NZ726053B2 - Substituted 4-phenylpiperidines, their preparation and use - Google Patents

Abstract

The present invention provides a compound having the structure: wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than H; R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle or a pharmaceutically acceptable salt thereof.

Description

SUBSTITUTED 4-PHENYLPIPERIDINES, THEIR PREPARATION AND USE This ation claims priority of U.S. Provisional Application No. 61/986,578, filed April 30, 2014, the contents of which are hereby incorporated by reference.

Throughout this application, n publications are referenced in parentheses. Full citations for these publications may be found immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention relates.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for sing the features of the ion. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

The invention was made with government support under Grant numbers NS067594 and NS074476 awarded by the al Institutes of Health.

The government has certain rights in the invention.

Background of the Invention Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It is estimated that 62.9 million individuals worldwide have the most prevalent atrophic (dry) form of AMD; 8 million of them are Americans. Due to increasing life expectancy and current demographics this number is expected to triple by 2020.

There is tly no FDA-approved ent for dry AMD. Given the lack of ent and high prevalence, development of drugs for dry AMD is of upmost importance. Clinically, atrophic AMD represents a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called macula (1). Histopathological and al imaging s indicate that eceptor degeneration in dry AMD is red by abnormalities in the retinal pigment epithelium (RPE) that lies beneath photoreceptors and provides critical metabolic support to these light-sensing neuronal cells. Experimental and clinical data indicate that excessive lation of cytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin) in the RPE is a major trigger of dry AMD (2-9). In addition to AMD, dramatic accumulation of lipofuscin is the hallmark of rdt Disease (STGD), an inherited form of juvenile-onset macular degeneration. The major cytotoxic component of RPE lipofuscin is pyridinium bisretinoid A2E e 1). Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE (40, 41). Formation of A2E and other lipofuscin inoids, such as A2-DHP-PE hydropyridinephosphatidylethanolamine ) and atRALdi-PE (all-trans-retinal dimerphosphatidylethanolamine ), begins in photoreceptor cells in a non- enzymatic manner and can be considered as a by-product of the properly functioning visual cycle.

A2E is a product of sation of all-trans retinaldehyde with phosphatidyl-ethanolamine which occurs in the retina in a non- enzymatic manner and, as illustrated in Figure 4, can be considered a by-product of a properly functioning visual cycle (10). Light-induced isomerization of 11-cis retinaldehyde to its ans form is the first step in a signaling cascade that mediates light perception. The visual cycle is a chain of biochemical reactions that regenerate visual pigment (11-cis retinaldehyde conjugated to opsin) following exposure to light.

As cytotoxic bisretinoids are formed during the course of a normally functioning visual cycle, partial pharmacological inhibition of the visual cycle may represent a treatment gy for dry AMD and other disorders characterized by excessive accumulation of lipofuscin (25- 27, 40, 41).

Summary of the Invention The present invention provides a compound having the structure: R4 R2 R5 R1 O B wherein R1, R2, R3, R4, and R5 are each ndently H, n, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than H O , or a pharmaceutically acceptable salt thereof.

[FOLLOWED BY PAGE 3A] In a ular aspect, the present invention provides a compound having the structure: R4 R2 R5 R1 O B wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than R6 is H, OH, or halogen; and B has the structure: X Q ? d Z2 , wherein a, ß, ?,and d are each independently absent or present, and when present each is a bond; X is C or N; Z1 is N; Z2 is N or NR7, wherein R7 is H, C1-C4 alkyl, or oxetane; and Q is a tuted or unsubstituted 5, 6, or 7 membered ring structure, [FOLLOWED BY PAGE 3B] wherein the substituent in Q when present is H, halogen, CN, CF3, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)-(C1-C6 alkyl), C(O)2-(C1-C6 alkyl), C(O)-NH2 C(O)NH-(C1-C6 alkyl), C(O)- (C6 aryl), C(O)-(C6 heteroaryl), C(O)- pyrrolidine, C(O)-piperidine, C(O)- piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)- CO2(C1-C6 alkyl) or SO2-(C1-C6 alkyl), and wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than N NH , or a pharmaceutically acceptable salt f.

In another particular aspect, the t invention provides a method for the preparation of Compound 81: (Compound 81) by conversion from nd 33: [FOLLOWED BY PAGE 3C] (Compound 33).

In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims.

That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the ed claims.

[FOLLOWED BY PAGE 4] Brief Description of the s Figure 1. Structure of bisretinoid A2E, a cytotoxic component of retinal lipofuscin.

Figure 2. Structure of bisretinoid atRAL di—PE (all-transretinal dimer-phosphatidyl ethanolamine), a cytotoxiccomponent of retinal lipofuscin. R1 and R2 refer to various fatty acid tuents.

Figure 3. Structure of bisretinoid A2-DHP—PE, a cytotoxic component of retinal lipofuscin.

Figure 4. Visual cycle and biosynthesis of A2E. A2E biosynthesis begins when a portion of all—trans—retinal escapes the visual cycle (yellow box) and non—enzymatically reacts with phosphatidyl- ethanolamine forming the A2E precursor, A2—PE. Uptake of serum retinol to the RPE (gray box) fuels the cycle.

Figure 5. Three—dimensional structure of the RBP4~TTR~retinol complex. eic TTR is shown in blue, light blue, green and yellow (large boxed region). RBP is shown in red (unboxed region) and retinol is shown in gray (small boxed region) (28).

Figure 6. Structure of fenretinide, [N—(4—hydroxy—phenyl)retinamide, 4HRP], a retinoid RBP4 antagonist.

Figure 7. Schematic depiction of the HTRF-based assay format for characterization of RBP4 antagonists disrupting retinol—induced RBP4- TTR interaction.

Figure 8. Effect of nd 81 Treatment on Bisretinoid Accumulation in Eyes of /— mice 06; unpaired t—test).

Figure 9. Serum. RBP4 Levels in Compound 81— and vehicle-treated Abca4—/— mice.

Detailed Description of the Invention The t invention provides a compound having the structure: R4 R2 R5 R1 wherein R1, R2] R3] R4 and are each I R5 independently H, halogen, CF3 or C1—C4 8.].le , wherein two or more of R1, R2, R3, R4, or R5 are other than R5 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, n when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than 93 NI£o or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound having the structure: R4 R2 wherein R1, R2, R3, RF and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, RL or R5 are other than R6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R1 is CF3, R2is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2is CF3, R3 is H, R4 is CFL and R5 is H, or R1 is Cl, R2is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, Rgis H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, RziS F, R3 is H, R4 is H, and R5 is H, then B is other than (5; N14 NH O 1; \ \ \ or N‘NH or a ceutically acceptable salt thereof.

In some embodiment, the compound wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than 43 Nl N‘NH In some embodiment, the compound wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than 9; NH or a pharmaceutically acceptable salt thereof.

In some embodiment, the compound having the structure: In some embodiment, the compound wherein R1, R2, R3, R4, R5 and R5 are each independntly H, Cl, F, or CF3.

In some embodiment, the compound wherein R1 is CF3, Rzis F, R3 is F, R4 is H, and R5 is H, or R1 is CF3, Rgis F, R3 is H, R4 is H, and R5 is H, or R1 is CF3, Rzis F, R3 is H, R4 is F, and R5 is H, or R1 is CF3, RziS H, R3 15 F, R4 is F, and R5 is H, or R1 is CF3, RziS H, R3 15 H, R4 is H, and R5 is F, or R1 is CF3, Rgis H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2iS H, R3 is H, R4 is Cl, and R5 is H, or R1 is CF3, RziS Cl, R3 is H, R4 is H, and R5 is H, or R1 is H, Rgis CF3, R3 is H, R4 is CFh and R5 is H, or R1 is Cl, RziS H, R3 is H, R4 is F, and R5 is H, or R1 is Cl, RziS F, R3 is H, R4 is H, and R5 is H.

In some embodiment, the compound wherein B has the structure: wherein a, B, x,and 5 are each independently absent or present, and when present each is a bond; X is C or N; Z1 is N; 22 is N or NRW n R7 is H, C1—C4 alkyl, or oxetane; Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

In some ment, the compound wherein B has the structure: wherein when dis present, then Z1 and Z2 are N, X is N,B is present, and x and 8 are absent; and when dis absent, then Z1 is N, Z2 is N—R7, X is C, B and 8 are present, and x is absent.

In some embodiment, the compound wherein B has the ure: wherein n is an integer from 0-2; a, B, x, 8, a, and ¢ are each independently absent or present, and when present each is a bond; Z1 iS N; Z2 is N or N'R7, wherein R7is H, C1—Cm alkyl, or oxetane; X is C or N; and Y1, Y2, Y3, and each occurrence of Y4 are each independently CR8, CH" R8 is H, halogen, OCH3, CN, or CF3; and R9 is H, CN, oxetane, C1—C6 alkyl, C3—C6 cycloalkyl, (C1—C4 alkyl)(C3—C6 cycloalkyl), (C1—C6 alkyl)—OCH3, (C1—C6 alkyl)—CFL C(O)-—(C1-C6 alkyl), C(O)2—(C1—C5 alkyl), C(O)-NH2 C(O)NH-(C1-C6 alkyl), C(O)—(C6 aryl), C(O)~(C6 aryl), C(O)—pyrrolidine, C(O)~piperidine, C(O)—piperazine, (C1—C6 "C02H, (C1—C6 alkyl)-C02(C1—C6alkyl) or SOz-(Cl-Cs alkyl).

In some embodiment, the compound wherein B has the ure: g; YF"Y2 / \ Y3 \\\N n wherein n is O; Rvis H, C1-C4 alkyl, or oxetane; Y1 and Y3 are each CH2; and Y2 is N"R9, wherein R9 is H, CN, oxetane, C1—C6 alkyl, ycloalkyl, (C1—C4 alkyl)(C3—C6 lkyl), (C1~C6 alkyl)—OCH3, (C1—C6 alkyl)— CF3, C(O)—(C1—C6 alkyl), C(O)2—(C1—C6 alkyl), C(O)—NH2 C(O)NH~(C1—C6 alkyl), C(O)—(C5 aryl), C(O)—(C6 heteroaryl), C(O)—pyrrolidine, C(O)—piperidine, C(O)—piperazine, (C1—C6 alkyl) "COzH, (C1-C6 alkyl) "COQ (C1"C6 alkyl) or SOz‘(C1"C6 alkyl).

In some embodiment, the compound wherein B has the structure: wherein n is l; R7is H, C1—C4 alkyl, or e; Y1, Y2 and Y4 are each CH2; and Y3 is N—Rg, wherein R9 is H, CN, oxetane, C1—C6 alkyl, ycloalkyl, (C1—C4 alkyl)(C3—C6cycloalkyl), (Cl-Cealkyl)—OCH3, (Cl—Csalkyl)— CF3, C(O)—(C1*C6 alkyl) , C(O)2‘(C1*C6 alkyl), C(O)—NH2 C(O)NH—(C1—C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)—pyrrolidine, C(O)-piperidine, C(O)—piperazine, (Cl‘Ce alkyl) ‘C02H, (C1—C6 alkyl) *COz(C1‘C6 alkyl) or 502- (C1-C6 alkyl).

In some embodiment, the nd wherein B has the structure: 3 "Vi wherein n is l; R7is H, C1—C4 alkyl, or oxetane; Y1, Y3 and Y4 are each CH2; and Y2 is N-R9, wherein R9 is H, CN, oxetane, C1—C6 alkyl, C3—C6cycloalkyl, (C1—C4 alkyl) (C3"C6 cycloalkyl) , (Cl—"C6 alkyl) "OCH3, (Cl—‘Ce alkyl) - CF3, C(O)—(C1—C6 alkyl) , C(O)2‘(C1*C6 alkyl), C(O)—NH2 C(O)NH—(C1—C6 alkyl), C(O)—(C6 aryl), C(O)—(C6 heteroaryl), C(O)—pyrrolidine, C(O)—piperidine, iperazine, (C1—C5 alkyl) 'COzH, (C1-C5 alkyl) "C02 (C1-C6 alkyl) or 502‘ (C1-C6 alkyl).

In some embodiment, the compound wherein B has the structure: Mfr NF N/R9 "F \H \H \ or H In some embodiment, the compound wherein R9 is H, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, t"BL1, CH2CH(CH3)2, CH2C(CH3)3, CH2CF3, CH2CH2CF3, CH20CH3, CH2CH20CH3, ef\/[LOHI érk/lCLO/"Bu, HIKA or §‘<>° In some embodiment, the compound n R9 is SOg'CH3, C (0) ‘CH3, C (O) "CH2CH3, C (O) ‘CHZCHQCHJ, C (O) "CH (CH3) 2, C (O) -CH2CH (CH3)2 C( O) —-t-Bu, C( O) —OCH3, C( O) NHCH3, hahoioic *o *0do, In some ment, the compound n S o R7 is H, CH3, CH2CH3, CH(CH3)2, or ‘—<> In some embodiment, the compound wherein B has the structure: wherein Y1, Y2, Y3 and Y4 are each independently CR3 or N, wherein each RB is independently H, halogen, OCH3, CN, or CF3.

In some embodiment, the compound wherein B has the structure: 8,! N‘ R? N‘ I R8] ff" Na In some ment, the compound wherein each R9 is CN or OCHy In some embodiment, the compound having the structure: ‘NH N‘NH N‘NH N‘NH F F F3C CF3 ca CI F CF3 of of? \s_ \S— N o N N/ N N/ N’"<} N N/?\ O O O O \ \ x \ \ \ \ \ N‘NH N~NH N~NH N~NH NFNH NFNH N~NH N‘NH N~NH I I I I I F3C F F F3C F CF3 CF3 CF3 j'L H N N N N NH N UH O \ O O \ \ \ \ \ N~NH N~NH N~NH I or I or a pharmaceutically acceptable salt of the compound.

In some embodiment, the compound wherein the structure: F F F F F F CF3 CF3 CF3 Cl C! CN CN CN CN CN N‘N N~N N\N N\N F3C CF3 Cl Cl F CF3 CF3 CF3 CF3 OCH3 CN CN CN CN N N / N f ,- N N / / OJYN / OJYN / okrN / / / x OJYN \ / h} / \ / OJYN / N N\‘N Ix} ‘ N I O r I or a ceutically acceptable salt of the compound.

In some embodiment, the compound having the structure: F F F F F F gen gen Cl Cl CFa E CFa H H H N N N or a pharmaceutically acceptable salt of the compound.

The present invention provides a ceutical composition comprising any one of the above compounds and a pharmaceutically' acceptable carrier.

The present invention provides a method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a subject afflicted therewith comprising administering to the subject an effective amount of any one of the above compounds.

The t invention provides a pharmaceutical composition comprising the compound of the present invention and a ceutically acceptable carrier.

The present invention provides a method for ng a disease characterized by excessive lipofuscin accumulation in the retina in a t ted therewith comprising administering to the subject an effective amount of the compound of the present invention or a composition of the present invention.

In some embodiments, the disease is further characterized by bisretinoid—mediated macular degeneration.

In some embodiments, the amount of the compound is effective to lower the serum concentration of RBP4 in the subject.

In some embodiments, the amount of the compound is ive to lower the retinal concentration of a bisretinoid in lipofuscin in the subject. 3O In some embodiments, the inoid is AZE. In some embodiments, the bisretinoid is isoAZE. In some embodiments, the bisretinoid is A2— DHP-PE. In some embodiments, the bisretinoid is atRAL di-PE.

In some embodiments, the disease characterized by excessive lipofuscin lation in the retina is Age—Related Macular Degeneration.

In some embodiments, the disease characterized by excessive lipofuscin accumulation in the retina is dry (atrophic) Age-Related r Degeneration.

In some embodiments, the disease terized by excessive lipofuscin accumulation in the retina is rdt Disease.

In some embodiments, the disease characterized by excessive lipofuscin accumulation in the retina is Best disease.

In some embodiments, the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform pathy.

In some embodiments, the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt—like macular dystrophy In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

In some ments, R9 is H, C1-C4 alkyl, C3-Cecycloalkyl, (C1—C4 alkyl)—CE3, (C1~C4 alkyl)—OCH3,(C1-C4 alkyl)—halogen, SO2-(C1"C4 alkyl), SOz—(C1~C4 alkyl)—CE3, SOg—(Cl—C4 alkyl)—OCH3, l—C4 alkyl)—halogen, C1-C4 alkyl), C(O)-(C1~C4 alkyl)-CE3, C(O)-(C1—C4 alkyl)—OCH3, C(O)-(C1-C4 alkyl)— halogen, C(O)-NH-(C1-C4 alkyl) , C(O)~N(C1-C4 alkyl)2, (C1—C4 alkyl)-C(O)OH, C(O)~NH2 or oxetane.

In some embodiments, R9 iS H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, t—Bu, CH20CH3, CH2CF3, CH2Cl, CH2F, CH2CH20CH3, CH2CH2CF3, g o CH3CH2C1, CH2CH2F, or ‘<> In some embodiments, R9 iS SOg‘CH}, SOZ‘CHZCH3, SOf‘CHzCHzCHa, 802‘ )2, SOg"CH2CH(CH3)2, SOz—t-‘Bu, SOg-CHzoCH3, SOg—CH2CF3, SOz'CHgCl, SOg-CHZF, SOz-CHZCHzoCI-Ia, SOg—CH2CH2CF3, SOg-CHgCHzCl, SOg-CHzCI-IgF, or In some embodiments , R9 is C (0) -CH3, C (O) —CH2CH3, C (O) zCI-h, C(O)- CH (CH3) 2, C (O) ~CH2CH (CH3) 2, C (O) -t-Bu, C (O) —CH20CH3, C (O) -CH2CF3, C(O)- CHzCl, C (O) -C,H2F C (O) -CH2CHZOCH3, C (O) -CH2CH2CF3, C (O) ~CH2CH2Cl, C(O)- QL<> "9* ,or QL'W/ In some embodiments, the compound having the structure: F F F F F CF3 i :CFa :CF3 EC}: N ii N N N 0%B 0%B 0%B I 0%B I I F i F F30 01:3 Cl Cl F CFa N N N N O¢7J\\B o¢¢i\\a Oé¢i\\8 Oé¢l\\B , I I I Cl Cl CF3 CF3 CFa O B O B O I Or B or a pharmaceutically acceptable salt f.

In some embodiments of the compound, B has the structure: f F 1" CN \ \ 31" c: OCHa \ \ fYQ/OCHB\ N‘NH N‘NH OZS’NHCHa The present ion provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable The present invention provides a method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of a compound of the present invention or a composition of the present invention In some embodiments of the method, wherein the disease is further characterized by bisretinoid~mediated r degeneration.

In some embodiments of the method, wherein the amount of the compound is effective to lower the serum concentration of RBP4 in the mammal.

In some embodiments of the method, wherein the amount of the compound is effective to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal.

In some embodiments of the , wherein the bisretinoid is A2E. In some embodiments of the method, wherein the bisretinoid is isoAZE. In some embodiments of the method, wherein the bisretinoid is A2—DHP—PE.

In some embodiments of the , wherein the bisretinoid is atRAL di—PE.

In some embodiments of the method, wherein the disease characterized by excessive lipofuscin accumulation in the retina is lated Macular Degeneration.

In some embodiments of the method, wherein the disease characterized by excessive lipofuscin accumulation in the retina is dry (atrophic) Age-Related Macular Degeneration.

In some embodiments of the method, wherein the e characterized by excessive lipofuscin accumulation in the retina is rdt Disease.

In some ments of the method, wherein the disease characterized by excessive lipofuscin accumulation in the retina is Best disease.

In some embodiments of the method, wherein the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy. 3O In some ments of the method, wherein the e characterized by excessive lipofuscin lation in the retina is Stargardt—like macular dystrophy.

In some embodiments, bisretinoid—mediated macular degeneration is Age— Related Macular Degeneration or Stargardt Disease.

In some embodiments, the bisretinoid-mediated macular degeneration is Age—Related Macular Degeneration.

In some ments, the bisretinoid—mediated macular ration is dry (atrophic) Age—Related Macular Degeneration.

In some embodiments, the inoid—mediated r degeneration is Stargardt Disease.

In some embodiments, the bisretinoid—mediated macular degeneration is Best disease.

In some embodiments, the bisretinoid—mediated macular degeneration is adult vitelliform maculopathy.

In some embodiments, the bisretinoid—mediated macular degeneration is Stargardt-like macular phy.

The bisretinoid~mediated macular degeneration may se the 2O accumulation of lipofuscin deposits in the retinal t epithelium.

As used herein, "bisretinoid lipofuscin" is lipofuscin containing a cytotoxic bisretinoid. Cytotoxic bisretinoids include but are not necessarily limited to A2E, isoA2E, atRAL divPE, and A2—DHP—PE (Figure l, 2, and 3).

The present ion provides non~retinol piperidine compounds comprising a 3,4—difluoro—2—(trifluoromethyl)phenyl moiety. This feature significantly increases the potency and improves pharmacokinetic characteristics of the molecules.

The present invention provides non—retinol piperidine compounds comprising a 3,5~difluoro—2—(trifluoromethyl)phenyl moiety. This feature icantly increases the potency and improves pharmacokinetic characteristics of the molecules.

