnight. The reaction e was concentrated and the residue was purified by reverse phase chromatography using a Gilson system, eluting with 40% - 100% acetonitrile in 0.1% TFA water solution to provide the title compound. 1H NMR —l75— [Annotation] sak (500 MHz, dimethylsulfoxide-d 6) 8 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 - 7.49 (m, 3H), 7.36 (q, 2H), 6.95 (d, 1H), 6.77 (s, 1H), 4.96 (s, 2H), 3.87 - 3.91 (m, 4H), 3.01 (t, 2H), 2.11 - 2.17 (m, 5 H), 1.63 - 1.74 (m, 2H), 1.56 (d, 2H), 1.38 - 1.51 (m, 6 H), 1.00 (s, 3H).

EXAMPLE 73 6-[8-(imidazo[1,2-a]pyrazinylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 73A imidazo[1,2-a]pyrazinamine 2,2,2-Trif1uoro-N-(imidazo[1,2-a]pyraziny1)acetamide (prepared as described in W02004/05 8266Al, 520 mg) was dissolved in 7N NH3 in methanol (4.0 mL), and heated at 68 °C in a sealed tube for 6 hours. The reaction mixture was then cooled and concentrated to provide the title nd.

EXAMPLE 73B imidazo[1,2-a]pyrazinylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting EXAMPLE 73A for thiazolo[4,5- b]pyridineamine in E 30D, with the exception that 1/ 1 CHZClZ/ethyl e, then 100% ethyl acetate were used for the eluents.

EXAMPLE 73C 6-[8-(imidazo[1,2-a]pyrazinylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl (tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid EXAMPLE 73B (85 mg) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After ng at room temperature overnight the reaction mixture was concentrated, then dissoved in CHZClZ (10 mL) and washed with water (5 x 15 mL). The organic layer was dried over NaZSO4. After filtration and concentration, the residue was triturated with CH3CN (10 mL) to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) 5 ppm 11.49 (br s, 1H), 8.93 (s, 1H), 8.64 (dd, 1H), 8.55 (s, 1H), 7.92 (d, 1H), 7.51 (m, 2H), 7.37 (d, 1H), 7.33 (t, 1H), 7.27 (s, 1H), 6.90 (d, 1H), 4.92 (s, 2H), 3.88 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H), 1.54 (br nL9H) E 74 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'— (tricyclo[3.3. 1.13’7]dec-l-ylsulfanyl)-3,4'-bipyridinecarboxylic acid EXAMPLE 74A —176— [Annotation] sak tert-butyl 6-(8 o [d]thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2'-fluoro- 3'-methyl-3,4'-bipyridinecarboxylate The title compound was prepared by substituting roiodomethylpyridine for EXAMPLE 20A in EXAMPLE 20B.

E 74B tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)—yl)-2'- (tricyclo[3.3.1.13’7]dec-l-anylthio)-3'-methyl-3,4'-bipyridinecarboxylate To a solution of EXAMPLE 74A (130 mg) in N,N-dimethylacetamide (4 mL) was added 1-admantanethiol (111 mg) and Cs2C03 (215 mg). The mixture was stirred at 120°C under microwave conditions (Biotage) for 2 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over NaZSO4. After filtration and evaporation of the solvent, the crude material was loaded on a column and eluted with % ethyl acetate in dichloromethane to provide the title compound.

EXAMPLE 74C 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'— (tricyclo[3.3. 1.13’7]dec-l-ylsulfanyl)-3,4'-bipyridinecarboxylic acid The title nd was prepared by substituting EXAMPLE 74B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 5 ppm 12.85 (s, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5 H), 7.03 (d, 1H), 6.83 (d, 1H), 5.00 (s, 2H), 3.93 (t, 2H), 3.03 (t, 2H), 2.26 (m, 5 H), 2.01 (m, 3H), 1.95 (s, 3H), 1.71 (m, 6 H).

EXAMPLE 75 2- { 6-[(methylsulfonyl)carbamoyl]-5 -[5 l(tricyclo[3.3.1.13’7]decylmethyl)-1H- pyrazolyl]pyridin-2 -yl} -N-( [ 1 ,3 ]thiazolo [5 ,4-b]pyridinyl)-1,2,3 ,4- tetrahydroisoquinolinecarboxamide The title compound was prepared by tuting EXAMPLE 24B for EXAMPLE 3F in EXAMPLE 17, with the exception that chromatography on silica gel using 70/3 0/ l hexanes/ethyl acetate/acetic acid was used for the purification. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 11.82 (br s, 1H), 8.52 (dd, 1H), 8.15 (dd, 1H), 7.63 (d, 1H), 7.52 (m, 2H), 7.38 (t, 1H), 7.33 (t, 1H), 7.27 (s, 1H), 7.02 (d, 1H), 4.97 (s, 2H), 3.93 (t, 2H), 3.70 (s, 2H), 3.12 (s, 3H), 3.03 (t, 2H), 2.11 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

EXAMPLE 76 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'— (tricyclo[3.3.1.13’7]dec-l-ylamino)-3 ,4'-bipyridinecarboxylic acid EXAMPLE 76A 4-iodomethyl-N—(tricyclo[3.3.1.13’7]decyl)pyridinamine —177— [Annotation] sak The title compound was prepared by substituting adamantine-l-amine for cyclooctanamine in EXAMPLE 61A.

EXAMPLE 76B 2'-(adamantanylamino) [8 -(benzothiazolylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2 - yl]-3'-methyl-[3,4']bipyridinylcarboxylic acid tert-butyl ester The title compound was prepared by substituting EXAMPLE 76A for E 20A in EXAMPLE 20B.

EXAMPLE 76C 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'— (tricyclo[3.3.1.13’7]dec-l-ylamino)-3 ,4'-bipyridinecarboxylic acid EXAMPLE 76B (100 mg) in tetrahydrofuran (8 mL) and methanol (5 mL) was d with 2 N aqueous NaOH (5 mL) at 50°C for 5 days, , and acidified to pH 1.

The mixture was concentrated and the residue was purified reverse phase chromatography using a Gilson system, eluting with 30% -70% acetonitrile in 0.1 TFA/water to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d 6) 5 ppm 12.87 (s, 2H), 8.03 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.64 (d, 1H), 7.44 - 7.52 (m, 3H), 7.33 - 7.40 (m, 2H), 7.07 (d, 1H), 6.63 (s, 1H), 5.03 (s, 2H), 3.95 (s, 2H), 3.03 (t, 2H), 1.93 (s, 3H), 1.71 - 1.81 (m, 3H), 1.63 - 1.70 (m, 3H).