The present invention provides non—retinol piperidine compounds comprising di— or trisubstitued phenyl moiety. This feature significantly increases the y and improves pharmacokinetic characteristics of the molecules.

Except where otherwise specified, when the structure of a compound of this invention es an tric carbon atom, it is understood that the nd occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration.

It is to be tood accordingly that the isomers g from such asymmetry (e.g., all enantiomers and diastereomers) are ed within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form. by classical separation techniques and by chemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by ative chromatography on a chiral column.

The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes e those atoms having the same atomic number but different mass numbers.

By way of general example and t limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C~13 and C— It will be noted that any notation of a carbon in structures throughout 3O this application, when used without further notation, are intended to represent all isotopes of , such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as UL 2H, or 3H.

Furthermore, any nds containing 2H or 3H may specifically have the structure of any of the compounds sed herein.

Isotopically-labeled compounds can generally be ed by conventional techniques known to those skilled in the art using appropriate isotopically—labeled reagents in place of the non-labeled reagents employed.

The term "substitution", "substituted" and "substituent" refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable nd. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n— propyl, isopropryl, n—butyl, tert—butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; kyloxy, such as benzyloxy (phenylmethoxy) and p~trifluoromethylbenzyloxy (4— oromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p— toluenesulfonyl; nitro, yl; mercapto; sulfanyl groups, such as methylsulfanyl, ulfanyl and propylsulfanyl; cyano; amino groups, such as amino, amino, dimethylamino, mino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) tuents can be the same or different.

In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise.

In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These e, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

It is understood that substituents and tution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to e compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure s.

In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the s tuents, i.e. R1, R2, etc. are to be chosen in conformity with well—known principles of chemical ure connectivity.

As used herein, "alkyl" is intended to include both branched and straight-Chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cn as in "Cl—Cnalkyl" is defined to include groups having 1, 2 ...... , n—l or n s in a 3O linear or branched arrangement, and specifically includes , ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec— butyl and so on. An embodiment can be C1—Cm alkyl, C2—Cu alkyl, C3— Cu alkyl, C4—Cm alkyl and so on. An embodiment can be Cr{h alkyl, C2—C8 alkyl, C3—C8 alkyl, C4—C8 alkyl and so on. "Alkoxy" represents an alkyl group as bed above attached through an oxygen bridge.

The term "alkenyl" refers to a non—aromatic hydrocarbon l, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of omatic — carbon double bonds may be present. Thus, Cz—Cn alkenyl is defined to include groups having 1, 2...., n—l or n carbons. For example, "C2—C6 alkenyl" means an l radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon—carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, yl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be tuted if a substituted alkenyl group is indicated. An embodiment can be C2-Cu alkenyl or C2—C3 alkenyl.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non~aromatic carbon~carbon triple bonds may be present. Thus, Cg—Cn alkynyl is defined to include groups having 1, 2...., n—l or n carbons. For example, "C2—C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and l carbon—carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon—carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon—carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl.

As described above with t to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted l group is indicated. An embodiment can be a C2—Cnalkynyl. An ment can be C2-Cm alkynyl or C3—C9 alkynyl.

Alkyl groups can be unsubstituted or substituted with one or more substituents, including but not limited to halogen, alkoxy, hio, trifluoromethyl, difluoromethyl, methoxy, and hydroxyl.

As used herein, "C1—C4 alkyl" includes both branched and straight— chain C1—C4 alkyl.

As used herein, "heteroalkyl" includes both branched and ht—chain saturated aliphatic hydrocarbon groups having at least 1 heteroatom within the chain or branch.

As used herein, "cycloalkyl" includes cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

As used herein, "heterocycloalkyl" is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms ed from the group consisting of O, N and S, and includes bicyclic groups.

"Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, linyl, rpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains nitrogen, it is understood that the corresponding N—oxides thereof are also encompassed by this definition.

As used herein, "aryl" is ed to mean any stable clic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include but are not limited to: phenyl, p—toluenyl (4—methylphenyl), naphthyl, tetrahydro— naphthyl, indanyl, thryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non—aromatic, it is understood that attachment is via the aromatic ring.

The term "alkylaryl" refers to alkyl groups as described above wherein one or more bonds to hydrogen ned therein are replaced by a bond to an aryl group as described above. It is understood that an "alkylaryl" group is connected to a core molecule h a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not d to, benzyl (phenylmethyl), p~trifluoromethylbenzyl (4— oromethylphenylmethyl), l—phenylethyl, 2-phenylethyl, 3— phenylpropyl, 2~phenylpropyl and the like.

The term "heteroaryl" as used herein, represents a stable clic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group ting of O, N and S. Bicyclic aromatic heteroaryl groups include but are not limited to phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6—membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5— or 6—membered aromatic (unsaturated) heterocyclic ring having two en atoms; (c) fused to a ered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5—membered aromatic (unsaturated) heterocyclic ring having one heteroatom ed from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, yrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, nyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, nyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4—dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, oimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, 3O dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, oazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, ydrothienyl, acridinyl, carbazolyl, inyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, uranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, dinyl, pyrrolyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the atom containing ring, respectively. If the heteroaryl ns en atoms, it is understood. that the corresponding N-oxides thereof are also encompassed by this definition.

As used herein, "monocycle" includes any stable polycyclic carbon ring of up to 10 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements e but are not limited to: cyclobutyl, entyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl. As used herein, "heteromonocycle" includes any monocycle containing at least one heteroatom.

As used herein, "bicycle" includes any stable polycyclic carbon ring of up to 10 atoms that is fused to a polycyclic carbon ring of up to atoms with each ring being independently tituted or substituted. Examples of such non—aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene.

As used herein, "heterobicycle" includes any bicycle ning at least one heteroatom.

The term "phenyl" is intended to mean an ic six membered ring containing six carbons, and any substituted derivative thereof.

The term "benzyl" is intended to mean a methylene attached ly to a benzene ring. A benzyl group is a methyl group wherein a hydrogen is replaced with a phenyl group, and any substituted derivative thereof.

The term "pyridine" is intended to mean a aryl having a six~ membered ring containing 5 carbon atoms and 1 nitrogen atom, and any substituted derivative thereof.

The term "pyrazole" is intended to mean a heteroaryl having a five— membered ring ning three carbon atoms and two nitrogen atoms wherein the nitrogen atoms are adjacent to each other, and any substituted derivative thereof.

The term "indole" is intended to mean a heteroaryl having a five~ membered ring fused to a phenyl ring with the five—membered ring containing 1 nitrogen atom ly attached to the phenyl ring.

The term ne" is intended to mean a non—aromatic four—membered ring containing three carbon atoms and one oxygen atom, and any substituted derivative thereof.

The nds used in the method of the present invention may be prepared by techniques well know in organic synthesis and familiar to a practitioner rily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired The compounds of present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I.

Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) SU‘Edition (1996), s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (WileyeInterscience) 5th n (2007), and references therein, which 3O are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

The compounds of present ion Inay 1x3 prepared by techniques described herein. The tic methods used to prepare Examples 1- 103 are used to prepare additional piperidine compounds which are described in the embodiments herein.

The various R groups attached to the aromatic rings of the compounds sed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: on and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

Another aspect of the invention comprises a compound of the present invention as a pharmaceutical composition.

As used herein, the term "pharmaceutically active agent" means any substance or compound suitable for stration to a t and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of e, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and "Approved Drug Products with Therapeutic lence Evaluations" (U.S. Department Of Health And Human Services, 30th edition, 2010), which are hereby incorporated by nce. Pharmaceutically active agents which have t carboxylic acid groups may be modified in accordance with the t invention using standard fication reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently 3O be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.

The compounds of the present invention may be in a salt form. As used herein, a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat a disease, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or c acid salts of basic residues such as ; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid.

Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, ates, formates, tartrates, maleates, malates, citrates, tes, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non—toxic, inorganic and organic acid or base addition salts of compounds of the present ion. These salts can be prepared in situ during the final isolation and cation of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable c or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, ate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, te, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 9).

A salt or pharmaceutically acceptable salt is contemplated for all compounds disclosed herein. In some embodiments, a pharmaceutically acceptable salt or salt of any of the above compounds of the present invention. 3O As used herein, "treating" means ting, slowing, halting, or reversing the progression of a disease or infection. Treating may also mean improving one or more symptoms of a disease or infection.

The compounds of the present invention may be administered in various forms, including those ed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant nds. This ation therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.

The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a ic herapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent ent being administered; the frequency of ent with; and the desired therapeutic effect.

A dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional agents. The compounds can be administered in oral dosage forms as tablets, capsules, pills, s, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also 3O be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by ion, topical application, or other s, into or onto a site of infection, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The compounds used in the method of the present ion can be administered in admixture with suitable pharmaceutical ts, extenders, excipients, or carriers (collectively ed to herein as a pharmaceutically able carrier) suitably selected with t to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co—administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to w or chew; other solid forms include granules, and bulk powders. s may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring , flow—inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or sions reconstituted from non—effervescent granules and effervescent preparations tituted from effervescent granules.

Such liquid dosage forms may contain, for example, suitable solvents, preservatives, fying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to 3O make them compatible with the type of injection or delivery system chosen.

Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 r & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); s Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the ceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate rs: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the ceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

Tablets may contain le binders, ants, disintegrating agents, coloring agents, flavoring , flow—inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non—toxic, ceutically acceptable, inert r such as lactose, gelatin, agar, starch, sucrose, glucose, methyl ose, magnesium te, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. le binders include starch, gelatin, natural sugars such as glucose or beta—lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium te, sodium 3O acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large allar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of —targeted emulsions.

The nds used in the method of the present invention may also be coupled. to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide~phenol, polyhydroxyethylasparta— midephenol, or polyethyleneoxide—polylysine substituted with palmitoyl residues. Furthermore, the compounds may be d to a class of biodegradable polymers useful in ing lled release of a drug, for example, polylactic acid, ycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose tives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as ned release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or c coated for selective disintegration in the gastrointestinal tract.

For oral stration in liquid dosage form, the oral drug components are combined with any oral, non—toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or sions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, ons and/or suspensions reconstituted from fervescent es and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying , suspending agents, diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, , aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necesSary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium e, or ascorbic acid, either alone or ed, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl— or — paraben, and chlorobutanol. Suitable ceutical carriers are described in ton's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin s well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

Parenteral and intravenous forms may also include minerals and other materials to make thenl compatible with the type of injection or delivery system .

Each embodiment disclosed herein is contemplated as being applicable to each of the other sed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

Unless the context clearly requires otherwise, hout the description and the claims, the words "comprise", "comprising" and the like are to be construed in an inclusive sense as opposed to an ive or exhaustive sense; that is to say in the sense of "including but not d to".

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental Details Materials and Methods T assay for retinal—induced RBP4-TTR interaction Binding of a desired RBP4 antagonist displaces retinol and s hindrance for RBP4—TTR interaction resulting in the decreased FRET signal e 7). Bacterially expressed MBP-RBP4 and ed TTR were used in this assay. For the use in the TR—FRET assay the maltose binding protein (MBP)—tagged human RBP4 nt (amino acids 19-201) was expressed in the Gold(DE3)pLysS E. coli strain (Stratagene) using the pMAL—c4x . Following cell lysis, recombinant RBP4 was purified from the soluble fraction using the ACTA FPLC system (GE Healthcare) equipped with the 5—ml the MBP Trap HP column. Human untagged TTR was purchased from Calbiochem. Untagged TTR was labeled directly with Eu3*Cryptate~NHS using the HTRF Cryptate Labeling kit from CisBio following the manufacturer’s recommendations. HTRF assay was performed in white low volume 384 well plates (Greiner-Bio) in a final assay volume of 16 ul per well. The reaction buffer contained 10 mM Tris—HCl pH 7.5, 1 mM DTT, 0.05% NP—40, 0.05% Prionex, 6% glycerol, and 400 mM KF. Each reaction contained 60 nM MBP—RBP4 and 2 nM TTR—Eu along with 26.7nM of anti—MBP antibody conjugated with d2 (Cisbio). Titration of test compounds in this assay was conducted in the presence of 1 uM retinol. All reactions were assembled in the dark under dim red light and incubated overnight at +4OC wrapped in aluminum foil. TR—FRET signal was ed in the SpectraMax M5e ode Plate Reader ular Device). scence was excited at 337 nm and two readings per well were taken: Reading 1 for time—gated energy transfer from Eu(K) to d2 (337 nm excitation, 668 nm emission, counting 3O delay 75 microseconds, counting window 100 econds) and Reading 2 for Eu(K) time—gated fluorescence (337 nm excitation, 620 nm emission, counting delay 400 microseconds, counting window 400 microseconds). The TR’FRET signal was expressed as the ratio of fluorescence intensity: Flu%5/Flumo x 10,000.

Scintillation proximity RBP4 g assay Untagged human RBP4 purified from urine of tubular proteinuria patients was purchased from Fitzgerald Industries International. It was biotinylated using the EZ—Link Sulfo—NHS—LC*Biotinylation kit from Pierce following the manufacturer’s recommendations. Binding ments were med in 96-well plates (OptiPlate, PerkinElmer) in a final assay volume of 100 pl per well in SPA buffer (1X PBS, pH 7.4, lmM EDTA, 0.1%BSA, 0.5%CHAPS). The reaction mix ned 10 nM 3H—Retinol (48.7Ci/mmol; PerkinElmer), 0.3 mg/well avidin—PVT beads, 50 nM biotinylated RBP4 and a test compound. Nonspecific binding was determined in the presence of 20 uM of led retinol.

The reaction mix was assembled in the dark under dim red light. The plates were sealed with clear tape (TopSeal—A: 96—well late, PerkinElmer), wrapped in the aluminum foil, and allowed to equilibrate 6 hours at room temperature followed by overnight incubation at +40C.

Radiocounts were measured using a TopCount NXT counter rd Instrument Company).

General Procedure (GP) for Pre arin Intermediates for S nthesis of Piperidine Compounds | :"R1 I :"R1 N N H 04R Conditions: Al) ylic acid, HBTU, Et3N, DMF; A2) carboxylic acid, EDCI, HOBt, i-PrgNEt, DMF; A3) acid Chloride, Et3N, CH2C12.

General Procedure (GP—A1) for carboxamide formation: A mixture of amine I (1 equiv), desired carboxylic acid (1 equiv), triethylamine (Et3N) (3 equiv), and 2~(1H—benzotriazole—l—yl)-1,1,3,3— tetramethyluronium hexafluorophosphate (HBTU) (1.5 equiv) in DMF (0.25 M) was stirred at room temperature until the reaction was complete by LC—MS. The mixture was diluted with rho and extracted with EtOAc.

The combined organic extracts were washed with H20, brine, dried over Na2304, filtered and concentrated under reduced re. The ing residue was purified by silica gel tography al eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2Clz and a 90:9:1 mixture of CH2ClyMHh0H/concentrated NH40H) to afford the desired carboxamide II. The product structure was verified by 1H NMR and by mass analysis.

General ure (GP-A2) for carboxamide formation: A mixture of amine I (1 equiv), desired carboxylic acid (1 equiv),N, N; diisopropylethylamine (i—PrgNEt) (3 equiv), l-ethyl—3-(3— dimethylaminopropyl)carbodiimide (EDCI) (1.5 equiv) and hydroxybenzotriazole (HOBt) (1.5 equiv) in DMF (0.25 M) was d at room temperature until the reaction was complete by LC-MS. The mixture was diluted with H30 and extracted with EtOAc. The combined c extracts were washed with H20, brine, dried over Nazsoh filtered and concentrated under d. pressure. The resulting residue was purified by silica gel chromatography (typical eluents included either a e of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 mixture of CH2C12/CH30H/concentrated NH40H) to afford the desired carboxamide II. The product ure was verified by 1H NMR and by mass analysis.

General Procedure ) for carboxamide formation: A mixture of amine I (1 equiv), Et?q (3 equiv), and acid chloride (1 equiv) in CH2C12(O.25 M) was stirred at ambient temperature until the reaction was complete by LC—MS. The mixture was washed with H20, brine, dried over Nagso" filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (typical 3O eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 mixture of CH2ClyMHh0H/concentrated NH40H) to afford the desired carboxamides II. The product structure was verified by 1H NMR and by mass analysis.

General Procedures for Preparing (4-Phenylpiperidinyl)(4,5,6,7- tetrahydro-lH-pyrazolo[4,3~c]pyridin-3—yl)methanone Carboxamides IV \ \ I —R1 | 4‘1 / / H B YRa N ———-——> N N N~NH N~NH HI lV Conditions: B) acid chloride, Eth, CH2ClL General Procedure (GP—B) for carboxamide formation: A mixture of amine III (1 , desired acid chloride (1 equiv) and triethylamine (Et?w (3 equiv) in CH??g (0.25 M) was stirred from 0 °C to room ature until the reaction was complete by LC~MS. The mixture was diluted with H20 and extracted with CHQClg. The combined organic extracts were washed with H20, brine, dried over Na2504, filtered and concentrated under reduced pressure. The resulting residue was ed by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH??Q and a 90:9:1 mixture of CH2Clg/CH30H/concentrated NH40H) to afford the desired carboxamides IV. The product ure was verified by 1H NMR and by mass analysis.

General ures for Preparing (4-Pheny1piperidiny1)(4,5,6,7— tetrahydro-lH-pyrazolo[4,3—c]pyridin—3—y1)methanone Sulfonamides V |\—R1 \ | —R1 / / O\ ’R3 H C \'S\\O N N -———-> N N 0W 0W N‘NH N‘NH I" V Conditions: C) sulfonyl chloride, i—PrgNEt, CH2C12.

General Procedure (GP-C) for sulfonamide ion: A mixture of amine III (1 equiv), desired sulfonyl chloride (1 equiv) and i—PerEt (3 equiv) in CH2C12 (0.25 M) was stirred from 0 °C to room temperature until the reaction was complete by LC—MS. The mixture was diluted with H20 and extracted with CH2C12. The combined organic ts were washed with H20, brine, dried over Na2504, ed and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a n?xture of (HhClz and a 90:9:1 mixture of CH2Cl2/CH3OH/concentrated NHqOH) to afford the desired sulfonamides V.

The t structure was verified by 1H NMR and by mass analysis.

General Procedures for Preparing Alkylated (4-Phenylpiperidin ,6,7—tetrahydro—1H—pyrazolo[4,3—c]pyridin-3—yl)methanones VI \—-—R1 \ 1 1 —R1 / / H D Ba N N ———————> N N 0W 0W N~NH N‘NH "I V! Conditions: D) aldehyde or ketone, NaBH(OAc)3, CHZCl? General Procedure (GP-D) for sulfonamide formation: A mixture of amine III (1 equiv), desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv) in CH2C12 (0.25 M) was stirred for 16 hours at room temperature. To this was added sodium triacetoxyborohydride (NaBH(OAc)3) and the mixture d at room ature until the reaction was complete by LC—MS. The mixture was diluted with aqueous, saturated NaHCO3 solution and extracted with CH??g. The combined organic extracts were washed with H20, brine, dried over NagsOh filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 e of CH2C12/CH3OH/concentrated NHqOH) to afford the desired amines VI. The product structure was ed by 1H NMR and by mass analysis.

General Procedure for Preparing (4—Phenylpiperidinyl)(4,5,6,7- ydro-lH—pyrazolo[3,4-c]pyridin-3—yl)methanone Carboxamides \\ \\ I "R1 I ""R1 / / N ‘"‘"’"’ N N MO N‘NH N‘NH VH vm Conditions: E) acid chloride, EtaN, CH2ClL General Procedure (GP—E) for carboxamide formation: A mixture of amine VII (1 equiv), desired acid chloride (1 equiv) and ylamine (Et?n (3 equiv) in CHjHJ (0.25 M) was stirred from 0 °C to room temperature until the reaction was complete by LC—MS. The mixture was diluted with H20 and extracted with . The combined organic extracts were washed with H20, brine, dried over N82504, filtered and concentrated under reduced pressure. The resulting e was purified by silica gel chromatography (typical eluents included either a e of or hexanes and EtOAc or a mixture of CH2Cl2 and a 90:9:l mixture of CH2Clg/CH30H/concentrated NHqOH) to afford the desired carboxamides VIII. The product structure was verified by 1H NMR and by mass analysis.

General Procedures for Preparing (4—Phenylpiperidin—1-yl)(4,5,6,7— tetrahydro—lH-pyrazolo[3,4—c]pyridin~3~yl)methanone Sulfonamides Ix EEEETR1\ \ ‘ _—R1 / / N > N "/R NH ’§ 3 N‘NH N‘NH vn IX Conditions: F) sulfonyl chloride, i—PerEt, CH2ClL General Procedure (GP—F) for sulfonamide formation: A mixture of amine VII (1 , desired sulfonyl chloride (1 equiv) and i—PerEt (3 equiv) in CH2C12 (0.25 M) was stirred from 0 °C to room temperature until the reaction was complete by LC~MS. The e was diluted with H20 and extracted with CH2C12. The combined organic extracts were washed with H20, brine, dried over Na2504, filtered and concentrated under reduced pressure. The resulting residue was ed by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2Clz and a 90:9:1 mixture of CH2Clz/CH30H/concentrated NH4OH) to afford the desired sulfonamides IX.

The product structure was verified by 1H NMR and by mass analysis.

General ures for ing Alkylated (4—Phenylpiperidin-1— yl)(4,5,6,7-tetrahydro~1H-pyrazolo[3,4-c]pyridin—3—yl)methanones X 1 ._R1 R1 N "’—"——* N NH N'Ra O O \ \ \ \ N‘NH N‘NH V" X Conditions: G) aldehyde or ketone, NaBH(OAc)3, CH2C1L l Procedure (GP-G) for sulfonamide formation: A mixture of amine VII (1 equiv), desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv) in CH2C12 (0.25 M) was stirred for 16 hours at room temperature.

To this was added sodium triacetoxyborohydride (NaBH(0Ac)3) and the mixture stirred at room ature until the reaction was complete by LC—MS. The mixture was d with s, saturated NaHC03 on and extracted with CHQClL The combined organic extracts were washed with H20, brine, dried over Na2804, filtered and concentrated under d pressure. The resulting residue was ed by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 mixture of CH2C12/CH30H/concentrated NH40H) to afford the desired amines X. The product structure was verified by 1H NMR and by mass analysis.

General Procedures for Preparing (4-Phenylpiperidinyl)(1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3—y1)methanone Carboxamides XII \ \ I "R1 I "‘R1 / / N _"> N 31 NH N R3 N~NH N‘NH XI xn Conditions: H) acid chloride, Et3N, CH2ClL General Procedure (GP-H) for carboxamide formation: A mixture of amine XI (1 equiv), desired acid chloride (1 equiv) and triethylamine (Et?n (3 equiv) in CH?HJ (0.25 M) was stirred from 0 0C to room temperature until the reaction was complete by LC*MS. The mixture was diluted with H20 and extracted with CH2C12. The ed organic extracts were washed with H20, brine, dried over Na2804, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (typical eluents ed either a mixture of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 mixture of CH2C12/CH30H/concentrated NH40H) to afford the desired carboxamides XII. The product structure was verified by 1H NMR and by mass analysis.

General ures for Preparing (4-Phenylpiperidinyl)(1,4,5,6— tetrahydropyrrolo[3,4-c]pyrazol-3—yl)methanone Sulfonamides XIII I "R1 | —R1 / / | Q\ ,Ra N -———. N ,% 0WNH N o N‘NH N‘NH XI xm Conditions: I) yl chloride, i—PrgNEt, CH2Clb General Procedure (GP-I) for amide formation: A mixture of amine XI (1 equiv), desired sulfonyl chloride (1 equiv) and i—PrgNEt (3 equiv) in CH2C12 (0.25 M) was stirred from 0 °C to room ature until the reaction was complete by LC—MS. The mixture was diluted with H20 and extracted with CH2Cl2. The combined organic extracts were washed with H20, brine, dried over Na2804, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (typical eluents included either a e of or hexanes and EtOAc or a ndxture of CH?Hz and a 90:9:1 mixture of CHgClg/CH30H/concentrated. NH4OH) to afford. the desired. sulfonamides XIII. The product structure was verified. by Hi NMR and. by mass analysis.

General ures for Preparing Alkylated (4-Phenylpiperidin yl)(1,4,5,6—tetrahydropyrrolo[3,4-c]pyrazolyl)methanone XIV ) "R1 l ‘"R1 / / N "_____> N R NH N’3 O \ O \ \ \ N‘NH N‘NH XI XN Conditions: J) aldehyde or ketone, NaBH(OAc)3, CHzClL General Procedure (GP-J) for sulfonamide formation: A mixture of amine XI (1 , desired aldehyde or ketone (1.5 equiv) and HOAc (6 equiv) in CH2C12 (0.25 M) was stirred for 16 hours at room temperature. To this was added sodium toxyborohydride (NaBH(OAc)3) and the mixture stirred at room temperature until the reaction was complete by LC—MS. The mixture was diluted with aqueous, saturated NaHC03 solution and extracted with CHQClL The combined organic extracts were washed with H20, brine, dried over Nagsoh ed and concentrated under reduced. pressure. The resulting residue was purified by silica gel chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2Clz and a 90:9:1 mixture of CH2C12/CH30H/concentrated NHqOH) to afford the desired amines XIV. The product structure was verified by 1H NMR and by mass analysis.

Preparation 4—(3-Fluoro(trifluoromethyl)phenyl)piperidine Hydrochloride (5) O OTf CF3 in] CF 1. LiHMDS, THF, -78 "C (5 3 B(OH)2 Pd(PPh3)4. 2 M Nazcoa N 2. PhN(OSOZCF3)2. THF, -73 °c to 0 °C N DME, 80 °c Boc Boc N 1 2 F F CF3 2 N HCI m Etzo.

H2 (30 psi), 10% Pd/C -—-—~> -——-—-—--———-—-—-—-—--—-—-> EtOH, rt CHZCIZ, n N N -HCl Boc H 4 5 Step A: A solution of tert-butyl 4—oxopiperidine—l«carboxylate (1, 1.0 g, 5.02 mmol) in THF (30 mL) was cooled to —78 °C. LiHMDS (1.0 M solution in THF, 6.52 mL) was added dropwise over 30 min. The reaction was stirred at ~78 °C for l h, then a solution of NLphenyl— bis(trifluoromethanesulfonimide) (2.52 g, 7.05 mmol) in THE (5.0 mL) was added se over 30 min. The mixture stirred at 0 °C for 3 h, and was then concentrated under reduced re. The residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 100% EtOAc in s) to provide tert-butyl 4~ (((trifluoromethyl)sulfony1)oxy)~5,6-dihydropyridine-l(2H)v carboxylate (2) as a light yellow oil (1.50 g, 90%): 1H NMR (300 MHz, CDCl3) 5 5.75 (br s, 1H), 4.05—4.02 (m, 2H), 3.64~3.60 (m, 2H), 2.44- 2.42 (m, 2H), 1.46 (s, 9H).

Step B: A mixture of tert-butyl rifluoromethyl)sulfony1)oxy)— ,6—dihydropyridine—l(2H)—carboxy1ate (2, 3.50 g, 10.6 mmol), 3— fluoro—(2—trif1uoromethy1)phenyl boronic acid (2.19 g, 10.6 mmol), Pd(PPh?4 (1.22 g, 1.06 mmol) , and 2 M NaZCO3 (62 mL) in DME (120 mL) was heated to 80 °C for 6 h. The mixture cooled to ambient temperature and was diluted with 5% aqueous LiCl solution (100 mL). The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with brine (2 x 50 mL) and concentrated under reduced pressure. The residue was diluted in CH2C12 (100 mL) and sent through a 300 mL silica gel plug, eluting with 10 % EtOAc in hexanes (800 mL).

The resulting filtrate was trated under reduced pressure and was chromatographed over silica gel (Isco CombiFlash Rf unit, 80 g Redisep column, 0% to 50% EtOAc in hexanes) to provide utyl 4— (3—fluoro-2—(trifluoromethyl)phenyl)—5,6—dihydropyridine—l(2H)— carboxylate (3) as a light yellow oil (2.39 g, 69%): 1H NMR (300 MHz, DMSO—dm 5 7.75-7.61 (m, 1H), .36 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), .54 (m, 1H), 3.97~3.86 (m, 2H), 3.57~3.45 (m, 2H), 2.31— 2.18 (m, 2H), 1.42 (s, 9H).

Step C: A mixture of tert—butyl 4-(3-f1uoro—2—(trifluoromethyl) phenyl)~5,6—dihydropyridine~l(2H)—carboxy1ate (3, 4.7 g, 13.6 mmol) and 10% Pd/C (1.0 g) in EtOH (100 mL) was placed under an atmosphere of H2 (30 psi) at ambient temperature for 18 IL the mixture was filtered through a Celite, and the filtrate was trated under 3O reduced pressure to give tert-butyl 4—(3—fluoro—2— (trifluoromethyl)phenyl)piperidine-l—carboxylate (4) as a clear oil (4.80 g, >99%): 1H NMR (300 MHz, DMSO—d6) 5 7.72—7.60 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.30 (dd, J = 12.3, 8.1 Hz, 1H), 4.18—4.00 (m, 2H), 3.ll~2.95 (m, 1H), .64 (m, 2H), 1.76—1.51 (m, 4H), 1.42 (s, 9H).

Step D: To a solution of utyl 4—(3-fluoro-2 (trifluoromethyl)phenyl)piperidine—l~carboxylate (4, 4.70 g, 13.6 mmol) in CH2C12 (40 mL) was added 2 N HCl (2.0 M in Etgo, 40 mL). The mixture stirred at ambient temperature for 18 h and was diluted with Etzo (100 mL). The resulting precipitate was collected by filtration to give luoro(trifluoromethyl)phenylpiperidine hloride as a white powder (5, 3.69 g, 96%): 1H NMR (300 MHz, DMSO~da 5 9.09~ 8.80 (m, 2H), 7.83—7.70 (m, 1H), 7.44—7.29 (m, 2H), 3.42~3.31 (m, 2H), 3.29~3.15 (m, 1H), 3.14—2.95 (m, 2H), 2.11—1.91 (m, 2H), 1.89, 1.76 (m, 2H); ESI MS m/z 248 [M + H]+.

Preparation 4-(3,4—Dif1uoro(trifluoromethyl)pheny1)piperidine (8) +P F O‘B’O CF21 \ Pd(PPh3)4, 2 M N32C03 N DME. 80 °C Boc N F 7 H2 (30 psi), 10% Pd/C EtOH, rt 8 Step A: A mixture of tert-butyl ,5,5—tetramethyl«1,3,2— dioxaborolan~2-yl)—5,6~ dihydropyridine—l(2H)—carboxylate (6, 57.4 g, 185 mmol), 3 1—bromo—3,4—difluoro—2—(trifluoromethyl)benzene (48.5 g, 185 mmol), Pd(PPh?4 (21.5 g, 18.5 mmol) , and 2 M NaQCO3 (150 mL) in DME (500 mL) was heated to 80 °C for 16 h. The mixture cooledto ambient temperature and was diluted with 5% aqueous LiCl solution (100 mL).

The mixture was extracted with EtOAc (3 x 200 mL), and the combined organic extracts were washed with brine (2 x 200 mL) and concentrated under reduced pressure. The residue was diluted in CH2C12 (100 mL) and sent through a 300 mL silica gel plug, eluting with 10 % EtOAc in hexanes (800 mL). The resulting filtrate was concentrated under reduced pressure and was chromatographed over silica gel (Isco CombiFlash Rf unit, 3 x 330 g Redisep columns, 0% to 50% EtOAc in s) to provide tert—butyl 4-(3,4-difluoro—2—(trifluoromethyl) )~5,6—dihydropyridine-l(2H)—carboxylate (7) as a white solid (59.0 g, 92%): 1H NMR (300 MHz, CDC13) 87.34~7.28 (m, 1H), 6.93 (m, 1H), 5.55 (br, 1H), 4.01 (br, 2H), 3.60 (m, 2H), 2.30 (m, 2H), 1.50 (s, 9H); MS (ESI+) m/z 308 [M+H~CH?]+.

Step B: A mixture of tert—butyl 4-(3,4—difluoro—2—(trifluoromethyl) phenyl)~5,6—dihydropyridine—1(2H)—carboxylate (7, 59.0 g, 162.3 mmol) and 10% Pd/C (5.0 g) in EtOH (200 mL) was placed under an atmosphere of H2 (30 psi) at ambient temperature for 72 h. the n?xture was ed through a Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidine-l—carboxylate (8) as a white solid (57.9 g, 97%): 1H NMR (300 MHZ, CDC13) 57.36—7.28 (m, 1H), 7.12 (m, 2O 1H), 4.24 (br, 2H), 3.06 (m, 1H), 2.80 (m, 2H), .52 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 310 [M+H—C?h]+.

Preparation 4-(5-F1uoro(trifluoromethyl)pheny1)piperidine hloride (11) OTf CFS @ c:F3 B(OH)2 Pd(PPh3)4, 2 M Nazco3 N DME, so °C 800 N F F CF3 CF3 H2 (1 atm), Pto2 2 N HCI in EtZO "W". "M EtOAc, rt CHzClz, rt N N -HC| Boc H 10 11 Step A: A e of tert—butyl 4—(((trifluoromethyl)sulfonyl)oxy)u ,6—dihydropyridine—1(2H)~carboxylate (2, 1.10 g, 3.32 mmol), 5— fluoro-(2-trifluoromethyl)phenyl boronic acid (0.69 g, 3.32 mmol), Pd(PPh?4 (0.384 g, 0.332 mmol), and 2 M Na2C03 (20 mL) in DME (50 mL) was heated at 80 °C for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4 x 50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco lash Rf unit, 40 g Redisep column, % to 80% EtOAc in hexanes) to provide tert-butyl 4* (5—fluoro~2—(trifluoromethyl)phenyl)—5,6—dihydropyridine—1(2H)- carboxylate (9) as a clear oil (0.542 g, 48%): 1H NMR (300 MHz, DMSO— d5) 8 7.80 (dd, J'= 8.4, 6.0 Hz, 1H), 7.42—7.27 (m, 2H), 5.62 (br s, 1H), 3.97—3.87 (m, 2H), 3.51 (t, J'= 5.7 Hz, 2H), 2.34—2.23 (m, 2H), 1.42 (s, 9H).

Step B: A mixture of tert—butyl 4-(5—fluoro—2—(trifluoromethyl) phenyl)—5,6-dihydropyridine—1(2H)—carboxylate (9, 0.542 g, 1.58 mmol) and HCl (2 N solution in Eth, 10 mL) in CHQClz (20 mL) stirred at ambient temperature for 18 h. The reaction mixture was diluted with Eth (30 mL), and the resulting itate was collected by filtration to provide 4—(5—fluoro—2—(trifluoromethyl) phenyl)—1,2,3,6~ ydropyridine hydrochloride (10) as a white solid (0.393 g, 88%): 1H NMR (300 MHz, DMSO—de) 8 9.26—9.00 (m, 2H), 7.84 (dd, J‘= 8.7, 5.4 Hz, 1H), 7.46—7.36 (m, 1H), 7.24 (dd, J‘= 9.3, 2.4 Hz, 1H), 5.67 (br s, 1H), 3.76-3.64 (m, 2H), 3.27 (t, J = 5.1 Hz, 2H), 2.70—2.40 (m, Step C: A mixture of 4—(5~fluoro(trifluoromethyl)phenyl)~1,2,3,6— tetrahydropyridine hydrochloride (10, 0.393 g, 1.41 mmol) and Pt02 (0.095 mg, 0.42 mmol) in EtOAc (14 mL) was stirred at t temperature for 18 h under a balloon of H2. The mixture was filtered over Celite, and the te was concentrated under reduced pressure and dissolved in (4 mL). To this solution was added HCl (2 N in Eth, 4.0 mL) and the resulting mixture stirred at t temperature for 20 min. The resulting suspension was diluted with EtzO (20 mL) and the solids were collected by filtration to e 4-(5— fluoro—2— (trifluoromethyl)phenyl)piperidine hydrochloride (11) as a white solid (309 mg, 78%): 1H NMR (300 MHz, DMSO-ds) 8 8.81 (br s, 2H), 7.80 (dd, J = 9.3, 6.0 Hz, 1H), 7.39—7.26 (m, 2H), 3.43—3.30 (m, 1H, overlaps with H20), 3.24—2.97 (m, 3H), 2.11~1.90 (m, 2H), 1.88-1.75 (m, 2H); ESI MS m/z 248 [M + H]+.

Preparation 4-(2-Chlorof1uorophenyl)piperidine Hydrochloride (14) OTf Cl \ B(OH)2 Pd(PPh3)4. 2 M Na2CO3 N DME, 80 °C Boc N F F C' C' H2 (1 atm), Pto2 2 N HCI in Et20 ——-—————-—-—-—-——-—-—-—-—> —-—-—-——-——-————-——————> EtOAc, rt CHZCIZ, rt N N -HC| Boc H 13 14 Step A: A mixture of tert~butyl 4—(((trifluoromethyl)sulfonyl)oxy)— ,6-dihydropyridine-l(2H)—carboxylate (2, 1.18 g, 3.56 mmol), 2— chloro—3—fluorophenyl boronic acid (0.621 g, 3.56 mmol), Pd(PPh?q (0.411 g, 0.356 mmol) and 2 M Na2C03 (20 mL) in DME (50 mL) was heated at 80 °C for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by tion through a Celite pad. The filtrate was washed brine solution (4 x 50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep , % to 80% EtOAc in hexanes) to provide utyl hloro-3—fluorophenyl)— ,6—dihydropyridine—l(2H)—carboxylate (12) as a clear oil (0.579 g, 52%): 1H NMR (300 MHZ, DMSO~dd 5 7.43—7.31 (m, 2H), 7.16—7.10 (m, 1H), 5.81—5.72 (m, 1H), .93 (m, 2H), 3.53 (t, J = 5.7 Hz, 2H), .31 (m, 2H), 1.43 (s, 9H).

Step B: A e of tert—butyl 4—(2~chloro—3—f1uoropheny1)—5,6— dihydropyridine—1(2H)— carboxylate (12, 0.488 g, 1.41 mmol) and Pt02 (0.109 g, 0.48 mmol) in EtOAc (15 mL) was stirred at ambient temperature for 18 h under a balloon of H2. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure and dissolved in CH2C12 (4 mL). To this on was added HCl (2 N in Etzo, 4.0 mL) and the ing mixture stirred at t temperature for 20 min. The ing suspension was diluted with Et20 (20 mL) and the solids were collected by filtration to provide tert—butyl-4—(2— chlorofluorophenyl)piperidine—l carboxylate (13) as a clear semi— solid (0.471 g, 95%): 1H NMR (300 MHz, DMSO—dE) 8 7.43—7.19 (m, 3H), 4.17—4.01 (m, 2H), 3.20—3.03 (m, 1H), 2.95—2.68 (m, 2H), 1.79—1.65 (m, 2H), l.58~1.45 (m, 2H), 1.41 (s, 9H).

Step C: To a solution of tert-butyl 4—(2nchloro-3~ fluorophenyl) piperidine-l—carboxylate (13, 0.520 g, 1.66 mmol) in CH2C12 (10 mL) 2O under an atmosphere of N2 was added HCl (2 N in Etzo, 10 mL) solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with Eth (20 mL). The resulting precipitate was collected by filtration and washed with Etzo to provide 4—(2—chloro fluorophenyl)piperidine hydrochloride (14) as a white solid (309 mg, 74%): 1H NMR (300 MHZ, DMSO-dd 5 8.81—8.55 (m, 2H), 7.47—7.37 (m, 1H), 7.36~7.27 (m, 1H), 7.21-7.13 (m, 1H), 3.43—3.20, (m, 3H), 3.17— 2.97 (m, 2H), 2.00-1.73 (m, 4H).

Preparation 4—(2-Chlorof1uorophenyl)piperidine Hydrochloride (17) OTf Cl (i m B(OH)2 Pd(PPh3)4, 2 M Na2CO3 N DME, 80 °C F F m Cl 2 N HCI in EtZO H2 (1 atm). PtOz —-————————-> \ ———————-—-————-———> , rt rt N ,HCI EtOAc.

N .HCI H H 16 17 Step A: A mixture of tert~butyl rifluoromethyl)sulfony1)oxy)— ,6—dihydropyridine—1(2H)—carboxylate (2, 1.10 g, 3.3 mmol), 2- chloro—5efluorophenyl boronic acid (0.58 g, 3.3 mmol), Pd(PPh?4 (0.38 g, 0.33 mmol), and 2 M Na2C03 (20 mL) in DME (50 mL) was heated at 80 °C for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4 x 50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4—(2—chloro—5 fluorophenyl)— ,6-dihydropyridine-l(2H)—carboxylate (15) as a clear oil (0.57 g, 55%): 1H NMR (300 MHz, DMSO-dd 5 7.53-7.46 (m, 1H), 7.23~7.14 (m, 2H), 5.79—5.74 (m, 1H), 4.00-3.92 (m, 2H), 3.52 (t, J = 5.7 Hz, 2H), .32 (m, 2H), 1.43 (s, 9H).

Step B: To a solution of tert—butyl 4—(2~chlorofluorophenyl)—5,6— dihydropyridineal(2H)—carboxylate (15, 0.573 g, 1.84 mmol) in CH2C12 2O (11 mL) was added HCl (2.0 N on in Eth, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction mixture was d with Eth (30 mL), and the resulting precipitate was collected by filtration to provide 4-(2—chloro-5—fluorophenyl)—l,2,3,6— tetrahydropyridine hydrochloride (16) as a white solid (0.267 g, 80%): 1H NMR (300 MHZ, DMSO—dg) 5 9.15 (br s, 2H), 7.54 (dd, J = 9.0, 5.4 Hz, 1H), 7.29~7.17 (m, 1H), 7.14 (dd, J = 9.3, 3.0 Hz, 1H), 5.84—5.79 (m, 1H), 3.76—3.68 (m, 2H), 3.28 (t, J = 5.7 Hz, 2H), 2.62—2.53 (m, 2H); ESI MS m/z 212 [M + H]+.