E 77 6- [8 -(imidazo[1,2 -b]pyridazinylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl- 1-(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid E 77A 6- [8 -(imidazo[1,2 idazinylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl- 1-(tricyclo[3.3. 1 .13’7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester The title compound was prepared by substituting imidazo[1,2-b]pyridazinamine for thiazolo[4,5-b]pyridineamine in EXAMPLE 30D, with the exception that 45-60% ethyl acetate in CHC13 was used for the eluent.

EXAMPLE 77B 6- [8 -(imidazo[1,2 -b]pyridazinylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl] -3 - [5-methyl- 1-(tricyclo [3.3 .1 decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 77A for EXAMPLE 1F in EXAMPLE 1G. 1H NMR (400 MHz, dimethylsulfoxide-d6) 5 ppm 11.41 (br s, 1H), 8.50 (dd, 1H), 8.49 (s, 1H), 8.02 (d, 1H), 7.49 (m, 2H), 7.37 (d, 1H),7.33 (t, 1H), 7.27 (s, 1H), 7.25 (dd, 1H), 6.92 (d, 1H), 4.92 (s, 2H), 3.88 (t, 2H), 3.71 (s, 2H), 3.00 (t, 2H), 2.10 (s, 3H), 1.93 (br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H). —178— [Annotation] sak EXAMPLE 78 ethyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([1,3]thiazolo[5 ,4- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid EXAMPLE 78A 3-[5-methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([1,3]thiazolo[5 ,4- c]pyridinylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid tertbutyl ester The title compound was prepared by substituting thiazolo[5,4-c]pyridinamine for thiazolo[4,5-b]pyridineamine in EXAMPLE 30D.

EXAMPLE 78B 3-[5-methyl(tricyclo[3.3.1.13’7]decylmethyl)-1H-pyrazolyl]—6-[8-([1,3]thiazolo[5 ,4- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid The title compound was ed by substituting EXAMPLE 78A for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 5 ppm 13.77 — 13.39 (s, 1H), 12.75 (s, 1H), 9.46 (s, 1H), 8.70 (d, 1H), 8.03 (d, 1H), 7.71 — 7.64 (m, 1H), 7.55 — 7.45 (m, 2H), 7.40 (t, 1H), 7.26 (s, 1H), 6.97 (d, 1H), 4.98 (s, 2H), 3.89 (m, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (s, 3H), 1.60 (m, 12H).

E 79 6-[8-(1,3 -benzothiazolylcarbamoyl)—3,4-dihydroisoquinolin-2(1H)—yl]—3 -{1-[(5 - yspiro [2 .5 ]oct-5 thyl] methyl-1H-pyrazolyl}pyridinecarboxylic acid E 79A spiro[2.5]octanone 3-Ethoxycyclohexenone (25 g) was dissolved in l ether (5 00 mL), and tetraisopropoxytitanium (55 mL) was added, followed by the addition of ethyl magnesium bromide (3.0M in diethyl ether, 180 mL) over 30 minutes. The reaction was stirred at room temperature for another two hours, and quenched by the careful addition of water (250 mL).

The mixture was filtered through diatomaceous earth, and rinsed with diethyl ether. The filtrate was transferred to a separatory funnel, the aqueous layer was drawn off, andp- toluenesulfonic acid monohydrate (2 g) was added to the organic layer, which was stirred at room temperature for two days. The on mixture was washed with saturated aqueous NaHC03 and brine, then dried over NaZSO4. The mixture was filtered, and concentrated and chromatography on silica gel using 93/7 hexanes/ethyl acetate provided the title compound.

EXAMPLE 79B -((5 -methyl-1H-pyrazolyl)methyl)spiro[2.5]octan-5 -ol Tetrahydrofuran (50 mL) was cooled to -76 °C, n-butyllithium (2.5M in tetrahydrofuran, 7.0 mL) was added, and the solution was cooled back to -76 °C. 1,5- Dimethyl-lH-pyrazole (1.5 g) was added dropwise, and the reaction was stirred for 75 —179— [Annotation] sak minutes. EXAMPLE 79A (2.15 g) was added dropwise, and the mixture was stirred for another 15-20 minutes. The reaction mixture was warmed to room temperature, and partitioned between saturated NH4Cl and ethyl acetate. The organic layer was washed with brine, dried over NaZSO4, filtered, and concentrated. tography on silica gel using 4/1 hexanes/ethyl acetate provided the title compound.

EXAMPLE 79C 1-((5 -methoxyspiro [2 . 5 ] 5 -yl)methyl)methyl-1H-pyrazole EXAMPLE 79B (1 g) was dissolved in N,N-dimethylformamide (15 mL), then iodomethane (0.85 mL) and 95% sodium hydride (340 mg) were added. The reaction was stirred at room temperature for 2.5 hours, then diluted with water and ted with ethyl acetate. The organic layer was washed with brine and dried over sodium e. Filtration and concentration provided the title compound.

EXAMPLE 79D 4-bromo((5-methoxyspiro[2 .5 ]octan-5 -yl)methyl)-5 -methyl-1H-pyrazole EXAMPLE 79C (1.1 g) was dissolved in methylformamide (12 mL), and N- bromosuccinimide (840 mg) was added. The reaction mixture was d at room temperature for 2.5 hours, and diluted with water and extracted with ethyl acetate. The c layer was washed with 20% aqueous Na2803 and brine. The organic layer was dried over NaZSO4, filtered and concentrated to provide the title compound.

EXAMPLE 79E 1-((5-methoxyspiro [2.5 ]octan-5 -yl)methyl)methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)—1H-pyrazole The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE 3C in EXAMPLE 3D.

EXAMPLE 79F 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)—yl]—3 -{1-[(5 - methoxyspiro [2 .5 ]oct-5 -yl)methyl] -5 -methyl-1H-pyrazolyl}pyridinecarboxylic acid utyl ester The title compound was prepared by tuting EXAMPLE 79E for EXAMPLE 3D and EXAMPLE 1E for E 14C in EXAMPLE 14D.

EXAMPLE 79G 6-[8-(1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3- {1 -[(5- methoxyspiro [2 .5 ]oct-5 -yl)methyl] methyl-1H-pyrazolyl}pyridinecarboxylic acid EXAMPLE 79F (40 mg) was dissolved in tetrahydrofuran (0.2 mL) and methanol (0.3 mL). To the mixture was added 1N LiOH (0.35 mL), and the reaction mixture was stirred at 60 oC overnight. After cooling to room temperature, the mixture was diluted with water (5 mL), 2N aqueous HCl (0.18 mL) was added, and the solution was extracted with —180— [Annotation] sak ethyl acetate and concentrated. The residue was purified by Prep HPLC using a Gilson system eluting with 20-80% acetonitrile in 0.1% water. The desired ons were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) 5 ppm 12.85 (V br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48 (m, 2H), 7.43 (d, 1H), 7.36 (m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.96 (s, 2H), 4.19 (d, 1H), 4.09 (d, 1H), 3.89 (t, 2H), 3.09 (s, 3H), 3.01 (t, 2H), 2.12 (s, 3H), 1.58 (br m, 3H), 1.43 (br m, 3H), 1.20 (br m, 2H), 0.31 (br m, 2H), 0.23 (br m, 2H).