Step C: A e of 4—(5—fluoro—2~(trifluoromethyl)phenyl)—1,2,3,6- tetrahydropyridine hydrochloride (16, 0.310 g, 1.31 mmol) Pt02 (0.085 g, 0.37 mmol), and HOAc (71 uL, 1.31 mmol) in EtOAc (12 mL) stirred at ambient temperature for 18 under an here of H2 (1 atm). The reaction mixture was diluted with EtOAc (50 mL) and CHJOH (5 mL) and filtered over Celite and the filtrate was concentrated under reduced pressure and dissolved in CH??g (5 mL). To this solution was added HCl (2.0 N solution in Etzo, 2.0 mL) and the mixture stirred at ambient temperature for 5 min. The resulting suspension was diluted with Etzo (20 mL) and the solids collected by filtration to give hloro—5 fluorophenyl) piperidine hydrochloride (17) as an off—white solid (215 mg, 48%): 1H NMR (300 MHz, DMSO-de) 5 8.93—8.20 (m, 2H), 7.58—7.48 (m, 1H), 7.22~7.12 (m, 1H), 7.11~7.01 (m, 1H), 3.43-3.30 (m, 2H), 3.29~ 3.16 (m, 1H), 3.14—2.89 (m, 2H), 2.01—1.68 (m, 4H); ESI MS m/z 214 [M + H]+.

Preparation 4—(3,5—Bis(trifluoromethyl) ) piperidine hloride (20) F30 CF3 F3C CF3 6 B(OH)2 Pd(PPh3)4, 2 M Na2C03 N DME, 80 °C Boc N F3C CF3 F3C CF3 2 N HCI in E120 H2 (1 atm), PtO2 ———-——-—-———-—-——> \ .__,_____,—_—__> CHzclz, rt N 'HCl EtOAC, rt N 'HCI H H 19 20 Step A: A solution of tert—butyl rifluoromethyl)sulfonyl)oxy)~ 5,6~dihydropyridine—1(2H)-carboxylate (2, 1.10 g, 3.32 mmol) and (3,5— bis(trifluoromethyl)phenyl)boronic acid (1.42 g, 3.32 mmol), Pd(PPh?4 (0.38 g, 0.33 mmol) and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80 °C for 6 h. The e cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4 x 50 mL) and trated under reduced pressure. The\ ing residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4~(3,5—bis(trifluoromethyl) phenyl)-5,6-dihydropyridine—1(2H)—carboxylate (18) as ea yellow oil (0.891 g, 68%): 1H NMR (300 MHz, DMSO-de) 6 8.09—8.04 (m, 2H), 8.00— 7.96 (m, 1H), 6.53~6.42 (m, 1H), 4.09—4.00 (m, 2H), 3.55 (t, J = 5.7 Hz, 2H), 2.60—2.52 (m, 2H), 1.43 (s, 9H).

Step B: To a solution of tert—butyl 4—(3,5 bis(trifluoromethyl) phenyl)-5,6—dihydropyridine—1(2H)—carboxylate (18, 0.891 g, 2.25 mmol) in CH2C12(13.5 mL) in CH2C12 (11 mL) was added HCl (2.0 N solution in Eth, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction e was diluted with Et20 (30 mL), and the resulting precipitate was collected by filtration to provide 4~(3,5- bis(trifluoromethyl)phenyl)—1,2,3,6~tetrahydropyridine hydrochloride (19) as a white solid (0.452 g, 60%): 1H NMR (300 MHz, DMSO‘de) 5 9.34 (br s, 2H), 8.14—8.09 (m, 2H), 8.08—8.04 (m, 1H), 6.59—6.53 (m, 1H), 3.83%3.74 (m, 2H), 3.38—3.25 (m, 2H), 2.83—2.71 (m, 2H); ESI MS m/z 296 [M + H]+.

Step C: A mixture of *bis(trifluoromethyl)phenyl)—1,2,3,6— tetrahydropyridine hydrochloride (19, 452 mg, 1.37 mmol), ammonium formate (0.863 g, 13.7 mmol), and 10% Pd/C (0.332 g) in CH3OH (10 mL) was heated at reflux for 7 h. The deture was cooled to ambient temperature and was filtered over Celite. The filtrate was trated and the resulting residue was diluted in CH??g (8 mL) and CH3OH (2 mL). To this on was added HCl (2.0 N solution in Etzo, 6 mL). The resulting solids were ted by filtration to give 4—(3,5—bis(trifluoromethyl)phenyl)piperidine hydrochloride (20) as a white solid (376 mg, 82%): 1H NMR (300 MHZ, DMSO-dg) 5 9.05~8.58 (m, 2H), 8.03—7.97 (m, 1H), 7.95~7.87 (m, 2H), 3.44—3.29 (m, 2H, overlaps with H20), 3.19—2.88 (m, 3H), 2.09—1.80 (m, 4H); ESI MS m/z 298 [M + Preparation 4—(2—Fluoro(trifluoromethyl) phenyl) dine Hydrochloride (23) on F CF: (5 F CF: B(OH)2 Pd(PPh3)4, 2 M Nazcoa N DME. 80 "0 Bee N H2 (1 atm),mp2 lat—"*2:2 N HClin EtOAc rt CH2C12,r‘t N -HC| Boc H 22 23 Step A: A mixture of tert-butyl 4-(((trifluoromethyl)sulfony1)oxy)— hydropyridine— 1(2H)—carboxylate (2, 1.20 g, 3.62 mmol), and 6— fluoro—(2—trifluoromethyl)phenyl boronic acid (0.528 g, 2.53 mmol), Pd(PPh?4 (0.292 g, 0.253 mmol), and 2 M Na2C03 (20 mL) in DME (30 mL) was heated to 80 °C for 4 h. The mixture cooled to ambient temperature, was diluted with EtOAc (50 mL), and ed h a Celite pad.

The organic filtrate was washed with saturated sodium bicarbonate solution (2 x 30 mL), H30 (30 ml), and concentrated to under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g p column, % to 10% EtOAc in hexanes) to provide tert~butyl 4—(2—fluoro—6—(trifluoromethyl) phenyl)-5,6—dihydropyridine—1(2H)—carboxylate (21) as a clear oil 2O (0.479 g, 39%): 1H NMR (300 MHz, DMSO-de) 6 7.66—7.51 (m, 3H), 5.68 (s, 1H), 4.04—3.82 (m, 2H), .39 (m, 2H), 2.39—2.02 (m, 2H), 1.43 (s, 9H).

Step B: A mixture of tert—butyl 4—(2-fluoro—6—(trifluoromethyl) phenyl)~5,6-dihydropyridine~1(2H)—carboxylate (21, 0.479 g, 1.41 mmol) and Pt03 (0.095 g, 0.42 mmol) in EtOAc (15 mL) and HOAc (82 uL, 1.4 mmol) stirred at t temperature for 72 h under an atmosphere of H2 (1 atm). The mixture was diluted with EtOAc (50 mL) and filtered over Celite. The filtrate was concentrated and the residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 24 g Redisep column, % to 15% EtOAc in hexanes) to e tert—butyl 4~ (2-fluoro(trifluoromethyl)phenyl)piperidine—l—carboxylate (22) as a white solid (0.219 g, 45%): 1H NMR (300 MHz, DMSO—de) 5 7.62—7.48 (m, 3H), 4.15—3.94 (m, 1H), 3.10—2.94 (m, 2H), 2.93—2.67 (m, 2H), 2.00—1.79 (m, 2H), 1.67—1.55 (m, 2H), 1.42 (s, 9H).

Step C: To a on of tert—butyl 4-(2-fluoro(trifluoromethyl) phenyl)piperidine—l—carboxylate (22, 0.219 g, 0.63 mmol) in CH2C12(4 mL) was added 2 N HCl (2.0 N on in Eth, 4 mL), and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with EtzO (50 mL) and the solids were collected by filtration to give 4—(2-fluoro-6—(trifluoromethyl)phenyl) piperidine hydrochloride (23) as an offwhite solid (158 mg, 88%): 1H NMR (300 MHz, DMSO—de) 5 8.82 (br s, 1H), 8.50 (br s, 1H), 7.66—7.48 (m, 3H), 3.42—3.33 (m, 2H), 3.24—2.95 (m, 3H), 2.35~2.15 (m, 2H), .74 (m, 2H); ESI MS m/z 248 [M + H]+.

Preparation 4-(3,5-Difluoro(trifluoromethyl)phenyl)piperidine Hydrochloride (28) O. ,O (5 F F F\E;[:? F F 3 1 HBr NaNOz HZO--5°C Boc PdDPPF.NaZC03 2. CuBr - 5°C to n CF3 DME, H20, 85 "C 24 25 26 F F Hzm%mm 2NHQma? EtOH, n CH2C|2.r1 27 28 Step A: A suspension of 3,5—difluoro—2~(trifluoromethyl)aniline (24, 1.0 g, 5.07 mmol) in a 48% s HBr (8 mL) and Hg) (8 mL) was stirred at — 5 °C for 5 min. To the suspension, NaN02 (350 mg, 5.07 mmol) was added in a 10 mL aqueous solution dropwise maintaining — 5 °C. The resulting mixture was stirred at — 5 °C for l h then CuBr (1.09 g, 7.63 mmol) was added portion—wise and the resulting suspension was allowed to slowly warm to ambient temperature. After 4 hours, the resulting solution was extracted with hexanes (3 x 75 mL).

The combined organics were dried over Nagsoh filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, pure hexanes) to afford 1—bromo~3,5—difluoro—2- (trifluoromethyl)benzene (25) as a light yellow liquid (1.01 g, 68%). 1H NMR (300 MHZ, CDCl3) 5 7.34~7.28 (m, 1H), 6.99~6.85 (m, 1H).

Step B: A e of 1—bromo—3,5«difluoro—2—(trifluoromethyl)benzene (25, 0.200 g, 0.76 mmol) and tert—butyl 4-(4,4,5,5etetramethyl—l,3,2— dioxaborolan-Z—yl)—5,6—dihydropyridine-l(2H)—carboxylate (0.237 g, 0.76 mmol), Pd(dppf) (0.056 g, 0.077 mmol), and 2 N Na2CO3 (2 mL, 4 2O mmol) in DME (3 mL) was heated to 85 °C for 5 h. The mixture was diluted with H20 (50 mL) and extracted with CH2C12 C3 x 75 mL). The combined organics were dried over Na2SO4, concentrated under reduced pressure, and the resulting residue was chromatographed over silica gel (24 g Redisep , 0 ~ 25% EtOAc in hexanes) to afford tert— butyl 4—(3,5—difluoro(trifluoromethyl)phenyl)—5,6—dihydropyridine —1(2H)—carboxylate (26) as a light yellow oil (0.325 g, 90%).1H NMR (300 MHz, CDCl3) 6 6.92~6.80 (m, 1H), 6.78—6.68 (m, 1H), 5.58 (s, 1H), 4.06-3.94 (m, 2H), 3.69—3.53 (m, 2H), 2.36—1.24 (m, 2H), 1.50 (s, 9H). 3O Step C: A e of tert—butyl 4—(3,5—difluoro—2—(trifluoromethyl) phenyl)n5,6—dihydropyridine—1(2H)-carboxylate (26, 0.750 g, 2.11 mmol) and 10% Pd/C (1.0 g) in EtOH (50 mL) d at ambient temperature under an atmosphere of Hg for 24 1L The mixture was filtered through Celite and the filtrate concentrated under reduced re to afford tert—butyl 4—(3,5—difluoro-2—(trifluoromethyl) phenyl)piperidine—l~carboxy1ate (27) as a white solid (535 mg, 829).O 1H NMR (300 MHZ, CDCl3) 5 6.97-6.85 (m, 1H), 6.85-6.69 (m, 1H), 4.37 - 4.16 (m, 2H), 3.23—3.05 (m, 2H), 2.89-2.71 (m, 2H), 1.86—1.51 (m, 4H), 1.48 (s, 9H).

Step D: A solution of tert—butyl —dif1uoro—2~ (trifluoromethyl)phenyl)piperidine—l-carboxylate (27, 0.590 g, 1.61 mmol) in CH2C12(10 mL) and HCl (2.0 N solution in Etzo, 10 mL) stirred at ambient temperature for 18 h. The resulting solids were filtered to afford 4-(3,5-difluoro—2-(trifluoromethyl)phenyl)piperidine hydrochloride (28) as a white solid (0.309 g, 63%).1H NMR (300 MHz, CDCla) 5 7.01—6.94 (m, 1H), 6.94—6.76 (m, 1H), 3.82-3.60 (m, 2H), 3.42‘3.02 (m, 3H), 2.22~l.99 (m, 4H).

Preparation (4 - (3-F1uoro-2 - (trifluoromethyl) phenyl) piperidin yl)(4,5,6,7-tetrahydro—1H—pyrazolo[3,4—c]pyridin—3-yl)methanone Hydrochloride (30) N/ I CF3 CF3 \N NBoc EDCLHOBt N -HCl Et, DMF, rt 0 \ H \ 2 N HCl/EtZO __.______2, N I rt NH -HCl Step A: To a solution of 4-(3—fluor0w2~trifluoromethyl) phenylpiperidine hydrochloride (5, 0.080 g, 0.28 mmol), 6—(tert- butoxycarbonyl)—4,5,6,7—tetrahydro—lH—pyrazolo[3,4-c]pyridine~3— carboxylic acid (0.098 g, 0.67 mmol), and diisopropylethylamine (0.15 mL, 0.85 mmol) in DMF (5.3 mL) was added EDCI (0.065 mg, 0.34 mmol) and HOBt (46 mg, 0.34 mmol), and the deture stirred at ambient temperature for 24 h. The mixture was diluted with Hg) (30 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with a ted brine solution (4 x 30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 10% CH30H in CH2Cleith 0.1% NquH in CH2C12) to provide utyl 3—(4-(3—fluoro—2—(trifluoromethyl)phenyl) piperidine-l— carbonyl)—4,5—dihydro—1H4pyrazolo[3,4—c]pyridine—6(7H)-carboxylate (29) as a white solid (66 mg, 47%):1H NMR (300 MHz, d 5 13.20— 12.78 (m, 1H), 7.73—7.59 (m, 1H), 7.46 (d, J'= 7.2 Hz, 1H), 7.37—7.24 (m, 1H), 4.90~4.60 (m, 2H), .43 (m, 2H), 3.60-3.48 (m, 2H), 3.28—2.98 (m, 2H), .69 (m, 1H), 2.65~2.5O (m, 2H, overlaps with solvent), 1.87—1.56 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + H]+.

Step B: To a solution of utyl 3—fluoro—2— (trifluoromethyl)phenyl)piperidine—l-carbonyl)—4,5—dihydro—lH— pyrazolo[3,4—c]pyridine—6(7H)—carboxylate (29, 0.066 g, 0.13 mmol) in 2O CHhClg(2 mL) was added HCl (2 mL, 2.0 N solution in EtzO). The mixture stirred at ambient temperature for 18 h, was diluted with EtzO (30 mL), and the resulting solids were collected by filtration to give (4—(3—fluoro—2*(trifluoromethyl) phenyl)piperidin—l*yl)(4,5,6,7— tetrahydro-lHprrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (30) as a white solid (0.027 g, 47%): 1H NMR (300 MHz, DMSO~dd 5 9.46—9.20 (m, 2H), 7.74—7.61 (m, 1H), 7.46 (d, J'= 8.1 Hz, 1H), 7.37— 7.25 (m, 1H), 4.70~4.44 (m, 2H), 4.34—4.22 (m, 2H), 3.50—3.10 (m, 4H), 2.93—2.76 (m, 3H), 1.86—1.60 (m, 4H); ESI MS m/z 468 [M + H]+.

Preparation ( (4- (3-Fuoro (trifluoromethyl)pheny1)piperidin-1~y1) (4 5 6 , , , 7-tetrahydro—1H—pyrazolo [4 , 3-c]pyridin—3-y1)methanone Hydrochloride (32) N/ NBoc I CF3 CF ‘N EDCI. HOBt H Boc N 'HCl i—PerEt, DMF, rt 0 H \ \ 2 N HCl/Etzo H CHZCb,n 'HC' Step A: To a solution of 4—(3—fluoro—2—trifluoromethyl) phenylpiperidine hydrochloride (5, 0.080 g, 0.28 mmol), 5—(tert— butoxycarbonyl)—4,5,6,7—tetrahydro~1H—pyrazolo[3,4-c]pyridine—3— carboxylic acid (0.098 g, 0.67 mmol), and diisopropylethylamine (0.15 mL, 0.85 mmol) in DMF (5.3 mL) was added EDCI (0.065 mg, 0.34 mmol) and HOBt (46 mg, 0.34 mmol), and the mixture d at ambient temperature for 24 h. The mixture was diluted with rho (30 mL) and extracted with EtOAc (4 x 30 mL). The combined organic ts were washed with a saturated brine solution (4 x 30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 4% to 10% CH30H in CH2C12with 0.1% NH4OH in CH2C12) to provide tert—butyl 3—(4—(3~ fluoro-2— uoromethyl)phenyl) dine-l— carbonyl)—6,7—dihydro~1H—pyrazolo[4,3—c] ne—5(4H)—carboxy1ate (31) as a white solid (0.109 g, 77%): 1H NMR (300 MHz, DMSO~de) 5 13.20—12.78 (m, 1H), 7.73—7.59 (m, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.37—7.24 (m, 1H), .60 (m, 2H), 4.53~4.43 (m, 2H), 3.60—3.48 (m, 2H), 3.28—2.98 (m, 2H), 2.85—2.69 (m, 1H), 2.65—2.50 (m, 2H, overlaps with solvent), l.87«1.56 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + H]+.

Step B: To a on of tert—butyl 3—(4-(3~fluoro-2— (trifluoromethyl)phenyl)piperidine-l-carbonyl)«6,7-dihydro—1H- pyrazolo[4,3—c]pyridine~5(4H)-carboxylate (31, 0.148 g, 0.30 mmol) in CH2C12(2 mL) was added HCl (2 mL, 2.0 N solution in Etzo). The mixture stirred at ambient temperature for 18 h, was diluted with Etgo (30 mL), and the resulting solids were collected by filtration to give (4—(3—fluoro—2-(trifluoromethyl)phenyl)piperidin—1—yl)(4,5,6,7— ydro—lHprrazolo[4,3~c]pyridin-3—yl)methanone hydrochloride (32) as a white solid (0.097 g, 75%): 1H NMR (300 MHz, DMSO—dd 5 9.46‘ 9.20 (m, 2H), 7.74—7.61 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.37—7.25 (m, 1H), 4.70—4.44 (m, 2H), 4.34—4.22 (m, 2H), 3.50~3.10 (m, 4H), .76 (m, 3H), 1.86~1.60 (m, 4H); ESI MS m/z 468 [M + H]+.

Preparation ((4—(3,4-Dif1uoro(trifluoromethyl)pheny1)piperidin—1— yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin—3—y1)methanone Trifluoroacetic Acid Salt (34) 1.TFA,CH2Cb,n CF3 __.

HOzC HBTU,LPQNEL[3MF,n N o Boc 4;\Y/<;::pBoc N/ I Q\\NH \N NBOC H 33 ____.l______. N CHzclz' rt NH 'TFA 34 Step A: To a solution of tert—butyl —difluoro—2— (trifluoromethy1)pheny1)piperidine~1—carboxy1ate (9, 41.1 g, 113 mmol) in CH2C12(50 mL) was added TFA (50 mL). The mixture was stirred at ambient temperature for 1 h and was concentrated under d pressure. The e was dissolved in DMF (240 mL) and to this solution was added isopropylethylamine (72.4 g, 560 mmol), followed by t~butoxycarbonyl)~4,5,6,7—tetrahydro-1H— pyrazolo[3,4—c]pyridine—3-carboxylic acid (30.1 g, 113 mmol), and HBTU (74.7 g, 169 mmol). The mixture stirred at ambient temperature for 16 h, was diluted with EtOAc (1 L) and washed with EhO (1.4 L).

The organic layer was washed with brine (3 x 600 mL), dried over Na2804, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (30—80% EtOAc in hexanes) to give utyl 3—(4-(3,4—difluoro~2— uoromethyl)phenyl)piperidine—l—carbonyl)—4,5-dihydro—1H~ pyrazolo[3,4—c]pyridine—6(7H)~carboxylate (33) as a white solid (41.2 g, 71%): 1H NMR (300 MHz, CDCl3) 610.47 (hr, 1H), 7.37—7.29 (m, 1H), 7.15 (m, 1H), 4.74 (br, 2H), 4.60 (s, 2H), 3.66 (br, 2H), 3.23 (m, 1H), 3.02 (br, 2H), 2.72 (m, 2H), 1.91—1.65 (m, 4H), 1.89~1.66 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 515 [M+H]+.

Step B: To a solution of tert—butyl 3—(4~(3,4-difluoro—2—(trifluoro— methyl) phenyl) piperidine—l—carbonyl)—4,5~dihydro—1H—pyrazolo [3,4- c]pyridine—6(7H)—carboxylate (33, 41.2 g, 80.0 mmol) in CH??g (150 mL) was added TFA (70 mL). The mixture stirred at ambient temperature for 16 h and was then concentrated under reduced pressure to give ((4— (3,4udifluoro—2-(trifluoromethyl)phenyl) piperidin~1~yl)(4,5,6,7— tetrahydro—lH—pyrazolo[3,4—c]pyridin—3—yl)methanone TFA salt (34) as an off—white solid (40.0 g, >99%). The material was used as is without spectral characterization.

Preparation (4-(3,4-Difluoro(trifluoromethyl)phenyl)piperidin—lyl )(4,5,6,7-tetrahydro-1H-pyrazolo[4,3~c]pyridinyl)methanone Trifluoroacetic Acid Salt (36) 1. TFA, CHZCIZ, rt CF3 WW H020 HBTU i—PerEt DMF rt Boc N31NBoc N‘NH 9 N H iiFH 35 1 TFA CHZCl2,rt 2. NaHC03 OWN‘NH Step A: To a solution of tert—butyl 4-(3,4-difluoro-2— uoromethyl)phenyl)piperidine—l—carboxylate (9, 41.1 g, 113 mmol) in CH2C12(50 mL) was added TFA (50 mL). The mixture was d at ambient temperature for 1 h and was concentrated under reduced pressure. The residue was dissolved in DMF (240 mL) and to this solution was added N,N4diisopropylethylamine (72.4 g, 560 mmol), followed by t—butoxycarbonyl)-4,5,6,7—tetrahydro—1H—pyrazolo [3,4~c]pyridine—3—carboxylic acid (30.1 g, 113 mmol), and HBTU (74.7 g, 169 mmol). The mixture stirred at ambient temperature for 16 h, was diluted with EtOAc (1 L) and washed with H20 (1.4 L). The organic layer was washed with brine (3 x 600 mL), dried over Na2804, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (30~80% EtOAc in s) to give tert~butyl 3—(4-(3,4—difluoro-2—(trifluoromethyl) phenyl)piperidine— 1—carbonyl)~6,7~dihydro~1H~pyrazolo[4,3~c] pyridine-5(4H)— ylate (35) as a white solid (0.068 g, 80%): 1H NMR (300 MHz, CDC13) 510.23 (br, 1H), 7.36—7.28 (m, 1H), 7.15 (m, 1H), 4.86 (br, 2H), 4.62 (s, 2H), 3.72 (br, 2H), 3.27—2.74 (m, 5H), 1.90—1.64 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 515 [M+H]+.

Step B: To a mixture of tert—butyl 3,4—difluoro—2- uoromethyl) phenyl) piperidine—l-carbonyl)~6,7-dihydro~1H— pyrazolo[4,3-c]pyridine—5(4H)-carboxylate (35, 41.2 g, 80.0 mmol) and CH??a (150 mL) was added TFA (70 mL). The mixture was stirred at ambient temperature for 16 h and was concentrated under d pressure. The residue was dissolved in CHZClzand the solution washed with saturated NaHC03, dried over Na2504, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0—20% CH3OH in ) to give (4-(3,4—difluoro—2~ (trifluoromethyl) phenyl) piperidin—l—yl)(4,5,6,7—tetrahydro~lH> pyrazolo[4,3~c]pyridin—3—yl)methanone (36) as a white solid (0.052 g, 95%): 1H NMR (300 MHz, CDCl? 5 7.36~7.27 (m, 1H), 7.14 (m, 1H), 4.92 (m, 2H), 4.04 (s, 2H), 3.27—2.69 (m, 7H), 1.89-1.65 (m, 4H); MS (ESI+) m/z 415 [M+H]+.

Preparation (4~(3,4-Difluoro-2—(trifluoromethyl)phenyl)piperidin—1- y1)(1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol—3-yl)methanone Hydrochloride (38) 1. TFA, CHZCIZ, rt HBTU i-PerEt DMF rt N HOZC Boc 0W3": NBoc N~NH 9 NfI N H 37 1 TFA ,rt _._____.. 2. NaHCO3 OWH Step A: To a solution of tert—butyl 4—(3,4-difluoro—2— (trifluoromethyl)phenyl)piperidine-l—carboxylate (9, 0.100 g, 0.27 mmol) in CH2C12(10 mL) was added TFA (2 mL). The mixture was stirred at ambient temperature for 1 h and was trated under reduced pressure. The residue was dissolved in DMF (2 mL) and to this solution was added 5— (tert-butoxycarbonyl)—1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole—3—carboxylic acid (0.073 g, 0.28 mmol), HBTU (0.191 g, 0.43 mmol), and N,N>diisopropylethylamine (0.11 g, 0.864 mmol). The mixture stirred at t ature for 16 h and was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0—90% EtOAc in hexanes) to give tert—butyl 3—(4~(3,4— difluoro-2—(trifluoromethyl)phenyl)piperidine~1~carbonyl)—4,6— dihydropyrrolo[3,4—c]pyrazole-5(1H)‘carboxylate (37) as a white solid (0.132 g, 91%): 1H NMR (300 MHz, CDCl3) 5 10.39 (br, 1H), 7.38—7.30 (m, 1H), 7.15—7.08 (m, 1H), .26 (m, 6H), 3.26—3.20 (m, 2H), 2.92 (br, 1H), 1.96v1.66 (m, 4H), 1.51 (s, 9H); MS (ESI+) m/z 501 [M+H]+.

Step B: To a mixture of tert-butyl 3-(4—(3,4—difluoro-2—(trifluoro- methyl)phenyl) piperidine—l—carbonyl)—4,6—dihydropyrrolo [3,4—c] pyrazole-5(1H)-carboxylate (37, 0.132 g, 0.26 mmol) and CH2C12(1 mL) was added TFA (1 mL). The mixture stirred at ambient temperature for 2 h and was concentrated under reduced pressure. The residue was dissolved in and the solution was washed with saturated NaHCOL dried over Na2SO4, ed, and concentrated under reduced pressure.

The resulting residue was tographed over silica gel (0—20% CH3OH in CH2Cl? to give (4—(3,4—difluoro—2-(trifluoromethyl)phenyl) piperidin—l-yl) (1,4,5,6—tetrahydropyrrolo [3,4-c]pyrazol—3-yl) methanone (38) as a white solid (0.070 g, 66%): 1H NMR (500 MHz, CDCl? 57.36—7.31 (m, 1H), 7.12 (m, 1H), 4.82 (br, 1H), 4.38 (br, 1H), 4.11 (s, 2H), 4.09 (s, 2H), 3.24 (m, 2H), 2.89 (br, 1H), 1.93—1.68 (m, 4H); MS (ESI+) m/z 401 [M+H]+.

Preparation (4-(2-Chlorofluorophenyl)piperidin—l-yl)(4,5,6,7— tetrahydro-alyrazolo[3,4—c]pyridinyl)methanone hloride N/ 1 c: c: \N NBoc EDCLHOBt mm. N N ‘HCI l-PerEt, DMF,. rt N\ ‘NH\ H 2 N HCI/EtZO .__...__._, N CHZCIZ» rt NH -HCl Step A: To a e of 4—(2~chloro—3-fluorophenyl)piperidine hydrochloride (14, 0.796 g, 3.18 mmol), t—butoxycarbonyl)— 4,5,6,7—tetrahydro—lH—pyrazolo[3,4—c]pyridine-3—carboxylic acid (0.935 g, 3.50 mmol), and diisopropylethylamine (1.7 mL, 9.76 mmol) in DMF (30 mL) was added EDCI (0.853 g, 4.45 mmol) and HOBt (0.601 g, 4.45 mmol). The mixture stirred at ambient temperature for 120 h, was concentrated under reduced pressure, and the obtained residue was chromatographed over silica gel (Isco lash Rf unit, 40 g p column, 0% to 100% ethyl acetate in hexanes) to provide tert—butyl 3— (4—(2—chloro—3—(fluorophenyl)piperidine—l—carbonyl)—4,5—dihydro—1H— pyrazolo[3,4~c]pyridine—6(7H)—carboxylate (39) as a white solid (0.694 g, 47%): 1H NMR (300 MHz, CDCl3) 6 7.24—7.18 (m, 1H), 7.06—7.00 (m, 2H), 4.93—4.42 (m, 3H), 3.67—3.65 (m, 2H), 3.39—3.01 (m, 3H), 2.73—2.70 (m, 2H), 2.l4~l.94 (m, 2H), l.7l~l.68 (m, 2H), 1.49—1.44 (m, 11H); ESI MS m/z 463 [M + H]+.

Step B: To a solution of tert~butyl 3—(4-(2achloro-3— (fluorophenyl)piperidine-l-carbonyl)-4,5—dihydro—lHprrazolo[3,4— c]pyridine—6(7H)~carboxylate (39, 0.694 g, 1.50 mmol) in CH2C12(7 mL) was added 2 M HCl in Etzo (16 mL). The mixture stirred at ambient temperature for 6 h, was diluted with EtzO (30 mL), and the resulting solids were collected by filtration to give (4~(2—chloro-3— phenyl)piperidin—l—yl)(4,5,6,7—tetrahydro-1H—pyrazolo[4,3—c] pyridin—3—yl)methanone hydrochloride (40) as an off—white solid (0.509 g, 94%): 1H NMR (300 MHz, DMSO-de) 5 13.18 (br s, 1H), 9.31 (br s, 2H), 7.38—7.23 (m, 3H), 4.69—4.65 (m, 2H), 4.49—4.21 (m, 2H), 3.39— 3.11 (m, 4H), 2.99—2.84 (m, 3H), .54 (m, 4H); ESI MS m/Z 363 [M + H]+.

Preparation (4—(2—Chloro—3—fluorophenyl)piperidin-l—yl)(4,5,6,7- tetrahydro-alyrazolo[4,3-c]pyridinyl)methanone Hydrochloride - HOZC C! Ngj?:::TBoc \N EDCLHOBt H Boc ——-——-——--—-—~—-———> N N N .HCI i‘PerEt, DMF, rt H 0%(}‘NH 2 N HCI/EtZO H CH C! ,n 'HC' 2 2 0% Step A: To a solution of 4-(2~chloro—3—fluorophenyl)piperidine hydrochloride (14, 90 mg, 0.36 mmol), 5-(tert-butoxycarbonyl)— 4,5,6,7-tetrahydro—1H—pyrazolo[4,3—c]pyridine—3— ylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in DMF (7.8 mL) was added EDCI (83 mg, 0.43 mmol) and HOBt (58 mg, 0.43 mmol). The resulting on was stirred at ambient temperature for 24 h. The reaction mixture was diluted with Hg) (30 mL), and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH30H in CH2Cngith 0.1% NH4OH in CH2C12) to provide tert-butyl 3*(4—(2-chloro—3—fluorophenyl)piperidine—1~ carbonyl)~6,7—dihydro-1prrazolo[4,3—c]pyridine—5(4H)—carboxylate (41) as a white foam (139 mg, 82%):1H NMR (500 MHz, DMSO—dd 5 13.11— 12.91 (m, 1H), 7.39—7.32 (m, 1H), 7.30—7.22 (m, 2H), 5.28w5.13 (m, 1H), 4.75—4.60 (m, 1H), 4.49—4.36 (m, 2H), .53 (m, 2H), 3.33— 3.25 (m, 1H, overlaps with H20), 3.24-3.08 (m, 1H), 2.91—276 (m, 1H), 2.67 (t, J = 5.5 Hz, 2H), 1.91—1.75 (m, 2H), .50 (m, 2H), 1.41 (s, 9H); ESI MS m/z 463 [M + H]+.

Step B: To a solution of tert—butyl 3—(4—(2-chloro—3— fluorophenyl)piperidine—l—carbonyl)-6,7—dihydro-1H—pyrazolo[4,3— c]pyridine—5(4H)~carboxylate (41, 125 mg, 0.27 mmol) in CH2C12(2 mL) was added HCl (2.0 N solution in Etzo, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction e was diluted with Etzo (20 mL) and the resulting solids were ted by filtration to give (4—(2—chloro—3—fluorophenyl)piperidin—l—yl)(4,5,6,7—tetrahydro- 1H—pyrazolo[4,3—c]pyridin—3—yl)methanone hydrochloride as a white 2O solid (42, 93 mg, 86%): 1H NMR (300 MHz, DMSO—ds) 8 9.37 (br s, 2H), 7.42~7.21 (m, 3H), .13 (m, 1H), 4.74—4.57 (m, 1H), 4.25~4.14 (m, 2H), 3.44—3.14 (m, 4H, overlaps with H20), 3.00—2.75 (m, 3H), 1.93—1.77 (m, 2H), 1.70—1.47 (m, 2H) missing N—H pyrazole; ESI MS m/z 363 [M + H]+.

Preparation (4-(5-F1uoro(trifluoromethy1)pheny1)piperidin-lyl )(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin—3-y1)methanone Hydrochloride (44) N/ | CF3 \N NBoc EDCLHOBt —-—————-———-—-——> N I-PI'ZNEt, DMF.. N 'HCI rt H 0% 2NHOEQO __________, N CH2Cb,n NH -HC| Step A: To a solution of 4-(5-fluoro—2—(trifluoromethyl) phenyl)piperidine hloride (11, 93 mg, 0.33 mmol), 6—(tert— carbonyl)—4,5,6,7~tetrahydro—1H—pyrazolo[3,4— c]pyridine—3— carboxylic acid (88 mg, 0.33 mmol), and diisopropylethylamine (0.17 mL, 0.99 mmol) in DMF (6.0 mL) was added EDCI (76 mg, 0.40 mmol) and HOBt (54 mg, 0.40 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction e was diluted with rho (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated brine solution (4 x 20 mL) and trated to dryness under reduced pressure. The obtained e was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% MeOH in CH2Cl2With 0.1% NHAOH in CHgClg) to provide tert—butyl 3—(4—(5—fluoro—2— (trifluoromethyl) phenyl) piperidine—l—carbonyl) -4,5—dihydro—lH—pyrazolo[3,4- c]pyridine— 6(7H)—carboxylate (43) as a white film (110 mg, 67%):\ 1H NMR (300 MHZ, DMSO-dw 6 l2.76 (m, 1H), 7.82—7.71 (m, 1H), 7.62~7.50 (m, 1H), 7.33—7.18 (m, 1H), 4.92*4.76 (m, 1H), 4.74—4.59 (m, 1H), 4.53*4.39 (m, 2H), 3.54 (t, J = 5.7 Hz, 2H), 3.21-3.01 (m, 2H), 2.86—2.69 (m, 1H), 2.66—2.53 (m, 2H), 1.83—1.62 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + H]+ Step B: To a solution of tert—butyl 3-(4-(5~fluoro-2—(trifluoromethyl) phenyl) piperidine-l-carbonyl) ihydro-lH—pyrazolo[3,4- C]pyridine—6(7H)-carboxylate (43, 107 mg, 0.21 mmol) in CH2C12<2 mL) was added HCl (2N in Et20, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was diluted with EtzO (20 mL) and the resulting solids were collected by filtration to provide (4-(5—fluoro-2— (trifluoromethyl) )piperidin—l-yl)(4,5,6,7— tetrahydro—1H>pyrazolo [3,4-c] pyridine3eyl)methanone hydrochloride (44) as a white solid (66 mg, 71%): 1H NMR (500 MHz, DMSO—da) 5 l3.52— l3.l3 (m, lH), 9.41 (br s, 2H), 7.77 (dd, J'= 9.0, 5.7 Hz, 1H), 7.62- 7.50 (m, 1H), 7.32*7.2l (m, lH), 5.00-4.83 (m, 1H), .58 (m, 1H), 4.37~4.l9 (m, 2H), 3.41—3.24 (m, 2H, overlaps with H20), 3.22—3.04 (m, 2H), 2.94—2.73 (m, 3H), .64 (m, 4H); ESI MS m/z 397 [M + H]+.

Preparation (4-(5-Fluoro—2—(trifluoromethyl)phenyl)piperidin—1- yl)(4,5,6,7—tetrahydro-1H-pyrazolo[4,3—c]pyridin-3—yl)methanone Hydrochloride (46) F N2j]:::TBOC CF3 ‘N EDCLHom —-—————-—-—-———————-————-—-—-—> N N N 'HCI i-PTZNEt, DMF, rt 0 2 N HCI/EtZO F: :CFSH CH2C|2,rt 0W4" Step A To a solution of 4—(5—fluoro—2—trifluoromethyl) phenylpiperidine hydrochloride (11, 90 mg, 0.32 mmol), 5~(tert— butoxycarbonyl)~4,5,6,7—tetrahydro—1H—pyrazolo[4,3—c]pyridine~3— carboxylic acid (85 mg, 0.32 mmol), and diisopropylethylamine (0.17 mL, 0.96 mmol) in DMF (5.8 mL) was added EDCI (74 mg, 0.38 mmol) and HOBt (52 mg, 0.38 mmol). The ing solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H20 (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated brine solution (4 x 20 mL) and concentrated to dryness under d pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g p column, 0% to 5% MeOH in CH2C12with 0.1% NH4OH in CHZClz) to e tert—butyl 3-(4—(5—fluoro~2—(trifluoromethyl)phenyl) piperidine—l—carbonyl)-6,7—dihydro—1H—pyrazolo[4,3-c]pyridine-5(4H)- carboxylate (45) as a white film (120 mg, 80%): 1H NMR (300 MHz, DMSO— d6) 5 12.96 (br s, 1H), 7.76 (dd, J = 9.0, 5.7 Hz, 1H), 7.61~7.51 (m, 1H), 7.30— 7.18 (m, 1H), 5.34—5.16 (m, 1H), 4.76—4.58 (m, 1H), 4.53— 4.38 (m, 2H), 3.65—3.52 (m, 2H), 3.22~3.01 (m, 2H), 2.60—2.43 (m, 3H, overlaps with solvent), .65 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + H]+.

Step B: To a solution of tert-butyl 3—(4—(5—fluoro-2— (trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7—dihydro—1H— pyrazolo[4,3~c]pyridine—5(4H)—carboxylate (45, 120 mg, 0.24 mmol) in CH2C12(2 mL) was added HCl(2N in Etgo, 2 mL). The mixture stirred for 18 h at ambient temperature. Additional HCl (2N in Etzo, 1 mL) was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with Etgo (20 mL) and the resulting solids were collected by filtration to provide (4—(5—fluoro—2— (trifluoromethyl)phenyl)piperidin—l—yl)(4,5,6,7~tetrahydro-1H— pyrazolo [4,3—c]pyridin—3—yl)methanone hloride (46) as a white 3O solid (104 mg, 99%): 1H NMR (300 MHz, DMSO—ds) 5 9.54—9.19 (m, 2H), 7.84 (dd, J = 9.0, 5.7 Hz, 1H), 7.60—7.51 (m, 1H), 7.3217‘20 (m, 1H), .32—5.12 (m, 1H), .60 (m, 1H), 4.29~4.16 (m, 2H), 3.43—3.30 (m, 2H, overlaps with H20), 3.26—3.06 (m, 2H), 2.95 (t, J = 5.4 Hz, 2H), 2.89—2.72 (m, 1H), 1.84—1.65 (m, 4H) missing N—H pyrazole; ESI MS m/z 397 [M + H]+.

Preparation (4-(2-Chlorof1uorophenyl)piperidin—l-yl)(4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridinyl)methanoneHydrochloride ‘N NBoc EDCLHOBt __.—_______. N N -HCl I—Pr2NEt, DMF, rt 0 H \ \ 2NHQEQO ____________. N CH2CI2, rt NH -HCl 0 \ Step A: To a solution of 4—(2—chloro—5—fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 6—(tert-butoxycarbonyl)- 4,5,6,7-tetrahydr0*1H-pyrazolo[3,4-c]pyridine—3—carboxylic acid (104 mg, 0.39 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (65 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting on was stirred at ambient temperature for 18 h. The on mixture was d with H20 (20 mL) and extracted with EtOAc (4 x 20 mL). The combined c extracts were washed with a saturated brine solution (9 x 20 mL), H20 (2 x 20 mL) and concentrated to dryness under d pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert~butyl 3—(4—(2— chloro—5~fluorophenyl)piperidine-l-carbonyl)—4,5—dihydro—lH—pyrazolo [3,4—c]pyridine—6(7H)— carboxylate (47) as a white solid (57 mg, 44%): 1H NMR (300 MHz, DMSO—de) 6 13.l6~12.78 (m, 1H), 7.48 (dd, J = 9.0, .7 Hz, 1H), 7.28 (dd, J'= 10.5, 3.3 Hz, 1H), 7.17—7.05 (m, 1H), 4.90~ 4.59 (m, 2H), 4.53—4.40 (m, 2H), 3.62~3.48 (m, 2H), 3.28—3.07 (m, 2H), 2.92—2.73 (m, 1H), 2.64—2.50 (m, 2H, overlaps with solvent), 1.93- 1.69 (m, 2H), 1.68-— 1.49 (m, 2H), 1.42 (S, 9H); ESI MS m/Z 463 [M + Step B: To a solution of tert—butyl 3-(4—(2-chloro—5—fluorophenyl) piperidine—l—carbonyl) ~4 , 5—dihydro-1H—pyrazolo [3, 4—c] pyridine— 6(7H)-carboxylate (47, 57 mg, 0.12 mmol) in CH2Clz (2 mL) was added HCl (2N in Etgo, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was trated under d pressure to yield (4-—(2-chloro—5—fluorophenyl)piperidin—l-yl) (4 , 5, 6, 7—tetrahydro—lH—pyrazolo [3, 4‘c] pyridin-3—-yl)methanone hydrochloride (48) as a white solid (43 mg, 87%): 1H NMR (300 MHz, DMSO—dg) 5 9.42 (br s, 2H), 7.49 (dd, J: 8.7, 5.4 Hz, 1H), 7.28 (dd, J: 10.2, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 4.71-4.43 (m, 2H), 4.32— 4.23 (m, 2H), .14 (m, 4H, overlaps with H20), 2.91-2.72 (m, 3H), 1.89—1.73 (m, 2H), 1.69—1.50 (m, 2H), missing N-—H pryazole; ESI MS m/z 363 [M + H]+.