EXAMPLE 80 6-[8-(1 ,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]( l - { [3- {2-[2-(2- methoxyethoxy)ethoxy] ethoxy}tricyclo[3.3. l .13’7]dec-l-yl]methyl}methyl-lH-pyrazol yl)pyridinecarboxylic acid EXAMPLE 80A l-[(3- {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo [3 .3. l . l 3’7]dec- l -yl)methyl]- 1H- pyrazole The title compound was prepared by tuting EXAMPLE 26A for EXAMPLE 7A and 2-(2-(2-methoxyethoxy)ethoxy)ethanol for methanol in EXAMPLE 7B.

EXAMPLE 80B l-l-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.13’7]dec-l-yl]methyl} - 1 H-pyrazole The title compound was ed by substituting EXAMPLE 80A for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 80C l-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.l.13’7]dec-l-yl]methyl} bromo-5 -methyl- 1 H-pyrazole The title compound was prepared by substituting EXAMPLE 80B for EXAMPLE 3B in EXAMPLE 3C, with the modification that the title compound was d by RP-HPLC on a Gilson system, eluting with a gradient of 20% to 100% itrile in water containing 0.1% V/V trifluoroacetic acid.

EXAMPLE 80D tert-butyl 6-(8-(benzo [d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl)-3 - (l- { [3 -(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.13’7]dec-l-yl]methyl}methyllH-pyrazolyl inate The title compound was prepared by substituting EXAMPLE 80C for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 80E —181— ation] sak 6-[8-( l ,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]( l - { [3- {2-[2-(2- yethoxy)ethoxy] ethoxy}tricyclo[3.3. l .13’7]dec-l-yl]methyl}methyl-lH-pyrazol yl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 80D for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, ylsulfoxide-d 6) 5 ppm 12.84 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78 (s, 1H), 3.49 (m, 6H), 3.43 (m, 6H), 3.22 (s, 3H), 3.02 (t, 2H), 2.11 (m, 5H), 1.53 (m, 12H).

EXAMPLE 81 6- [8-( l ,3-benzothiazol-2 -ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)—yl] (5 -methyl { [3 - (methylsulfonyl)tricyclo [3 .3 . l . l 3’7]dec- l -yl]methyl}- l H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 81A 3 -(lH-pyrazol-l -ylmethyl)tricyclo [3 .3 . l . l 3’7]decane-l -thiol A solution of EXAMPLE 26A (2.0 g) and thiourea (2.0 g) in a solvent mixture of acetic acid (20 mL) and 48% aqueous HBr solution (10 mL) was heated to 100 0C for 24 hours. The on was concentrated to dryness, and the residue was dissolved in 20% v/v ethanol in water (100 mL). Solid sodium hydroxide (10 g) was added, and the mixture was stirred overnight. The solution was acidified to pH 1 with concentrated HCl solution, and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with onal ethyl acetate (2 x 100 mL). The combined organic layers were washed with water, dried over NaZSO4, d, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 10-50% ethyl acetate in hexane, to give the title product.

EXAMPLE 81B 1- { [3 -(methylsulfanyl)tricyclo[3.3.l .13’7]dec-l-yl]methyl}-lH—pyrazole To a solution of EXAMPLE 81A (3 00 mg) in methanol (2 mL) was added sodium methoxide (4 mL, 0.5 M in methanol). Iodomethane (0.5 mL) was added, and the reaction heated to reflux for 3 hours. The reaction was cooled to room temperature and concentrated to s. The residue war purified by reverse phase HPLC, eluting with a gradient of 30% t0100% acetonitrile in water containing 0.1% v/v oroacetic acid, to give the title product.

EXAMPLE 81C -methyl-l-{[3-(methylsulfanyl)tricyclo[3.3.l.13’7]dec-l-yl]methyl}-lH—pyrazole The title compound was prepared by substituting EXAMPLE 81B for EXAMPLE 3A in EXAMPLE 3B.

EXAMPLE 8 lD —182— [Annotation] sak omethyl-1 - { [3 -(methylsulfonyl)tricyclo[3.3.1.13’7]decyl]methyl}-1H— pyrazole To a solution of EXAMPLE 81C (98 mg) in water (2 mL) was added N- bromosuccinimide (150 mg), and the reaction mixture was heated to reflux for 3 hours.

Additional N-bromosuccinimide (50 mg) was added, and the reaction was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and diluted with methylene chloride. The layers were separated, and the aqueous layer was extracted with additional methylene chloride ). The combined organic layers were washed with water, dried over NaZSO4, filtered, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 0 - 50% ethyl e in hexane, to provide the title compound.

EXAMPLE 81Etert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin- 2( l H)-yl)(5-methyl-l - { [3 ylsulfonyl)tricyclo[3.3. l . ec-l -yl]methyl}-1H- pyrazolyl)picolinate The title nd was prepared by substituting E 81D for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 8 1 F 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5 l { [3 - (methylsulfonyl)tricyclo [3 .3 . 1 . 1 3’7]decyl]methyl}- 1 H-pyrazolyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 81E for EXAMPLE 2B in E 2C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 8 ppm 12.85 (bs, 1H), 8.04 (d, , 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.36 (d, 2H), 7.30 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.80 (s, 2H), 3.02 (d, 2H), 2.19 (m, 11H), 1.57 (m, 6H).

EXAMPLE 82 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[1 -( {3 ,5- dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13’7]decyl}methyl)—5-methyl-1H- pyrazolyl]pyridinecarboxylic acid EXAMPLE 82A 2- { [3,5-dimethyl(1H—pyrazolylmethyl)tricyclo [3.3. 1 . 13’7]decyl]oxy } ethanol To a solution of EXAMPLE 38C (4.5 g) in ethane-1,2-diol (12 mL) was added triethylamine (3 mL) under nitrogen. The mixture was heated to 150 0C under microwave conditions (Biotage) for 45 minutes. The mixture was poured over water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water and brine, dried with NaZSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in hexane (1 L) followed by 5% methanol in methylene chloride (1 L), to give the title product.

EXAMPLE 82B —183— [Annotation] sak 2-( { 3,5 -dimethyl[(5 -methyl-1H-pyrazol- l -yl)methyl]tricyclo [3.3 - . l . ec-l yl}oxy)ethanol To a cold (-78 °C) solution of the EXAMPLE 82A (3.69 g) in tetrahydrofuran (50 mL) was added n-BuLi (20 mL, 2.5 M in hexane) under nitrogen. The mixture was stirred at -78 °C for 1.5 hours. Iodomethane (10 mL) was added by syringe, and the mixture was stirred for an additional 3 hours. The reaction mixture was then quenched by the addition of s ammonium chloride solution and extracted with ethyl e (2 x 200 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL), dried with NaZSO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound.

EXAMPLE 82C 1-( {3 ,5-dimethyl[2-(hydroxy)ethoxy]tricyclo[3.3 .1 - . 13’7]dec- l -yl}methyl)—4-iodo-5 - 1 H-pyrazole The title compound was prepared by substituting E 82B for EXAMPLE 16D in EXAMPLE 16E.

EXAMPLE 82D 2-( { 3- [(4-iodomethyl- lH—pyrazol-l -yl)methyl] -5 ethyltricyclo[3.3.1.13’7]dec- l-yl}oxy)ethyl methanesulfonate To a cold (0 oC) solution of EXAMPLE 82C (2.1 g) in methylene de (30 mL) was added triethylamine (1.42 g) followed by methanesulfonyl chloride (0.542 g). The mixture was stirred at room temperature for 1.5 hours and then was diluted with ethyl e (300 mL). The layers were separated, and the organic layer was washed with water (60 mL) and brine (60 mL), dried with NaZSO4, filtered and concentrated to give the title compound, which was used in the next step without further purification.

EXAMPLE 82E l-( { 3,5 -dimethyl[2-(methylamino)ethoxy]tricyclo[3.3. ]dec-l-yl}methyl) iodomethyl-lH-pyrazole A solution of the EXAMPLE 82D (2.5 g) in 2 M methylamine in methanol (15 mL) was heated to 100 °C for 20 minutes under microwave conditions (Biotage). The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (400 mL). The organic layer was washed with saturated aqueous NaHC03 solution (60 mL), water (60 mL) and brine (60 mL). The organic layer was dried with NaZSO4, filtered and concentrated to give the title compound, which was used in the next reaction t further purification.

EXAMPLE 82F tert—butyl [2-( {3 -[(4-iodomethyl-lH—pyrazol- l -yl)methyl]-5 ,7- dimethyltricyclo [3 .3 . l . l c- l -yl}oxy)ethyl]methylcarbamate —184— [Annotation] sak To a solution of EXAMPLE 82E (2.2 g) in tetrahydrofuran (30 mL) was added BocZO (1.26 g) and a catalytic amount of thylaminopyridine. The mixture was stirred at room temperature for 1.5 hours and diluted with ethyl acetate (3 00 mL). The solution was washed with saturated aqueous NaHC03, water (60 mL) and brine (60 mL). The organic layer was dried with NaZSO4, filtered and concentrated. The residue was purified by silica gel chromatography, g with 20% ethyl acetate in methylene de, to give the title compound.

EXAMPLE 82G tert—butyl {2-[(3,5-dimethyl{[5-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)- azolyl]methyl}tricyclo[3 .3. 1 .13’7]decyl)oxy]ethyl}methylcarbamate The title compound was prepared by substituting EXAMPLE 82F for EXAMPLE 59B in EXAMPLE 59C.

EXAMPLE 82H tert—butyl 6- [8 -(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2 ( 1H)-yl] -3 - {1 -[(3 -{2-[(tert—butoxycarbonyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl] -5 -methyl- 1H-pyrazolyl } pyridinecarboxylate A solution of a 3:1 ratio of dioxane and water (40 mL) was degassed with nitrogen for 45 minutes. This solution was added to EXAMPLE 1E (01.5 g), EXAMPLE 82G (1.48 g), potassium phosphate (02.82 g), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.121 g) and 1,3,5,7-tetramethyltetradecane-2,4,8-trioxaphosphaadamantane (0.194 g).

The mixture was degassed and heated to 90 °C under nitrogen overnight. The reaction mixture was cooled, diluted with ethyl acetate (100 mL), washed with water (three x 50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 20% to 40% ethyl acetate in methylene de, to give the title nd.

EXAMPLE 821 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[1 -( {3 ,5- yl[2-(methylamino)ethoxy]tricyclo[3.3.1.13’7]decyl}methyl)—5-methyl-1H- pyrazolyl]pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 82H for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.85 (s, 1H), 8.21 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m, 4H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (m, 6H), 3.54 (m, 2H), 3.01 (t, 4 H), 2.55 (t, 3H), 2.10 (s, 3H), 1.42 (s, 2H), 1.31 (m, 4 H), 1.08 (m, 6 H), 0.87 (s, 6H).

EXAMPLE 83 —185— [Annotation] sak 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]—3-(5 l { [3 - (2- {2-[2-(methylamino)ethoxy]ethoxy} ethoxy)tricyclo [3.3 - l H- . 1 . 13’7]decyl]methyl} pyrazolyl)pyridinecarboxylic acid EXAMPLE 83A 2- { [3-(1H—pyrazolylmethyl)tricyclo[3.3 .1 - . 13’7]dec-1 yl]oxy} ethoxy)ethoxy]ethanol The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE 7A and ethane-1,2-diylbis(oxy))diethanol for methanol in EXAMPLE 7B., with the modification that the title compound was purified by RP-HPLC on a Gilson system, eluting with a gradient of 20% to 100% itrile in water containing 0.1% v/v trifluoroacetic acid.

EXAMPLE 83B 2-{2-[2-({3-[(5-methyl-1H—pyrazol-l-yl)methyl]tricyclo[3.3.1 .13’7]dec-l- yl}oxy)ethoxy]ethoxy}ethanol To a cold (-78 OC) solution of EXAMPLE 83A (1.0 g) in tetrahydrofuran (10 mL) was added n-BuLi (5 mL, 2.5 M in hexane). The reaction mixture was stirred for 90 minutes, and thane (1 mL) was added. The reaction mixture was stirred at -78 °C for 90 minutes and quenched by the addition of 1 drop of trifluoroacetic acid. The reaction mixture was warmed to room temperature and concentrated to dryness. The residue was used in the subsequent step without further purification.

EXAMPLE 83C 2- {2-[2-( {3 -[(4-iodomethyl-1H—pyrazol-l-yl)methyl]tricyclo[3.3.1.13’7]dec-l- yl}oxy)ethoxy]ethoxy}ethanol To an t solution of EXAMPLE 83B (0.54 g) in N,N-dimethylformamide (5 mL) was added N-iodoosuccinimide (0.35 g). The reaction mixture was stirred for 2 hours, and the crude reaction solution was purified by C on a Gilson system, eluting with a gradient of 20% to 100% acetonitrile in water ning 0.1% v/v trifluoroacetic acid, to give the title compound.