Preparation (4— (2-Chloro—5-fluorophenyl) piperidin-l-yl) (4 , 5 , 6 , 7- tetrahydro-alyrazolo [4 , 3—c] pyridin-B—yl) one Hydrochloride / NBoc N l N EDCI HOBt N -HCl i-PrZNEt, DMF, rt H 0W0N‘NH 2 N HCI/EtZO H .___._.____—___... N N CH2Cl 'HCl 2 ,rt CW Step A: To a solution of 4—(2—chloro-5—fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 5—(tert—butoxycarbonyl)- 4,5,6,7—tetrahydro-1H—pyrazolo[4,3—c]pyridine-3— carboxylic acid (89 mg, 0.34 mmol), and ropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (64 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting on was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H20 (20 mL) and extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with a saturated brine solution (8 x 20 mL), H20 (20 mL), and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to give tert-butyl 3—(4—(2— chloro-5—f1uorophenyl)piperidine-l—carbonyl)—6,7—dihydro—1H>pyrazolo [4,3-c]pyridine—5(4H)—carboxylate (49) as a white solid (78 mg, 60%): 1H NMR (300 MHz, s) 5 12.96 (s, 1H), 7.48 (dd, J = 8.7, 5.4 Hz, 1H), 7.34—7.21 (m, 1H), 7.16—7.06 (m, 1H), 5.28—5.11 (m, 1H), 4.77» 4.57 (m, 1H), 4.53—4.38 (m, 2H), 3.66—3.52 (m, 2H), 3.30—3.04 (m, 2H, overlaps with H20), 2.92—2.61 (m, 3H), 1.92~1.74 (m, 2H), 1.69-1.49 (m, 2H), 1.41 (s, 9H); ESI MS m/z 462 [M + H]+.

Step B: To a solution of tert~buty1 3—(4—(2—chloro~5- fluorophenyl)piperidine—l—carbonyl)-6,7—dihydro—1H9pyrazolo[4,3— c]pyridine—5(4H)-carboxylate (49, 78 mg, 0.17 mmol) in CH2C12(2 mL) was added HCl (2N in Etzo, 2 mL). The mixture d for 18 h at t temperature. The reaction e was concentrated under reduced pressure to yield chloro—5—f1uorophenyl)piperidin—l- yl)(4,5,6,7—tetrahydro~1H4pyrazolo[4,3—c]pyridin—3—y1)methanone hydrochloride (50) as a white solid (64 mg, 94%): 1H NMR (300 MHz, DMSO—de) 5 9.19 (br s, 2H), 7.49 (dd, J = 8.7, 5.4 Hz, 1H), 7.27 (dd, J = 10.2, 3.0 Hz, 1H), 7.17—7.07 (m, 1H), 5.34—5.05 (m, 1H), 4.79— 4.56 (m, 1H), 4.38—4.19 (m, 2H), 3.44—3.07 (m, 4H, overlaps with H20), 3.01—2.76 (m, 3H), 1.92—1.73 (m, 2H), 1.71~1.50 (m, 2H), missing N—H pyrazole; ESI MS m/z 363 [M + H]+.

Preparation ,5—Bis(trifluoromethyl)phenyl)piperidin-1~yl) (4,5,6,7-tetrahydro—1H-pyrazolo[3,4~c]pyridin-3—yl)methanone Hydrochloride (52) F30 CF3 F3C CF3 NBoc EDCI, HOBt -———-——-————-—-————————————————-> N u -HC| hPQNELDMF,n O F3C CF3 2 N HCl/EtZO .....__..._..._____. N 0420)? rt NH 'HCl Step A: To a solution of 4—(3,5—bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.31 mmol), 6~(tert—butoxycarbonyl)~ 4,5,6,7—tetrahydro—1Hepyrazolo[3,4—c]pyridine—3—carboxylic acid (96 mg, 0.36 mmol), and ropylethylamine (0.16 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H20 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated brine solution (4 x 30 mL) and concentrated to dryness under reduced pressure. The obtained residue was tographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Clgwith 0.1% NH4OH in CH2C12) to provide tert—butyl 3-(4‘~ (3,5—bis(trifluoromethyl)phenyl)piperidine-l—carbonyl)—4,5-dihydro~ 1H—pyrazolo[3,4~c]pyridine—6(7H)—carboxylate (51) as a white film (76 mg, 45%): 1H NMR (300 MHz, DMSO—de) 6 13.13—12.77 (m, 1H), 8.02—7.98 (m, 2H), 7.96—7.91 (m, 1H), 4.91—4.59 (m, 2H), 4.53-4.41 (m, 2H), 3.60—3.46 (m, 2H), 3.21~3.03 (m, 2H), 2.85—2.69 (m, 1H), 2.63~2.54 (m, 2H, overlaps with solvent), 1.97—1.78 (m, 2H), 1.77—1.58 (m, 2H), 1.42 (s, 9H); ESI MS m/z 547 [M + H]+.

Step B: To a solution of tert—butyl 3—(4-(3,5-bis (trifluoromethyl)phenyl)piperidine—l~ carbonyl)—4,5-dihydro—lH‘ pyrazolo[3,4—c]pyridine—6(7H)—carboxylate (51, 75 mg, 0.14 mmol) in CH2C12(1 mL) was added HCl (2N in EtzO, 1 mL). The mixture stirred for 18 h at ambient temperature. The reaction e was d with EtzO (50 mL) and concentrated to yield (4-(3,5- bis(trifluoromethyl)phenyl)piperidin-l~yl)(4,5,6,7-tetrahydro—lH~ pyrazolo[3,4—C]pyridin—3-yl)methanone hydrochloride (52) as a yellow solid (79 mg, >99%): 1H NMR (300 MHz, DMSO—de) 5 9.37 (br s, 2H), 8.05~ 7.86 (m, 3H), 4.75-4.44 (m, 2H), 4.39—4.18 (m, 2H), 3.42—3.25 (m, 2H, overlaps with H20), 3.20~ 3.03 (m, 2H), .75 (m, 3H), 2.03—1.80 (m, 2H), 1.79—1.62 (m, 2H), missing N-H pyrazole; ESI MS m/z 447 [M + Preparation 5—Bis(trifluoromethyl)phenyl)piperidin-l— yl)(4,5,6,7—tetrahydro-1H-pyrazolo[4,3-c]pyridinyl)methanone Hydrochloride (54) F3C CF3 FSC CPS / NBoc N I \N EDCLHOBt —---—--——-—-—-———-——-—> N N N 'HCl i-Pr2NEt, DMF, rt 0 F3C CF3 2NHCUE§O : H CHZCb,n oéLj/<;l) 'HC' Step A: To a solution of 4~(3,5—bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), 5*(tert-butoxycarbonyl)- 4,5,6,7~tetrahydro—1Hepyrazolo[4,3-c]pyridine—3— carboxylic acid (81 mg, 0.30 mmol), and diisopropylethylamine (0.18 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H20 (30 mL). The resulting itate was collected by filtration to yield tert—butyl 3~(4—(3,5- bis(trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7*dihydro-1H— pyrazolo[4,3—c]pyridine—5(4H)~carboxylate (53) as a white solid (142 mg, 86%): 1H NMR (300 MHz, e) 5 12.95 (s, 1H), .97 (m, 2H), 7.95—7.90 (m, 1H), 5.31—5.13 (m, 1H), 4.76—4.58 (m, 1H), 4.52— 4.39 (m, 2H), 3.64—3.53 (m, 2H), 3.20—3.03 (m, 2H), .61 (m, 3H), 1.97—1.81 (m, 2H), l.78~1.58 (m, 2H), l.4l(s, 9H); ESI MS m/z 547 [M + H]+.

Step B: To a solution of tert—butyl 3~(4—(3,5- bis(trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7—dihydro—1H> pyrazolo[4,3—c]pyridine—5(4H)-carboxylate (53, 142 mg, 0.26 mmol) in 1:1 MeOH/ CH2C12(2 mL) was added HCl (2N in Etzo, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Eth (20 mL) and the resulting solids were collected by filtration to give (4—(3,5~bis(trifluoromethyl)phenyl)piperidin—l— yl)(4,5,6,7—tetrahydro—lH—pyrazolo[4,3—c]pyridin—3—yl)methanone hloride (54) as an off—white solid (127 mg, >99%): 1H NMR (500 MHz, DMSO—de) 5 9.28 (br s, 2H), 8.02—7.98 (m, 2H), 7.96—7.92 (m, 1H), .30—5.09 (m, 1H), 4.78—4.55 (m, 1H), 4.28-4.14 (m, 2H), .28 (m, 2H, overlaps with th), 3.26—3.07 (m, 2H), 3.02—2.90 (m, 2H), 2.89—2.75 (m, 1H), 2.00—1.82 (m, 2H), 1.80—1.61 (m, 2H), missing N—H 3O pyrazole; ESI MS m/z 447 [M + H]+. ation (4-(2~F1uoro(trifluoromethyl)phenyl)piperidinyl) (4,5,6,7-tetrahydro—1H-pyrazolo[3,4-c]pyridin—3—yl)methanone Hydrochloride (56) N\ I F CF3 F CF3 N EDCIHOBt’ ~—-———-———-———-———-—-——-——-———-—-—---—-——-—-----—-——-—> N u -HCI FPQNELDMF,H O F CF3 2 N HCl/EtZO CHzcb.? NH °HC| Step A: To a solution of 4—(2—fluoro—6—(trifluoromethyl) phenyl)piperidine hydrochloride (20, 83 mg, 0.29 mmol), 6—(tert~ butoxycarbonyl)~4,5,6,7—tetrahydro—1Hepyrazolo[3,4~c]pyridine—3— carboxylic acid (78 mg, 0.29 mmol), and diisopropylethylamine (0.15 mL, 0.88 mmol) in DMF (6.3 mL) was added EDCI (67 mg, 0.35 mmol) and HOBt (47 mg, 0.35 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H20 (20 mL) and resulting solids were collected by filtration. The obtained solids were chromatographed over silica gel (Isco lash Rf unit, 12 g Redisep column, % to 5% MeOH in with 0.1% NHAOH in CH2Cl? to provide tert-butyl 3-(4—(2—fluoro—6—(trifluoromethyl) phenyl) piperidine-l—carbonyl)~4,5—dihydro—1H4pyrazolo[3,4—c]pyridine—6(7H)- carboxylate (55) as a clear film (95 mg, 65%): 1H NMR (300 MHz, DMSO— d6) 8 13.27~12.72 (m, 1H), .45 (m, 3H), 4.86—4.56 (m, 2H), 4.55— 4.38 (m, 2H), 3.63—3.43 (m, 2H), .00 (m, 2H), 2.92—2.41 (m, 3H, overlaps with solvent), 2.13—1.84 (m, 2H), 1.80v1.61 (m, 2H), 1.42 (s, 9H); ESI MS m/z 496 [M + H]+.

Step B: To a solution of tert—butyl 2—fluor0*6— (trifluoromethyl)phenyl)piperidine—l—carbonyl)—4,5—dihydro—1H pyrazolo [3,4—c]pyridine—6(7H)—carboxylate (55, 94 mg, 0.19mmol) in CH2Clz<3 mL) was added HCl(2N in Etzo, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with EtzO (20 mL) and the e concentrated under reduced pressure to yield (4-(2-fluoro-6—(trifluoromethyl)phenyl)piperidin~l—yl) (4,5,6,7-tetrahydro~lH—pyrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (56) as a white solid (80 mg, 97%): 1H NMR (300 MHz, DMSO—de) 8 9.39—9.26 (m, 2H), .47 (m, 3H), 4.76—4.40 (m, 1H), 4.35—4.25 (m, 2H), 3.78—3.39 (m, 4H), 3.25—3.08 (m, 2H), 2.91—2.78 (m, 3H), 2.11—1.88(m, 2H), 1.81— 1.66 (m, 2H); ESI MS m/z 397 [M + Preparation (4-(2-Fluoro—6—(trifluoromethyl)pheny1)piperidin—l— yl)(4,5,6,7-tetrahydro—1H-pyrazolo[4,3—c1pyridin-3—yl)methanone Hydrochloride (58) F N2j]:::TBOC CF3 N EDC|,HOBt N ~HCI i—,Pr2NEt DMF rt 2 N HCl/EtZO CHZC|2,rt 0% .HCI Step A: To a solution of 4—(3,5—bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), 5—(tert—butoxycarbonyl)— 7~tetrahydro~lH~pyrazolo[4,3- c]pyridine~3~carboxylic acid (81 mg, 0.30 mmol), and diisopropylethylamine (0.18 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient ature for 18 h. The reaction mixture was diluted with H20 (30 mL). The resulting precipitate was ted by filtration to yield tert—butyl 3—(4—(3,5— bis(trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7—dihydro—1H— pyrazolo[4,3—c]pyridine—5(4H)—carboxylate (53) as a white solid (142 mg, 86%): 1H NMR (300 MHz, DMSO—de) 5 12.95 (s, 1H), 8.03—7.97 (m, 2H), 7.95—7.90 (m, 1H), 5.31—5.13 (m, 1H), 4.76—4.58 (m, 1H), 4.52— 4.39 (m, 2H), 3.64—3.53 (m, 2H), 3.20—3.03 (m, 2H), 2.87—2.61 (m, 3H), 1.97—1.81 (m, 2H), 1.78—1.58 (m,2H), l.41(s, 9H); ESI MS m/z 547 [M + Step B: To a solution of tert—butyl 3,5—bis (trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7—dihydro—1H— pyrazolo[4,3—c]pyridine—5(4H)—carboxylate (53, 142 mg, 0.26 mmol) in 1:1 MeOH/ CH2C12(2 mL) was added HCl (2N in Et20, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Etzo (20 mL) and the resulting solids were collected by filtration to give (4—(3,5— ifluoromethyl) phenyl)piperidin—l— yl)(4,5,6,7—tetrahydro—1H—pyrazolo[4,3—c]pyridin—3—yl)methanone hydrochloride (54) as an off—white solid (127 mg, >99%): 1H NMR (500 MHz, DMSO—dm 5 9.28 (br s, 2H), 8.02—7.98 (m, 2H), 7.96—7.92 (m, 1H), .30—5.09 (m, 1H), 4.78—4.55 (m, 1H), 4.28—4.14 (m, 2H), .28 (m, 2H, overlaps with PbO), .07 (m, 2H), 3.02—2.90 (m, 2H), 2.89—2.75 (m, 1H), 2.00—1.82 (m, 2H), 1.80—1.61 (m, 2H), missing N—H pyrazole; ESI MS m/z 447 [M + H]+.

Preparation (4—(3,5-Difluoro—2-(trifluoromethyl)phenyl)piperidin—1— yl)(4,5,6,7-tetrahydro—1H-pyrazolo[3,4-c]pyridinyl)methanone Hydrochloride (60) F F N/ I CF3 ‘N NBoc BHTU . NBoc IZ rt 0%N ~HCI t, DMF, F F 2 N HCl/EtZO ___..____.___, N CHZCI2- rt NH -HCl Step A: To a sion of 4—(3,5-difluoro-2—(trifluoromethyl) phenyl)piperidine hydrochloride (28, 500 mg, 1.66 mmol), 6—(tert- butoxycarbonyl)—4,5,6,7—tetrahydro~1prrazolo[3,4—c]pyridine—3v ylic acid (443 mg, 1.66 mmol), and diisopropylethylamine (36 uL, 2.04 mmol) in DMF (5 mL) was added HBTU (1.10 g, 2.49 mmol). The resulting mixture was stirred at ambient temperature for 18 h. the on was diluted in H20 (50 mL) and extracted with EtOAc (3 x 75 mL). The combined c extracts were dried over Na2304, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, 0 - 100% EtOAc in hexanes) to afford tert-butyl 3-(4—(3,5-difluoro~2— (trifluoromethyl)phenyl)piperidine~1—carbonyl)—4,5 dihydro—lH- pyrazolo[3,4—c]pyridine—6(7H)—carboxylate (59) as a white solid (200 mg, 23%).1H NMR (300 MHz, CDCl3) 5 7.017—6.876 (m, 1H), 6.876—6.741 (m, 1H), 5.306 (s, 1H), 4.632 (s, 2H), 3.776—3.581 (m, 2H), 2.762~ 2.631 (m, 2H), 1.986a1.653 (m, 4H), 1.500 (s, 9H), 1.399 — 1.189 (m, Step B: To a solution of tert‘butyl 3~(4—(3,5—difluoro—2-(trifluoro— methyl)phenyl)piperidine-l—carbonyl)-4,5-dihydro~lH-pyrazolo[3,4- dine—6(7H)~carboxylate (59, 94 mg, 0.19 mmol) in CH2C12(3 mm) was added HCl (2.0 N solution in EtzO, 3 mL). The mixture was stirred for 18 h at ambient temperature. The on mixture was diluted with Etzo (20 mL) and the mixture concentrated under reduced pressure to yield (4—(3,5-difluoro—2-(trifluoromethyl)phenyl) piperidin—l—yl) ,7-tetrahydro—1H—pyrazolo [3,4-c] pyridin—3-yl)methanone hydrochloride (60) as a white solid (80 mg, 97%).

Preparation 5-Difluoro(trifluoromethyl)phenyl)piperidin-1— yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl)methanone (62) F F F F (31F3 EDCLHOBt CF3 "@806\N H Boc IZ -HCI i-PerEt, DMF, rt o‘i\?/<;i) F F 61 LZNHmEmlcmdzn H W’ N N 2.NaHC03 CWN‘m Step A: To a suspension of 4-(3,5«difluoro—2~(trifluoromethyl) phenyl)piperidine hydrochloride (28, 500 mg, 1.66 Imnol), 5—(tert~ butoxycarbonyl)—4,5,6,7—tetrahydro—1prrazolo[3,4—c]pyridine—3‘ carboxylic acid (443 mg, 1.66 mmol), and diisopropylethylamine (36 uL, 2.04 mmol) in DMF (5 mL) was added HBTU (1.10 g, 2.49 mmol). The resulting mixture was stirred at ambient ature for 18 h. the reaction was diluted in H20 (50 mL) and extracted with EtOAc (3 x 75 mL). The combined organic extracts were dried over , filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, 0 — 100% EtOAc in hexanes) to afford tert—butyl 3—(4—(3,5—difluoro—2— (trifluoromethyl)phenyl)piperidine—l—carbonyl)—6,7—dihydro—1H— lo[4,3—c]pyridine— 5(4H)—carboxylate (61) as a white solid (200 mg, 23%).

Step B: To a solution of tert-butyl 3—(4—(3,5—difluoro—2— (trifluoromethyl) phenyl) piperidine—l—carbonyl)—6,7—dihydro—1H pyrazolo[4,3—c]pyridine—5(4H)—carboxylate (61, 94 mg, 0.19 mmol) in CH2C12(3 mL) was added HCl (2.0 N solution in EtzO, 3 mL). The mixture was stirred for 18 h at ambient ature. The reaction mixture was diluted with Eth (20 mL), washed with ted NaHC03 solution, and the concentrated under reduced pressure to yield (4—(3,5—difluoro—2— (trifluoromethyl) )piperidin—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo [4,3—c]pyridin—3— yl)methanone (62) as a white solid (80 mg, 97%): 1H NMR (500 MHz, DMSO—ds) 8 12.73 (s, 1H), 7.336 (m, 2H), .193—5.008 (m, 1H), 4.76—4.58 (br s, 1H), 3.75 (s, 2H), 3.25—3.04 (m, 2H), 2.94—2.84 (m, 1H), 2.84 — 2.71 (br s, 1H), 2.60—2.53 (m, 2H), 1.89—1.58 (m, 4H); ESI MS m/z 415.1 [M + H]+.