EXAMPLE 83D 2- ( {3 -[(4-iodomethyl-1H—pyrazol-l-yl)methyl]tricyclo[3.3.1.13’7]dec-l- yl } oxy)ethoxy] ethoxy} -N—methylethanamine To a cold (0 °C) solution of EXAMPLE 83C (0.445 g) and triethylamine (0.5 mL) in tetrahydrofuran (10 mL) was added methanesulfonyl chloride (0.07 mL). The mixture was d for 3 hours and transferred to a 20-mL microwave reaction vessel. Methanamine (4 mL, 2 M in methanol) was added, and the mixture was heated to 100 0C for 20 minutes under microwave (Biotage) conditions. The on mixture was concentrated to dryness, and the residue was purified by e-phase chromatography (Analogix system, C18 SF40-3 00 g —186— [Annotation] sak column), eluting with a gradient of % acetonitrile in water containing 0.1% V/V trifluoroacetic acid, to give the title t.

EXAMPLE 83E tert—butyl (2- {2- [2-( {3 -[(4-iodomethyl-1H—pyrazol-lyl l]tricyclo [3 . 3 . 1 3 ’7]decyl } oxy)ethoxy] ethoxy } ethyl)methylcarbamate The title compound was prepared by substituting EXAMPLE 83D for EXAMPLE 82E in EXAMPLE 82F.

EXAMPLE 83F tert—butyl methyl [2-(2- {2- [(3 - { [5 l(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H—pyrazolyl]methyl}tricyclo[3.3.1.13’7]dec yl)oxy]ethoxy}ethoxy)ethyl]carbamate The title compound was prepared by substituting EXAMPLE 83E for EXAMPLE 59B in EXAMPLE 59C.

EXAMPLE 83G tert—butyl 6- [8 -(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2 ( 1H)-yl] -3 - [5 -methyl( {3 -[(2,2,5-trimethyloxo-3 ,8,1 1 -trioxaazatridecan-l 3 - yl)oxy]tricyclo[3.3. 1 .13’7]decyl}methyl)—1H—pyrazolyl]pyridinecarboxylate The title compound was prepared by tuting E 83F for EXAMPLE 4A in EXAMPLE 4C.

EXAMPLE 83H 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl](5-methyl-1 - { [(3 - (2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.13’7]dec-l-yl]methyl}-1H- lyl)pyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 83G for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) 5 ppm 12.86 (bs, 1H), 8.37 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.47 (m, 2H), 7.36 (m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.96 (s, 1H), 3.88 (dd, 2H), 3.56 (m, 4H), 3.46 (m, 3H), 3.06 (m, 4H), 2.55 (m, 3H), 2.09 (m, 5H), 1.48 (m, 12H).

EXAMPLE 84 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[1-({8- [(benzyloxy)carbonyl]azabicyclo[3.2. 1]oct-3 -yl}methyl)-1H-pyrazolyl]pyridine carboxylic acid EXAMPLE 84A benzyl 8-azaspiro[bicyclo [3 .2. 1 ]octane-3,2'-oxirane]—8-carboxylate To a 500-mL, three-necked, round-bottomed flask ed with a magnetic stirring bar, a thermometer, and a condenser was charged tetrahydrofuran (163 mL), potassium tert- butoxide (6.6 g, 95% pure) and trimethylsulfoxonium iodide (13.0 g). The mixture was —187— [Annotation] sak heated to reflux and stirred for 3 hours. A solution of benzyl 3-oxo azabicyclo[3.2.1]octanecarboxylate (10.0 g) in tetrahydrofuran (37 mL) was added in one portion. The reaction mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and diluted with toluene (100 mL) and water. The water layer was separated and extracted with toluene (2x 50 mL). The combined organic layers were washed with water (3x 40 mL) and concentrated under vacuum to provide the title compound.

E 84B benzyl ylazabicyclo[3.2.1]octanecarboxylate To a cold (0°C) solution of EXAMPLE 84A (3.5 g) in tetrahydrofuran (40 mL) was added boron trifluoride diethyl ether complex (0.82 mL). The mixture was d at 3-5 0C for 3 hours. Aqueous saturated NaHC03 was added, followed by ethyl acetate (200 mL).

The organic layer was ted, washed with water (twice) and concentrated to dryness.

Toluene was added and the mixture was trated under vacuum to e the title compound.

EXAMPLE 84C benzyl 3 -(hydroxymethyl)—8-azabicyclo [3 .2. 1 ]octanecarboxylate To a solution of EXAMPLE 84B (3.4 g) in tetrahydrofuran (40 mL) was added NaBH4 (0.5 g). The mixture was stirred overnight. The solvent was evaporated and the residue was added to ethyl acetate (3 00 mL) and water (50 mL). The organic layer was washed with water and brine, dried over NaZSO4, and filtered. Evaporation of the solvent gave the crude title compound.

EXAMPLE 84D benzyl 3-((4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)-1H-pyrazolyl)methyl) azabicyclo[3.2.1]octanecarboxylate The title compound was prepared by substituting EXAMPLE 84C for 1- tanemethanol and ,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole for 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 2A.

EXAMPLE 84E 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3 -[1-({8- [(benzyloxy)carbonyl]azabicyclo[3.2.1]oct-3 -yl}methyl)-1H-pyrazolyl]pyridine carboxylic acid The title compound was prepared by substituting EXAMPLE 84D for EXAMPLE 1A in EXAMPLE 1F, and then tuting that product for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-d6) 8 ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.49 (m, 16 H), 6.94 (d, 1H), 5.06 (m, 2H), 4.94 (s, 2H), 3.89 (m, 3H), 3.00 (m, 2H), 1.84 (m, 3H), 1.59 (m, 2H), 1.29 (m, 6H). —188— [Annotation] sak EXAMPLE 85 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]-6'-oxo-1'- (tricyclo[3.3.1.13’7]decylmethyl)-1',6'-dihydro-3,3'-bipyridinecarboxylic acid E 85A 1-(tricyclo [3.3 .1 .13’7]decylmethyl)bromopyridin-2(1H)-one To an ambient sion ofNaH (185 mg, 4.63 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (30 mL) was added 5-bromopyridin-2(1H)—one (700 mg, 4.02 mmol). The reaction e was stirred for 15 minutes, and 1-(bromomethyl)adamantane (968 mg 4.22 mmol) was added. The mixture was heated to 120 °C overnight, cooled to room temperature, and quenched by the on of water and ether. The layers were separated, and the aqueous extracted with onal ether (twice). The combined organics were washed with brine, dried over NaZSO4, and filtered. Chromatography on silica gel, eluting with a gradient of 5 to 30% ethyl acetate in hexanes, provided the title compound.

EXAMPLE 85B tert-butyl 1'—(tricyclo[3.3. 1 .13’7]decylmethyl)(8-(benzo[d]thiazol ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]—2- carboxylate The title compound was prepared by tuting EXAMPLE 85A for E 4A in EXAMPLE 4C.

EXAMPLE 85C 6-[8-(1,3 -benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)—yl]-6'-oxo-1'- (tricyclo[3.3.1.13’7]decylmethyl)-1',6'-dihydro-3,3'-bipyridinecarboxylic acid The title compound was prepared by substituting EXAMPLE 85B for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) 8 ppm 12.85 (bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.66-7.54 (m, 3H), 7.50-7.31 (m, 5H), 7.01 (d, 1H), 6.39 (d, 1H), 4.98 (s, 2H), 3.90 (t, 2H), 3.66 (s, 2H), 3.01 (t, 2H), 1.92 (bs, 3H), .46 (m, 12H).

E 86 6-[8-(1,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)—yl](1-{[3,5- dimethyl(2- {2-[2-(methylamino)ethoxy] ethoxy} ethoxy)tricyclo[3.3. 1 .13’7]dec yl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid EXAMPLE 86A 1-{[3,5-dimethy1(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.13’7]dec- 1-yl]methyl}-1H-pyrazole The title compound was prepared by substituting EXAMPLE 38C for EXAMPLE 7A and 2,2'-(ethane-1,2-diylbis(oxy))diethanol for methanol in EXAMPLE 7B, with the modification that the title compound was purified by RP-HPLC on a Gilson system, eluting with a gradient of 20% to 100% acetonitrile in water containing 0.1% V/V trifluoroacetic acid. —189— [Annotation] sak EXAMPLE 86B 1-{[3,5-dimethyl(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.13’7]dec- ethyl } hyl- 1 H-pyrazole The title nd was ed by substituting EXAMPLE 86A for EXAMPLE 83A in EXAMPLE 83B.

EXAMPLE 86C l-{[3,5-dimethyl(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.l .13’7]dec- l-yl]methyl} iodomethyl- l H-pyrazole The title nd was prepared by tuting EXAMPLE 86B for EXAMPLE 83B in EXAMPLE 83C.

EXAMPLE 86D l-{ imethyl(2-{2-[2- (methylamino)ethoxy] ethoxy} ethoxy)tricyclo [3 .3. l . 13’7] decyl]methyl } iodo-5 -methyl- 1 H-pyrazole The title compound was prepared by substituting EXAMPLE 86C for EXAMPLE 83C in EXAMPLE 83D.

EXAMPLE 86E tert—butyl (2- {2-[2-( {3-[(4-iodo-5 -methyl-lH-pyrazol-l -yl)methyl]-5,7- dimethyltricyclo [3 . 3. l . 13’7]dec- l -yl}oxy)ethoxy]ethoxy}ethyl)methylcarbamate The title compound was prepared by substituting EXAMPLE 86D for EXAMPLE 82E in EXAMPLE 82F.

EXAMPLE 86F tert—butyl [2-(2- {2- [(3 ,5-dimethyl { [5 -methyl(4,4,5,5-tetramethyl- l ,3,2- dioxaborolan-2 -yl)- lH—pyrazol- l -yl]methyl}tricyclo[3.3. l .13’7]dec-l- yl)oxy]ethoxy} ethoxy)ethyl]methylcarbamate The title nd was prepared by substituting EXAMPLE 86E for EXAMPLE 59B in EXAMPLE 59C.

EXAMPLE 86G tert—butyl 6- [8 -( l ,3 -benzothiazol-2 -ylcarbamoyl)-3 ,4-dihydroisoquinolin-2 ( l H)-yl] -3 - [l-( {3 ,5 -dimethyl [(2,2,5 -trimethyloxo-3 ,8,l l-trioxaazatridecan- l 3 - yl)oxy]tricyclo [3 .3. l . l 3’7]dec- l -yl}methyl)methyl- lH—pyrazolyl]pyridinecarboxylate The title compound was prepared by substituting EXAMPLE 86F for E 4A in EXAMPLE 4C.

EXAMPLE 86H —l90— [Annotation] sak 6-[8-(1,3-benzothiazoly10arbam0y1)-3 ,4-dihydrois0quinolin-2(1H)-y1]—3-(1-{[3,5- dimethy1(2- {2-[2-(methy1amino)eth0xy] ethoxy} ethoxy)tricy010[3.3. 1 .13’7]dec y1]methy1} methy1- 1 H-pyrazo1y1)pyridinecarb0xylic acid The title compound was prepared by substituting E 86G for EXAMPLE 2B in EXAMPLE 2C. 1H NMR (300 MHz, dimethylsulfoxide-dG) 8 ppm 12.85 (bs, 1H), 8.33 (bs, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48 (m, 3H), 7.36 m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.86 (m, 4H), 3.63 (m, 2H), 3.55 (s, 4H), 3.05 (d, 4H), 2.56 (t, 2H), 2.10 (s, 3H), 1.27 (m, 6H), 1.06 (m, 6H), 0.85 (s, 6H). —191— WE

Claims (19)

CLAIM :

1. A compound having Formula (I) (R1)m (R2)n N N Z1 HN O Y1 L1 Y2 (R3)p Formula (I), or a therapeutically acceptable salt f, wherein X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Y1 is phenylene or C5-6 heteroarylene; ally fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y1 is ally substituted with one, two, three, or four tuents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, 5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N5, NO2, F, Cl, Br and I; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)- (CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, )s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; Y2 is C8-14 cycloalkyl, C8-14 cycloalkenyl, C8-14 heterocycloalkyl, or C8-14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8 cycloalkane, and C3-8 heterocycloalkene; wherein Y2 is ally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, 8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2, R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8, NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, 11173815.sak C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; Z1 is selected from the group consisting of 9, C(O)NR10R11, 1, NR10C(O)R11, NR10C(O)NR10R11, R10R11, NR10C(O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, R10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or Z1 is selected from the group consisting of N O O HN N O N O N HN O N OH N N OH N H N , , , , ,N H H O O O OH O O O O N N S OH Rk N O N Rk S OH , , , , ,H Rk H O O O O O OH OH O O N N N OH N Rk H , , , ,H H H O Rk O O O O O O S N S N S Rk N N N H Rk H , , and ;H at each occurrence, is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R2, at each occurrence, is independently selected from the group consisting of deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring ed from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R4, at each occurrence, is ndently selected from the group consisting of NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, O)R13, NR12S(O)2R14, NR12S(O)R14, S(O)2R14, S(O)R14 and R14; 11173815.sak R5, at each occurrence, is independently selected from the group ting of C1-6 alkyl, C2-6 alkenyl, C2-6 l, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 l, C2-6 alkynyl, and C1-6 kyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, , SO2NHR15, SO2N(R15)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and lkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, , C(O)R16, CO(O)R16, OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, OR16, O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, , SO2NHR16, SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, , C(O)H, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I; R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl, phenyl and (CH2)1-4 ; and R10 and R11, at each occurrence, are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, phenyl and (CH2)1- 4-phenyl; or 11173815.sak R10 and R11, or R10 and R9, er with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl; R12 and R13, at each occurrence, are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and -4 phenyl; R14, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2- 4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl; R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each is attached, are optionally combined to form a cyclyl; R15, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2- 4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and lkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents ndently ed from the group consisting of O-(C1-4 alkyl), NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I; R16, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2- 4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one substituent independently ed from the group consisting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3; q is 1, 2, or 3; s is 0, 1, 2, or 3; r is 0, 1, 2, or 3; n the sum of s and r is 0, 1, or 2; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2.