Example 1: Preparation of 1—(3-(4—(3—F1uoro—2—(trifluoromethyl) phenyl)piperidine—l—carbonyl)-4,5-dihydro—1H—pyrazolo[3,4-c1pyridin- 6(7H)-y1)ethanone (63) Step A: Following general procedure GP—El, ((4—(3—fluoro—2— (trifluoromethyl)phenyl)piperidin—l—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (30) and acetyl chloride were converted to 1—(3—(4—(3—fluoro—2—(trifluoromethyl) phenyl)piperidine-l—carbonyl)—4,5—dihydro—1H—pyrazolo[3,4—c]pyridin— 3O yl)ethanone as a white solid (20 mg, 73%): 1H NMR (500 MHz, DMSO—de) 5 13.18—12.83 (m, 1H), 7.73—7.60 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.35—7.26 (m, 1H), 4.91—4.49 (m, 4H), 3.71—3.57 (m, 2H), 3.25-3.06 (m, 2H), 2.85—2.48 (m, 3H, overlaps with solvent), 2.12— 2.05 (m, 3H), 1.83—1.66 (m, 4H); ESI MS m/z 439 [M +H]+. e 2: Preparation of (4-(3-Fluoro(trifluoromethyl)pheny1) piperidin-l-yl)(5-(methylsulfonyl)~4,5,6,7-tetrahydro-1H—pyrazolo [4,3-c]pyridinyl)methanone (64) Step A: Following general procedure GP-C, (4~(3-fluoro—2— (trifluoromethyl)phenyl)piperidin-l—yl)(4,5,6,7—tetrahydro—lH— pyrazolo[4,3—c]pyridin—3—yl)methanone hloride (32) and methanesulfonyl chloride were converted to (4-(3—fluoro-2— (trifluoromethyl)phenyl)piperidin—l—yl)(5—(methylsulfonyl)—4,5,6,7- tetrahydro-lH—pyrazolo[4,3-c]pyridin~3—yl)methanone as a white solid (23 mg, 41%): mp 243—246 °C; 1H NMR (500 MHz, DMSO-dd 5 13.03 (br s, 1H), 7.69—7.60 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.33—7.26 (m, 1H), .30-5.21 (m, 1H), 4.72—4.62 (m, 1H), 4.4l~4.24 (m, 2H), 3.52—3.39 (m, 2H), 3.27~3.09 (m, 2H), 2.95 (s, 3H), 2.85—2.74 (m, 3H), 1.85— 1.61 (m, 4H); ESI MS m/z 475 [M + H]+. e 3: Preparation of 3-(4—(3-Fluoro—2-(trifluoromethyl)phenyl) piperidine-l—carbonyl)—[1,2,4]triazolo[4,3-a]pyridine-S-carbonitrile Step A: To a solution of ethyl 6~bromo~[1,2,4]triazolo[4,3—a]pyridine— 3-carboxylate (75 mg, 0.28 mmol) in THE (2.3 mL) was added a on of LiOH-H2O (23 mg, 0.56 mmol) in H2O (1.5 mL). The mixture was stirred for 20 min and was neutralized with 2N HCl. The mixture was concentrated under d pressure. The obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2. To this mixture was added luoro—2—trifluoromethyl)phenylpiperidine hydrochloride (5, 78 mg, 0.28 mmol), benzotriazole—1-y1—oxy—tris-(dimethylamino)- phosphonium hexafluorophosphate (245 mg, 0.556 mmol), and diisopropylethylamine (107 mg, 0.834 mmol). The mixture was stirred at ambient ature for 18 h. The resulting e was diluted 3O with H20 (20 mL). The mixture was extracted with EtOAc (4 x 30 mL).

The combined organic layers were washed with 5% lithium chloride solution (4 x 20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) to provide (6—bromo—[1,2,4]triazolo[4,3—a]pyridin-3~yl)(4—(3—fluoro— 2-(trifluoromethyl)phenyl)piperidin—l—yl)methanone as an orange film (87 mg, 66%): 1H NMR (300 MHz, DMSO-dd 5 9.13-9.10 (m, 1H), 7.75*7.62 (m, 2H), 7.52~7.46 (m, 1H), 7.38-7.25 (m, 1H), 5.30—5.17 (m, 1H), 4.78—4.64 (m, 1H), 3.42—3.28 (m, 3H, overlaps with H20), 3.11—2.92 (m, 1H), 1.98—1.70 (m, 4H); ESI MS m/z 471 [M + H]+.

Step B: A solution of (6—bromo—[l,2,4]triazolo[4,3~a]pyridin~3—yl)(4* (3-fluoro-2—(trifluoromethyl)phenyl)piperidin—l—yl)methanone (87 mg, 0.19 mmol) and zinc cyanide (43 mg, 037 mmol) in DMF (2.0 mL) was sparged with Ar for 10 min. To the solution was added Pd(PPh?4 (21 mg, 0.019 mmol) the vessel was sealed and heated to 130 °C with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (3 x 30 mL).

The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 70% EtOAc in hexanes) and freeze dried to e 3—(4~(3~fluoro—2— (trifluoromethyl)phenyl)piperidine—lacarbonyl)-[l,2,4]triazolo[4,3— a] ne—6—carbonitrile as a white solid (52 mg, 67%): mp 188—190 °C; 1H NMR (500 MHz, DMSO—ds) 5 9.54—9.51 (m, 1H), 8.13 (dd, J = 9.5, 2O 1.0 Hz, 1H), 7.81 (dd, J = 9.5, 1.5 Hz, 1H), .65 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 12.5, 8.5 Hz, 1H), 5.17—5.09 (m, 1H), 4.78—4.70 (m, 1H), 3.44~3.28 (m, 2H, overlaps with H20), 3.09— 3.00 (m, 1H), 1.97—1.75 (m, 4H); ESI MS m/z 418 [M + H]+.

Example 4: Preparation of 3-(4-(3—Fluoro-2—(trifluoromethyl)pheny1) piperidine-l-carbonyl)-N=methyl-6,7—dihydro-1H%pyrazolo[4,3- c]pyridine-5(4H)—carboxamide (66) Step A: Following l procedure GP~E2, —fluoro-2~ (trifluoromethyl)phenyl)piperidin—l—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3~yl)methanone hydrochloride (30) and methyl isocyanate were converted to 3—(4—(3-fluoro—2—(trifluoromethyl) phenyl)piperidine-l—carbonyl)~N>methyl~6,7—dihydro—1prrazolo[4,3*c] ne—5(4H)—carboxamide as a white solid (32 mg, 41%): mp l65~l70 °C; 1H NMR (500 MHz, DMSO-d6) 5 13.03—12.85 (m, 1H), 7.70—7.62 (m, 1H), 7.46 (d, J'= 8.0 Hz, 1H), 7.30 (dd, J'= 12.0, 8.0 Hz, 1H), 6.58~ 6.49 (m, 1H), 5.19‘5.06 (m, 2H), 4.76~4.62 (m, 2H), 3.63—3.50 (m, 2H), 3.27—3.09 (m, 2H), .72 (m, 1H), 2.64 (t, J = 5.5 Hz, 2H), 2.59~ 2.54 (m, 3H), 1.84—1.59 (m, 4H); ESI MS m/z 454 [M + H]+.

Example 5: ation of (5-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridinyl)(4-(3-fluoro(trifluoromethyl) phenyl) piperidin-l-yl)methanone (67) Step A: ing general procedure GP—D, (4—(3—fluoro-2—(trifluoro- methyl) phenyl)piperidin-l—yl)(4,5,6,7—tetrahydro~lH-pyrazolo[4,3— c]pyridin—3—yl)methanone hydrochloride (32) and acetaldehyde were converted (5—ethyl-4,5,6,7~tetrahydro~lH—pyrazolo[4,3—c]pyridin~3— yl)(4—(3*fluoro—2—(trifluoromethyl) phenyl) piperidin—l—yl)methanone as a white solid (2.5 mg, 2%): 1H NMR (500 MHz, CD3OD) 57.64~7.53 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.13 (dd, J'= 12.0, 8.5 Hz, 1H), 4.90— 4.72 (m, 2H, overlaps with PhO), 3.62 (br s, 2H), 3_34-3.17 (m, 2H, overlaps with t), 2.92—2.78 (m, 5H), 2.68 (q, J x 7.0 Hz, 2H), 1.96—1.74 (m, 4H), 1.20 (t, J = 7.5 Hz, 3H) missing azole; ESI MS m/z 425 [M + H]+.

Example 6: Preparation of 3-(4-(3-Fluoro-2—(trifluoromethyl)phenyl) piperidine-l—carbonyl)-6,7—dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)- carboxylate (68) Step A: Following general procedure GP-Bl, (4—(3~fluoro—2—(trifluoro- methyl)phenyl)piperidin-1~yl)(4,5,6,7—tetrahydro—1H~pyrazolo[4,3—c] pyridina3-yl)methanone hydrochloride (32) and methyl chloroformate were converted to 3—(4—(3~fluoro«2—(trifluoromethyl) phenyl) piperidineel—carbonyl)—6,7—dihydro—1H—pyrazolo[4,3—c] pyridine-5(4H) —carboxylate as a white solid (62 mg, 60%): 1H NMR (500 MHz, DMSO—dw 13.11—12.94 (m, 1H), 7.68—7.61 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.29 (dd, J'= 12.5, 8.5 Hz, 1H), 5.33—5.16 (m, 1H), 4.74~4.60 (m, 1H), 4.56—4.41 (m, 2H), 3.68~ 3.58 (m, 5H), 3.26—3.08 (m, 2H), 2.85—2.74 (m, 1H), 2.70 (t, J = 5.5 Hz, 2H), 1.85—1.59 (m, 4H); ESI MS m/z 455 [M+ H]+.

Example 7: Preparation of (5-(Cyclopropylmethyl)-4,5,6,7—tetrahydro— 1prrazolo[4,3-c]pyridin—3~yl)(4-(3-fluoro—2-(trifluoromethyl) phenyl)piperidin—1—yl)methanone (69) Step A: Following general ure GP—Dl, (4—(3—fluoro—2~(trifluoro— methyl) phenyl)piperidin-1~yl)(4,5,6,7-tetrahydro-1H—pyrazolo [4,3— c]pyridin—3—yl)methanone hydrochloride (32) and cyclopropane carboxaldehyde were converted (5—(cyclopropylmethyl)—4,5,6,7- tetrahydro—lHprrazolo[4,3—c]pyridin~3-yl)(4—(3—fluoro—2—(trifluoro- methyl) phenyl)piperidin-l-yl)methanone as a white solid (33 mg, 81%): 1H NMR (500 MHz, DMSO—dg) 8 12.92~12.73 (m, 1H), 7.69—7.61 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 12.0, 8.5 Hz, 1H), 5.13—5.00 (m, 1H), 4.73-4.60 (m, 1H), 3.60~3.46 (m, 2H), 3.25~3.03 (m, 2H), 2.83—2.64 (m, 5H), 2.41—2.33 (m, 2H), 1.85—1.59 (m, 4H), .83 (m, 1H), 0.52—0.44 (m, 2H), 0.14~0.08 (m, 2H); ESI MS m/z 451 [M + H]+.

Example 8: Preparation of 3-(4—(3-Fluoro(trifluoromethyl)phenyl) piperidine-l—carbonyl)-6,7-dihydro-1H—pyrazolo[4,3-c]pyridine—5(4H)- carbonitrile (70) 2O Step A: Following general ure GP-D2, (4—(3—fluoro(trifluoro methyl) phenyl) din—l—yl) (4,5,6,7—tetrahydro—1H—pyrazolo[4,3— c]pyridin-3—yl)methanone hydrochloride (32) and cyanogen bromide were converted to 3—(4-(3-fluoro—2—(trifluoromethyl)phenyl)piperidine-1— carbonyl)-6,7—dihydro—1H"pyrazolo[4,3—c]pyridine-5(4H)—carbonitrile as a white solid (35 mg, 70%): 1H NMR (500 MHz, DMSO—de) 513.26—13.05 (m, 1H), 7.68—7.61 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 12.5, 8.5 Hz, 1H), 5.32«5.20 (m, 1H), 4.71—4.61 (m, 1H), 4.44—4.29 (m, 2H), 3.46 (t, J = 5.5 Hz, 2H), .09 (m, 2H), 2.87—2.73 (m, 3H), 1.85~1.59 (m, 4H); ESI MS m/z 422 [M + H]+.

Example 9: Preparation of (4-(3—Fluoro(trifluoromethyl)phenyl) piperidin-l-yl)(5-(2,2,2-trifluoroethyl)~4,5,6,7-tetrahydro—1H- pyrazolo[4,3-c]pyridin—3-yl)methanone (71) Step A: Following l procedure GP—D2, fluoro(trifluoro methyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H—pyrazolo[4,3~ c]pyridin*3—yl)methanone hydrochloride (32) and 2,2,2-trifluoroethyl trifluoromethanesulfonate were converted to (4-(3-fluoro—2— (trifluoromethy1)phenyl) piperidin—l—yl) (5—(2,2,2—trifluoroethyl)— 4,5,6,7—tetrahydro—1H—pyrazolo[4,3—c]pyridin—3—yl) methanone as a white solid (71 mg, 64%): mp 144~151 °C; 1H NMR (500 MHz, DMSO—de) 5 12.99—12.81 (m, 1H), 7.68—7.61 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), .26 (m, 1H), 5.20~5.08 (m, 1H), 4.69—4.61 (m, 1H), 3.82—3.69 (m, 2H), 3.50—3.30 (m, 2H, overlaps with H20), 3.24—3.06 (m, 2H), 2.92 (t, J = 6.5 Hz, 2H), .73 (m, 1H), 2.70 (t, J ll 5.5 Hz, 2H), .58 (m, 4H); E81 M5 m/z 479 [M + H]+.

Example 10: Preparation of (4-(3-F1uoro—2-(trifluoromethyl)phenyl) piperidin-l-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin—3—yl)methanone (72) Step A: Following general procedure GP—D2, (4—(3—fluoro—2— (trifluoromethyl) phenyl) piperidin—l-yl) (4,5,6,7—tetrahydro—1H~ pyrazolo[4,3—c]pyridin—3—yl)methanone hydrochloride (32) and 3—bromo~ 1,1,1—trifluoropropane were converted to (4—(3—f1uoro-2— (trifluoromethyl) phenyl)piperidin—1—yl)(5—(3,3,3-trif1uoropropyl)- 4,5,6,7-tetrahydro-1H—pyrazolo[4,3—c]pyridin-3—yl)methanone as a white solid (26 mg, 32%): mp 152—159 °C; 1H NMR (500 MHZ, DMSO-da 5 12.93~12.75 (m, 1H), 7.69—7.61 (m, 1H), 7.47—7.43 (m, 1H), 7.29 (dd, J = 12.0, 8.5 Hz, 1H), .00 (m, 1H), 4.71—4.62 (m, 1H), 3.58— 3.44 (m, 2H), 3.25~3.06 (m, 2H), 2.83—2.61 (m, 7H), 2.58~2.46 (m, 1H, overlaps with t), 1.84—1.59 (m, 4H); ESI MS m/z 493 [M + H]+.

Example 11: ation of (4—(3—F1uoro—2-(trifluoromethyl)phenyl) piperidin-l-yl)(5—(2—methoxyethyl)-4,5,6,7-tetrahydro-3aH>pyrazolo 4,3-c]pyridin-3~yl)methanone (73) 3o Step A: Following general procedure GP—G2, ((4—(3—fluoro-2—(trifluoro )phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H—pyrazolo [3,4~ c]pyridin-3—yl)methanone hydrochloride (30) and bromoethylmethyl ether were converted to 4—(3—fluoro—2—(trifluoromethyl)phenyl) piperidine-l—yl)(5—(2—methoxyethyl)—4,5,6,7~tetrahydro—3aH~pyrazolo[ 4,3—c]pyridin—3—yl)methanone as an off~white solid (28 mg, 56%): mp 147—151 °C; 1H NMR (300 MHz, d 5 2.82 (br S, 1H), 7.65‘7.27 (m, 3H), 5.18*5.09 (m, 1H), 4.75—4.60 (m, 1H), 3.51~3.45 (m, 2H), 3.27- 3.11 (m, 6H), .70 (m, 8H), 1.87—1.63 (m, 4H); ESI MS m/z 475 [M+ H] +.

Example 12: Preparation of luoro—2-(trifluoromethyl)phenyl) piperidine—l-yl)(5-(oxetan—3-yl)-4,5,6,7-tetrahydro-1Hkpyrazolo[4,3- c]pyridin-3—yl)methanone(74) Step A: Following general procedure GP—Dl, (4—(3—fluoro—2~ (trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H~ pyrazolo [4,3-c]pyridin—3—yl)methanone hydrochloride (32) and 3~ oxetanone were converted to 4—(3—fluoro—2—(trifluoromethyl)phenyl) piperidine—l—yl)(5—(oxetan—3~yl)~4,5,6,7—tetrahydro—1prrazolo[4,3— c]pyridin~3—yl)methanone as a white foam (30 mg, 29%): 1H NMR (300 MHz, CDCl3) 5 10.04 (br s, 1H), 7.48—7.42 (m, 1H), .17 (m, 1H), 7.06~7.02 (m, 1H), 5.22—4.81 (m, 2H), 4.74 (d, J = 6.6 Hz, 4H), 3.89— 3.81 (m, 1H), 3.62 (br s, 2H), 3.31—3.24 (m, 1H), 3.21—2.68 (m, 5H), 1.91~1.72 (m, 5H); ESI MS m/z 453 [M + H] +. 2O Example 13: Preparation of (6-Ethyl-4,5,6,7—tetrhydro—1H‘pyrazolo ]pyridin-3—yl)(4-(3-fluoro(trifluormethyl)phenyl)piperidin- 1-yl)methanone (75) Step A: Following general procedure GP—Gl, ((4—(3-fluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (30) and acetaldehyde were converted to (6—ethyl—4,5,6,7—tetrhydro—1H; lo[3,4—c]pyridin—3—yl) (4—(3—fluoro—2—(trifluormethyl) phenyl) piperidin-l—yl)methanone as a white solid (21 mg, 31%): 1H NMR (300 MHz, DMSO—de) 5 12.74 (br s, 1H), .65 (m, 1H), 7.48—7.27 (m, 3O 2H), 4.92—4.63 (m, 2H), 3.68—3.04 (m, 4H), 2.90—2.39 (m, 7H), 1.74— 1.55 (m, 4H), l.18~1.02 (m, 3H); ESI MS m/z 425 [M + H]+.

Example 14: Preparation of (4—(3-Fluoro—2-(trifluoromethyl)phenyl) piperidin—l—yl)(6—(3,3,3-trifluoropropyl)-4,5,6,7—tetrahydro-1H- pyrazolo[3,4-c]pyridin~3-yl)methanone (76) WO 68286 2015/028293 Step A: Following general procedure GP—Gl, ((4~(3—fluoro—2— uoromethyl) phenyl) piperidin—l—yl) ,7~tetrahydro-1H- pyrazolo[3,4—c]pyridinyl)methanone hydrochloride (30) and bromotrifluoromethyl propane were converted to 4—(3-fluoro—2~ (trifluoromethyl) phenyl) piperidin-l—yl) (6—(3,3,3-trifluoropropyl)— 7—tetrahydro-1H—pyrazolo[3,4—c]pyridin-3—yl)methanone as a white solid (19 mg, 15%): mp 162—166 °C; 1H NMR (300 MHz, DMSO—ds) 5 12.78 (br s, 1H), 7.72—7.65 (m, 1H), 7.48—7.27 (m, 2H), 4.92—4.63 (m, 2H), 3.57—3.53 (m, 2H), 3.27~3.09 (m, 2H), 2.88—2.39 (m, 9H), 1.77— 1.72 (m, 4H); ESI MS m/Z 493 [M + H]+.

Example 15: Preparation of (4—(3—Fluoro(trifluoromethyl)phenyl) piperidin-l-yl)(6—(2-methoxyethyl)~4,5,6,7-tetrahydro-3aH¥pyrazolo [3,4-c]pyridinyl)methanone (77) Step A: Following general procedure GP—Gl, ((4-(3-fluoro—2— (trifluoromethyl)phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H~ pyrazolo[ 3,4-c]pyridin—3~yl)methanone hydrochloride (30) and bromoethylmethyl ether were converted 4—(3—fluoro—2~ (trifluoromethyl)phenyl)piperidine-1~yl)(6—(2—methoxyethyl)~4,5,6,7— tetrahydro—3aHprrazolo[3,4—c]pyridinyl)methanone as a white solid (23 mg, 30%): 1H NMR (300 MHz, e) 5 12.72 (br s, 1H), 7.67—7.62 (m, 1H), 7.46 (d, J: 8.1 Hz, 1H), 7.33—7.27 (m, 1H), .63 (m, 2H), 3.57~3.48 (m, 4H), 3.27—3.05 (m, 5H), 2.81—2.49 (m, 7H), 1.77— 1.72 (m, 4H); ESI MS m/z 455 [M + H]+.