2. The compound or therapeutically acceptable salt of claim 1, wherein 11173815.sak Y1 is pyrrolyl, pyrazolyl, or triazolyl.

3. The compound or therapeutically acceptable salt of claim 1, wherein Y1 is pyridinyl or phenyl.

4. The compound or eutically acceptable salt of claim 1, wherein X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2- a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are optionally tuted with one, two, three or four R4.

5. The nd or eutically acceptable salt of claim 2, wherein Z1 is selected from the group consisting of O O HN N O N S OH N N , , and .H Rk

6. The compound or therapeutically acceptable salt of claim 1, wherein X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2- a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl; Y1 is pyrrolyl, pyrazolyl, triazolyl or pyridinyl; wherein Y1 is optionally tuted with one, or two substituents independently selected from the group consisting of R5, CN, F, Cl, Br and I; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-S- (CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, )s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and )s-S(O)2NR6A-(CR6R7)r; Y2 is C8-14 cycloalkyl, or C8-14 heterocycloalkyl; wherein Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, OR8, SO2R8, CO(O)R8, OH, F, Cl, Br and I; Z1 is selected from the group consisting of 11173815.sak O HN N O O N S OH N N , , and ;H Rk R1 is absent; R2, at each ence, is independently deuterium or C1-6 alkyl; R3 is absent; R5, at each occurrence, is independently C1-6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, heterocyclyl and lkyl; wherein the R8 C1-6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR16, SO2R16, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl; R16, at each ence, is independently selected from the group consisting of C1-4 alkyl, , and heterocycloalkyl; wherein the R16 C1-4 alkyl is ally substituted with one substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3; q is 1 or 2; s is 0 or 1; r is 0 or 1; n the sum of s and r is 0 or 1; m is 0; n is 0, 1, or 2; and p is 0.

7. The compound or therapeutically acceptable salt of claim 6, wherein Y1 is pyrrolyl, pyrazolyl, or triazolyl.

8. The compound or therapeutically acceptable salt of claim 6, wherein Y1 is pyridinyl. 11173815.sak

9. The compound or therapeutically acceptable salt of claim 2, wherein L1 is (CR6R7)q; and Y2 is selected from the group consisting of C8-14 cycloalkyl, and C8-14 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2.

10. The compound or therapeutically acceptable salt of claim 3, wherein L1 is (CR6R7)q; and Y2 is selected from the group consisting of C8-14 cycloalkyl, and C8-14 heterocycloalkyl; wherein R6 and R7, at each occurrence, are hydrogen; and q is 1 or 2.

11. The compound or therapeutically acceptable salt of claim 2, wherein L1 is selected from the group ting of (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-C(O)NR6A- (CR6R7)r, and (CR6R7)s-S(O)2NR6A-(CR6R7)r; Y2 is ed from the group consisting of C8-14 cycloalkyl, and C8-14 heterocycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen.

12. The compound or therapeutically acceptable salt of claim 3, wherein L1 is ed from the group consisting of (CR6R7)s-O-(CR6R7)r, )s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s- NR6A-(CR6R7)r, and (CR6R7)s-S(O)2NR6A-(CR6R7)r; Y2 is selected from the group consisting of C8-14 cycloalkyl, and C8-14 cycloalkyl; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and 11173815.sak R6 and R7, at each occurrence, are hydrogen.

13. The compound or eutically able salt of claim 1, wherein the compound has Formula (II), Formula (III) or Formula (IV): , , wherein X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[1,2- a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, and (CR6R7)s-S(O)2NR6A-(CR6R7)r; Y2 is C8-14 cycloalkyl, or C8-14 heterocycloalkyl; n Y2 is optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, OR8, SO2R8, CO(O)R8, OH, F, Cl, Br and I; Z1 is selected from the group consisting of O O HN N O N S OH N N , , and ;H Rk R1 is absent; 11173815.sak R2, at each occurrence, is independently deuterium or C1-6 alkyl; R3 is absent; RX, at each occurrence, is independently selected from the group consisting of R5, CN, F, Cl, Br and I; R5, at each occurrence, is independently C1-6 alkyl; R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl; R6 and R7, at each occurrence, are each independently hydrogen; R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, heterocyclyl and cycloalkyl; wherein the R8 C1-6 alkyl is optionally substituted with one substituent independently selected from the group consisting of R16, OR16, SO2R16, and NHR16; Rk, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl; R16, at each occurrence, is ndently selected from the group consisting of C1-4 alkyl, phenyl, and heterocycloalkyl; wherein the R16 C1-4 alkyl is optionally tuted with one substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3; q is 1 or 2; s is 0; r is 0 or 1; wherein the sum of s and r is 0 or 1; m is 0; n is 0, 1, or 2; o is 0 or 1; and p is 0.

14. The nd or therapeutically acceptable salt of claim 6, selected from the group consisting of 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1- clo[3.3.1.13,7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid; 11173815.sak 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3,5-dimethyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5- dimethyltricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3- hydroxytricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3- methoxytricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2- methoxyethoxy)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5,7- trimethyltricyclo[3.3.1.13,7]decyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3- ricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(propan yloxy)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- oxatricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl- 1-(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(morpholin yl)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3- methoxytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 11173815.sak N-(1,3-benzothiazolyl){6-[(methylsulfonyl)carbamoyl][5-methyl(tricyclo[3.3.1.13,7]dec- 1-ylmethyl)-1H-pyrazolyl]pyridinyl}-1,2,3,4-tetrahydroisoquinolinecarboxamide; N-(1,3-benzothiazolyl){6-[(cyclopropylsulfonyl)carbamoyl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide; -benzothiazolyl){5-[5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl] (2H-tetrazolyl)pyridinyl}-1,2,3,4-tetrahydroisoquinolinecarboxamide; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyanomethyl clo[3.3.1.13,7]decylmethyl)-1H-pyrrolyl]pyridinecarboxylic acid; 3-[5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl][8-([1,3]thiazolo[5,4- b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(tricyclo[3.3.1.13,7]dec- 1-ylmethoxy)-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-(morpholin yl)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- (tricyclo[3.3.1.13,7]decylmethoxy)-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-cyano [tricyclo[3.3.1.13,7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid; 3-[5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl][8-([1,3]thiazolo[4,5- b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid; 3-[5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl][8-([1,3]thiazolo[4,5- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5- dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-cyanomethyl[2- (tricyclo[3.3.1.13,7]decyl)ethyl]-1H-pyrrolyl}pyridinecarboxylic acid; 11173815.sak N-(1,3-benzothiazolyl){5-[5-cyanomethyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrrol- 3-yl][(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline amide; N-(1,3-benzothiazolyl){5-[5-cyanomethyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrrol- 3-yl][(cyclopropylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline carboxamide; N-(1,3-benzothiazolyl){5-(1-{[3-methoxytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H- pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline amide; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-methoxy-5,7- dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; N-(1,3-benzothiazolyl){5-(1-{[3-methoxytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H- pyrazolyl)[(morpholinylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide; N-(1,3-benzothiazolyl)[5-(1-{[3-methoxytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H- pyrazolyl){[(trifluoromethyl)sulfonyl]carbamoyl}pyridinyl]-1,2,3,4- tetrahydroisoquinolinecarboxamide; N-(1,3-benzothiazolyl){6-[(cyclopropylsulfonyl)carbamoyl](1-{[3- ytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-chloro [tricyclo[3.3.1.13,7]decylmethyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)(1,1-2H2)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2- methoxyethoxy)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 11173815.sak 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethyl)cyclooctyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(imidazo[1,2-a]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[3- (tetrahydro-2H-pyranylmethoxy)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazol yl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(2- yethyl)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-1,2,3-triazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[3- ytricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl(2- oxatricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'- [cyclooctyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-(2- methoxyethoxy)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridine- 2-carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1-[2- (methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl(2- oxatricyclo[3.3.1.13,7]decylmethyl)-1H-1,2,3-triazolyl]pyridinecarboxylic acid; 3-[5-methyl(2-oxatricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl][8-([1,3]thiazolo[5,4- b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid; 11173815.sak 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- (tricyclo[3.3.1.13,7]decylsulfonyl)-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyanomethyl(2- oxatricyclo[3.3.1.13,7]decylmethyl)-1H-pyrrolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-cyanomethyl [(3-methyloxatricyclo[3.3.1.13,7]decyl)methyl]-1H-pyrrolyl}pyridinecarboxylic acid; 6-[8-(imidazo[1,2-a]pyrazinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- (tricyclo[3.3.1.13,7]decylsulfanyl)-3,4'-bipyridinecarboxylic acid; 2-{6-[(methylsulfonyl)carbamoyl][5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazol yl]pyridinyl}-N-([1,3]thiazolo[5,4-b]pyridinyl)-1,2,3,4-tetrahydroisoquinoline carboxamide; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- (tricyclo[3.3.1.13,7]decylamino)-3,4'-bipyridinecarboxylic acid; 6-[8-(imidazo[1,2-b]pyridazinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 3-[5-methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl][8-([1,3]thiazolo[5,4- c]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(5- methoxyspiro[2.5]octyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazol yl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[3- (methylsulfonyl)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2- (methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridine carboxylic acid; 11173815.sak 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[3-(2-{2- [2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazol yl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({8- [(benzyloxy)carbonyl]azabicyclo[3.2.1]octyl}methyl)-1H-pyrazolyl]pyridine carboxylic acid; and 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2- {2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H- lyl)pyridinecarboxylic acid.

15. A compound or a therapeutically acceptable salt thereof, wherein the compound is selected from the group consisting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(spiro[3.5]non ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl [tricyclo[3.3.1.13,7]decylmethoxy]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl [tricyclo[3.3.1.13,7]decylmethoxy]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3- [tricyclo[3.3.1.13,7]decylmethoxy]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl clo[3.3.1.13,7]decyloxy]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(1,1- dioxidothiomorpholinyl)tricyclo[3.3.1.13,7]decyl]methyl}-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano [tricyclo[3.3.1.13,7]decylamino]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano [tricyclo[3.3.1.13,7]decylsulfanyl]phenyl}pyridinecarboxylic acid; 11173815.sak 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {[tricyclo[3.3.1.13,7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl [tricyclo[3.3.1.13,7]decylsulfamoyl]phenyl}pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {methyl[tricyclo[3.3.1.13,7]decylcarbonyl]amino}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl [tricyclo[3.3.1.13,7]decylcarbamoyl]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {methyl[tricyclo[3.3.1.13,7]decylmethyl]amino}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano (tricyclo[3.3.1.13,7]decylsulfonyl)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {methyl[(tricyclo[3.3.1.13,7]decyl]carbamoyl}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl[methyl(2- oxatricyclo[3.3.1.13,7]decylcarbonyl)amino]phenyl}pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {methyl[tricyclo[3.3.1.13,7]decyl]sulfamoyl}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(5- methoxyspiro[2.5]octyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; and 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6'-oxo-1'- (tricyclo[3.3.1.13,7]decylmethyl)-1',6'-dihydro-3,3'-bipyridinecarboxylic acid.

16. 6-[8-(1,3-Benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5- methyl(tricyclo[3.3.1.13,7]decylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid or a therapeutically acceptable salt f.

17. A pharmaceutical composition comprising an excipient and a therapeutically effective amount of the compound or therapeutically acceptable salt of any one of claims 1-16. 11173815.sak

18. The compound or therapeutically acceptable salt of any one of claims 1-16 for use in the manufacture of a medicament for treating bladder cancer, brain , breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic ia, colorectal cancer, esophageal cancer, hepatocellular cancer, blastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, te cancer, small cell lung cancer or spleen cancer.

19. The compound or therapeutically acceptable salt of any one of claims 1-16, and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent, for use in the manufacture of a medicament for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic cytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic ia, follicular lymphoma, a lymphoid ancy of T-cell or B-cell origin, melanoma, myelogenous ia, myeloma, oral cancer, ovarian cancer, all cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer. AbbVie Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 11173815.sak