Example 16: Preparation of 3—(4-(3—F1uoro—2-(trifluoromethyl)phenyl) piperidine-1~carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine—6(7H)- carbonitrile (78) Step A: Following general procedure GP—G2, ((4—(3—fluoro—2— (trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H— pyrazolo [3,4—c]pyridin-3—yl)methanone hydrochloride (30) and cyanogen e were converted to 3—(4—(3—fluoro—2-(trifluormethyl) phenyl)piperidine—l—carbonyl)—4,5~dihydro~1H>pyrazolo[3,4—c] pyridine—6(7H)-carbonitrile as a white solid (38 mg, 53%): mp 194v198 °C; 1H NMR (300 MHz, DMSOede) 5 12.98 (br s, 1H), 7.68—7.65 (m, 1H), 7.47 (d, J: 7.8 Hz, 1H), 7.34—7.27 (m, 1H), 4.92—4.63 (m, 2H), 4.48~ 4.40 (m, 2H), .38 (m, 2H), 3.27—3.05 (m, 2H), 2.88—2.71 (m, 3H), 1.77—1.72 (m, 4H); ESI MS m/z 422 [M + H]+.

Example 17: Preparation of (4—(3-fluoro(trifluoromethyl)phenyl) piperidin-l-yl)(6-oxetanyl)—4,5,6,7—tetrhydro-1H—pyrazolo[3,4— c]pyridine—3—yl)methanone(79) Step A: Following general ure GP—Gl, ((4—(3—fluoro—2— (trifluoromethyl)phenyl)piperidin—1-yl)(4,5,6,7-tetrahydro—1H— pyrazolo [3,4—c]pyridin—3—yl)methanone hydrochloride (30) and oxetan— 3—one were converted to (4—(3—fluoro—2— (trifluormethyl)piperidine—l— yl) (6—oxetan—3—yl) —4,5,6,7—tetrhydro—1H—pyrazolo[3,4—c] pyridine—3— yl)methanone as a white solid (30 mg, 39%): mp 1 °C; 1H NMR (300 MHz, DMSO—d@ 5 12.77 (br s, 1H), 7.70—7.63 (m, 1H), 7.47 (d, Jh 8.1 Hz, 1H),7.34—7.27 (m, 1H), 4.91—4.47 (m, 6H), 3.71—3.66 (m, 1H), 3.47— 3.34 (m, 2H), 3.28—3.06 (m, 2H), 2.93—2.78 (m, 1H), 2.74—2.53(m, 2H), 1.91—1.78 (m, 2H), 1.89—1.55 (m, 4H); ESI MS m/z 453 [M + H]+.

Example 18: Preparation of (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridin-3~yl)(4-(3-fluoro(trifluoromethyl) phenyl)piperidin—1—yl)methanone (80) Step A: Following general procedure GP—Gl, ((4—(3—fluoro—2—(trifluoro —methyl)phenyl)piperidin—l—yl)(4,5,6,7—tetrahydro—1H—pyrazolo[3,4— c]pyridin—3—y1)methanone hydrochloride (30) and cyclopropane carbaldehyde were converted to (6—ethyl—4,5,6,7—tetrhydro—1H— lo[3,4—c]pyridin—3—yl)(4—(3—fluoro—2—(trifluormethyl) phenyl) piperidin—l—yl)methanone as a white solid (23 mg, 34%): 1H NMR (300 MHz, DMSO—d@ 5 12.74 (br s, 1H), 7.72—7.65 (m, 1H), 7.47 (d, JE 7.8 Hz, 1H), 7.34—7.27 (m, 1H), 4.92—4.63 (m, 2H), 3.59—3.53 (m, 2H), .09 (m, 2H), 2.90— 2.39 (m, 7H), 1.81—1.62 (m, 4H), 0.92—0.85 3O (m, 1H), 0.52—0.48 (m, 2H), 0.14—0.10 (m, 2H); ESI MS m/z 451 [M + Example 19: 1-(3—(4-(3,4-Difluoro(trifluoromethyl)phenyl) piperidine—l-carbonyl)-4,5-dihydro-1H—pyrazolo[3,4-c]pyridin-6(7H)— yl)ethanone (81) Step A: Following general procedure GP—Gl, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo [3,4—c]pyridin—3—yl)methanone TFA salt (34) and acetyl chloride were converted to give 1—(3—(4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidine—l—carbonyl)—4,5—dihydro—1H— pyrazolo[3,4—c]pyridin—6(7H)—yl)ethanone as a white solid (29.2 g, 80%): 1H NMR (500 MHz, CDCl3) 510.59 (hr, 1H), 7.36—7.29 (m, 1H), 7.15 (m, 1H), 4.81 (br, 2H), 4.77 and 4.65 (s, 2H), 3.85 (br, 1H), 3.68 (m, 1H), 3.26—2.69 (m, 5H), 2.21 and 2.19 (s, 3H), 1.89—1.73 (m, 4H) MS (ESI+) m/z 457 [M+H]+.

Example 20: 1-(3-(4-(3,4—Dif1uoro—2—(trifluoromethyl)phenyl) piperidine—l-carbonyl)-6,7—dihydro—1H—pyrazolo[4,3—c]pyridin—5(4H)- yl)ethanone (82) Step A: Following general ure GP—Bl, (4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H— lo[4,3—c]pyridin—3—yl)methanone (36) and acetyl chloride were converted to 1—(3—(4—(3,4-difluoro—2—(trifluoromethyl)phenyl) piperidine—l—carbonyl)—6,7—dihydro—1H—pyrazolo[4,3—c]pyridin—5(4H)— yl)ethanone as a white solid (0.046 g, 85): 1H NMR (300 MHz, CDC13) 5 .15 (br, 1H), 7.36—7.27 (m, 1H), 7.15 (m, 1H), 5.33—4.72 (m, 4H), .73 (m, 2H), 3.30— 2.76 (m, 5H), 2.20 (s, 3H), 1.89—1.70 (m, 4H); MS (ESI+) m/z 457 [M+H]+.

Example 21: 1—(3-(4—(3,4—Dif1uoro—2—(trifluoromethyl)phenyl) dine—l—carbonyl)pyrrolo[3,4-c1pyrazol-5(1H,4H,6H)-yl)ethanone Step A: Following general procedure GP—Bl, (4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidin—l—yl)(1,4,5,6—tetrahydropyrrolo [3,4—c]pyrazol—3—yl)methanone (38) and acetyl chloride were converted to 1—(3—(4—(3,4—difluoro—2—(trifluoromethyl) phenyl) piperidine—l— carbonyl)pyrrolo[3,4—c]pyrazol—5(1H,4H,6H)-yl)ethanone as a white solid (0.045 g, 72%): 1H NMR (500 MHz, CDCl3) 610.92 (hr, 1H), 7.37— 7.32 (m, 1H), 7.12 (m, 1H), .21 (m, 6H), 3.29-2.88 (m, 3H), 2.18 and 2.16 (s, 3H), 1.97—1.70 (m, 4H); MS (ESI+) m/z 443 [M+H]+ Example 22: Preparation of 1-(3-(4-(3,4~difluoro—2-(trifluoro methyl)phenyl)piperidine—l-carbonyl)pyrrolo[3,4~c]pyrazol-5 (1H,4H,6H) ~yl)propan-1—one (84) Step A: Following general procedure GP—Hl, (4~(3,4—difluoro (trifluoromethyl)phenyl)piperidin—1—yl)(1,4,5,6—tetrahydropyrrolo [3,4—c]pyrazol-3—yl)methanone (38) and propionyl chloride were converted to 1-(3—(4—(3,4-difluoro—2—(trifluoromethyl)phenyl) dine-l~carbonyl)pyrrolo[3,4—c]pyrazol—5(1H,4H,6H)—yl)propan—1~ one as a white solid (37 mg, 51%): mp >260 °C; 1H NMR (500 MHz, CDCl? 8 7.38*7.3O (m, 1H), .10 (m, 1H), .61 (m, 5.5H), 4.46* 4.19 (m, 0.5H), 3.46—2.72 (m, 3H), 2.42—2.35 (m, 2H), 1.99—1.92 (m, 2H), 1.82—1.57 (m, 2H), 1.35—1.16 (m, 3H), missing N—H pyrazole; ESI MS m/z 457 [M + H]+.

Example 23: Preparation of 1—(3-(4—(3,4-difluoro—2-(trifluoro methyl)phenyl)piperidine—l-carbonyl)pyrrolo[3,4-c]pyrazol (1H,4H,6H) —yl)~2—methylpropan—1—one (85) Step A: Following general procedure GP—Hl, (4—(3,4-difluoro—2— uoromethyl)phenyl)piperidin—1~yl)(1,4,5,6—tetrahydropyrrolo [3,4~c]pyrazol—3wyl)methanone (38) and isobutyryl chloride were converted to 1—(3—(4—(3,4-difluoro—2— (trifluoromethyl) phenyl) piperidine—l—carbonyl)pyrrolo[3,4~c]pyrazol—5(1H,4H,6H)—yl)—2-methyl —l-one as a white solid (29 mg, 38%): mp 249—253 °C; 1H NMR (500 MHz, DMSO—de) 5 13.21, (br s, 1H), 7.81—7.68 (m, 1H), 7.57—7.47 (m, 1H), 4.83—3.65 (m, 6H), 3.29—2.67 (m, 4H), 1.82—1.61 (m, 4H), 1.05 (d, J = 9 Hz, 6H); ESI MS m/z 471 [M + H]+.

Example 24: Preparation of 1-(3—(4-(3,4—difluoro-2—(trifluoromethyl) 3O phenyl)piperidine-l—carbonyl)pyrrolo[3,4—c]pyrazol-5(1H,4H,6H)~yl)— ylbutan—1-one (86) Step A: Following general procedure GP-Hl, (4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidin—1—yl)(1,4,5,6-tetrahydropyrrolo [3,4~c]pyrazol-3—yl)methanone (38) and isovaleryl chloride were converted to 4—(3,4—dif1uoro—2—(trifluoromethy1)phenyl) piperidine—l—carbonyl)pyrrolo[3,4—c]pyrazol—5(1H,4H,6H)—y1)—3— methylbutan—l—one as a white solid (42 mg, 54%): 1H NMR (500 MHz, CDC13) 5 7.37— 7.28 (m, 1H), 7.17—7.08 (m, 1H), 4.95—4.53 (m, 5.5H), 4.43—3.90 (m, 0.5H), 3.34—2.70 (m, 3H), 2.30—2.19 (m, 3H), 1.98—1.89 (m, 2H), 1.80—1.58 (m, 2H), 1.05—0.94 (m, 6H) missing N—H pyrazole; E51 M5 m/z 485 [M + H]+.

Example 25: Preparation of (4—(3,4—difluoro—2—(trifluoromethyl) phenyl)piperidin—1—yl)(5—ethy1—4,5,6,7-tetrahydro-1H-pyrazolo[4,3— c]pyridin-3—yl)methanone (87) Step A: Following l procedure GP—Dl, (4—(3,4—dif1uoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo [4,3—c] pyridin—3—y1) methanone (36) and acetaldehyde were ted to (4—(3,4—dif1uoro—2—(trifluoromethy1)pheny1)piperidin—l— yl) (5—ethy1—4,5,6,7—tetrahydro—1H—pyrazolo [4,3—c]pyridin—3—y1) methanone as a white solid (35 mg, 36%): mp 185 — 190 °C; 1H NMR (300 MHz, DMSO'd?) 5 12.793 (s, 1H), 7.903—7.609 (m, 1H), 7.60—7.40 (m, 1H), 5.24—4.93 (m, 1H), .49 (m, 1H), 3.45 (s, 2H), 3.13 (s, 2H), 2.96—2.71 (m, 1H), 2.61 (s, 4H), 2.58—2.52 (m, 1H), 1.84—1.57 (br s, 4H), .97 (t, 3H); E51 M5 m/z 433.1 [M +H]+.

Example 26: Preparation of (5—(cyclopropylmethyl)-4,5,6,7-tetrahydro— 1prrazolo[4,3—c1pyridin—3-yl)(4—(3,4—difluoro—2-(trifluoromethyl) phenyl)piperidin-1—yl)methanone (88) Step A: Following general ure GP-Dl, (4—(3,4—dif1uoro—2— (trifluoromethyl)pheny1)piperidin—1—y1)(4,5,6,7—tetrahydro—1H— pyrazolo[4,3—c]pyridin—3—y1)methanone (36) and cyclopropane carbo— xaldehyde were converted to (5—(cyclopropy1methy1)—4,5,6,7— tetrahydro—lH—pyrazolo[4,3—c]pyridin—3—y1)(4—(3,4—dif1uoro—2—(tri— fluoromethyl)phenyl)piperidin—l—y1)methanone as a white solid (38 mg, 37%): No clear melt observed; 1H NMR (500 MHz, DMSO—d?) 5 12.80 (s, 1H), 7.80—7.66 (m, 1H), 7.54—7.45 (m, 1H), 5.19—5.03 (br s, 1H), 4.73— 4.58 (m, 1H), 3.66—3.46 (br s, 1H), 3.22—3.05 (br s, 2H), 2.85—2.63 (m, 4H), 1.83—1.59 (br s, 4H), 0.99—0.82 (br s, 1H), O.58~O.43 (m, 2H), 0.21—0.07 (br s, 2H); ESI MS m/z 469.2 [M + H]+. e 27: Preparation of 4-difluoro(trifluoromethyl) phenyl) piperidin—l-yl)(5-(oxetanyl)-4,5,6,7-tetrahydro-1H— pyrazolo [4,3-c]pyridinyl)methanone (89) Step A: Following general procedure GP-Dl, (4—(3,4~difluoro—2— (trifluoromethyl)phenyl)piperidin~1—yl)(4,5,6,7—tetrahydro—1H— lo[4,3-c]pyridin—3—yl)methanone (36) and 3—oxetanone were converted to (4-(3,4—difluoro-2—(trifluoromethyl)phenyl)piperidin yl)(5—(oxetan~3—yl)—4,5,6,7-tetrahydro—1prrazolo[4,3~c]pyridin—3— yl)methanone as a white solid (28 mg, 27%): mp 212 — 215 °C; 1H NMR (300 MHz, DMSO~dw 8 12.847 (3, 1H), 7.796~7.684 (m, 1H), 7.546—7.458 (m, 1H), 5.151 (d, 1H), 4.737-4.554 (m, 3H), 4.554—4.423 (m, 2H), 3.755~3.600 (m, 1H), 3.379 (s, 2H), 3.222—3.050 (br s, 2H), 2.844— 2.643 (m, 3H), 1.898—1.515 (br s, 4H); ESI MS m/z 471.2 [M H]+.

Example 28: Preparation of (4-(3,4—difluoro(trifluoromethyl) phenyl) piperidin-l—yl) (5—neopentyl-4,5,6,7-tetrahydro-1H- 2O pyrazolo[4,3-c]pyridin—3-yl)methanone one (90) Step A: Following general procedure GP—Dl, (4~(3,4—difluoro~2* (trifluoromethyl) phenyl) piperidin—l—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[4,3-c]pyridin*3—yl)methanone (36) and pivaldehyde were converted to (4—(3,4—dif1uoro~2-(trifluoromethyl)pheny1)piperidin—1— neopenty1—4,5,6,7—tetrahydro—1H—pyrazolo[4,3—c]pyridin—3—yl) methanone methanone as a white solid (11 mg, 10%): mp 203 ~ 210 °C; 1H NMR (500 MHz, DMSO—da 8 12.789 (3, 1H), 7.821—7.681 (m, 1H), 7.553— 7.424 (m, 1H), 5.216—5.064 (br s, 1H), 4.755~4.579 (br s, 1H), 3.686— 3.546 (m, 2H), 3.172—3.070 (m, 2H), 2.845—2.710 (m, 1H), 2.249 (s, 2H), 1.799—1.612 (m, 4H), 0.864 (s, 9H); ESI MS m/z 485.2 [M H]+.

Example 29: Preparation of methyl 3-(4-(3,4~dif1uoro (trifluoromethyl) phenyl)piperidine—l-carbonyl)-6,7—dihydro—1H- pyrazolo[4,3—c]pyridine-5(4H)-carboxylate (91) Step A: Following general procedure GP—Bl, (4~(3,4~difluoro—2— (trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[4,3—c]pyridin—3-yl)methanone (36) and methyl chloroformate were converted to methyl 3-(4—(3,4-difluoro—2—(trifluoromethyl) phenyl) piperidine~1~carbonyl)—6,7-dihydro—1H—pyrazolo[4,3—c] pyridine-5(4H)—carboxylate as a white solid (21 mg, 20%): mp 248 — 252 °C; 1H NMR (500 MHz, s) 8 12.924 (s, 1H), 7.763—7.692 (m, 1H), 7.540—7.472 (m, 1H), 5.358~5.152 (br s, 1H), 4.754—4.605 (br s, 1H), 4.650—4.418 (m, 2H), 3.705—3.581 (m, 6H), 3.119—3.1OO (m, 3H), 2.860—2.731 (m, 4H), 1.296—1.237 (m, 6H); ESI MS m/z 473.1 [M + H]+.

Example 30: Preparation of 3—(4-(3,4-dif1uoro—2—(trifluoromethyl) pheny1)piperidine- 1—carbony1)—N—methy1-6,7-dihydro-1H-pyrazolo[4,3— c]pyridine-5(4H)—carboxamide (92) Step A: ing general procedure GP—B2, (4—(3,4—difluoro—2~ (trifluoromethyl)phenyl)piperidin—1-yl)(4,5,6,7—tetrahydro—1H— pyrazolo[4,3-c]pyridin—3~yl)methanone (36) and methyl isocyanate were converted to 3-(4—(3,4—difluoro-2— (trifluoromethyl)phenyl) piperidine—l—carbonyl)—N—methyl~6,7—dihydro-lH—pyrazolo[4,3— c]pyridine-5(4H)—carboxamide as a white solid (28 mg, 36%): No clear melt observed; 1H NMR (500 MHz, DMSO—de) 6 12.895 (5, 1H), 7.780~7.692 (m, 1H), 7.538e7.472 (m, 1H), 6.579—6.49O (m, 1H), 5.202—5.086 (m, 1H), 4.743—4.622 (m, 1H), 4.465-4.332 (m, 2H), 3.499 (m, 2H), 3.209-3.095 (m, 2H), 2.73O (m, 1H), 2.673—2.602 (m, 2H), 2.602— 2.542 (m, 3H), 1.912—1.588 (m, 5H); ESI MS m/z 472.2 [M + H]+.

Example 31: Preparation of (4-(3,4—dif1uoro-2—(trifluoromethyl) pheny1)piperidin—1—y1)(5—(3,3,3—trif1uoropropy1)-4,5,6,7—tetrahydro- 1H—pyrazolo[4,3-c]pyridiny1)methanone (93) Step A: ing general procedure GP—D2, (4—(3,4~difluoro—2- (trifluoromethyl)phenyl)piperidin~1~yl)(4,5,6,7—tetrahydro~1H— pyrazolo[4,3~c]pyridin-3~yl)methanone (36) and 1,1,1—trifluoro—3— bromopropane were converted to (4—(3,4—difluoro—2—(trifluoromethyl) phenyl)piperidin—1—yl)(5—(3,3,3—trifluoropropyl)~4,5,6,7—tetrahydro~ azolo[4,3-c]pyridin—3—yl)methanone as a white solid (24 mg, 21%): mp 190 — 195 °C; 1H NMR (500 MHz, DMSO—de) 6 12.939~12.764 (m, 1H), 7.847-7.665 (m, 1H), 7.591—7.417 (m, 1H), 5.213-4.965 (m, 1H), 4.555 (m, 1H), 3.456 (m, 2H), 3.223~3.039 (br s, 2H), 2.853—2.698 (m, 5H), 2.623 (m, 2H), 2.596—2.522 (m, 1H), 1.859~ 1.589 (m, 4H); ESI MS m/z 511.1 [M + H]+.

Example 32: Preparation of (4—(3,4—dif1uoro—2-(trifluoromethyl) phenyl)piperidin—1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c1pyridin—3— y1)methanone (94) Step A: ing general procedure GP-D2, 4—difluoro—2— (trifluoromethyl) phenyl) piperidin-l—yl)(4,5,6,7—tetrahydro-1H— pyrazolo [4,3—c]pyridin—3—yl)methanone (36) and 2—methoxybromoethane were converted to (4—(3,4—difluoro~2—(trifluoromethyl)phenyl) piperidin—l—yl)(5—(2—methoxyethyl)—4,5,6,7—tetrahydro«1H— pyrazolo [ 4,3—c]pyridin—3-yl)methanone as a white solid (24 mg, 23%): mp 179 — 182 OC; 1H NMR (500 MHz, DMSO—de) 5 12.805 (s, 1H), 7.824a7.654 (m, 1H), 7.438 (m, 1H), 5.085 (s, 1H), 4.660 (s, 1H), 3.517 (s, 4H), 3.268 (s, 3H), 3.187—3.063 (m, 2H), 2.906—2.604 (m, 6H), 1.885—1.550 (m, 4H); ESI MS m/z 473.2 [M + H]+. 2O Example 33: Preparation of 3—(4-(3,4-difluoro(trifluoromethyl) phenyl)piperidine—l-carbonyl)—6,7~dihydro—1H-pyrazolo[4,3-c] pyridine-5(4H)-carbonitrile (95) Step A: Following general procedure GP—D2, (4-(3,4—difluoro—2~ (trifluoromethyl)phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H- pyrazolo[4,3—c]pyridin—3—y1)methanone (36) and cyanogen bromide were converted to 3—(4—(3,4—difluoro-2—(trifluoromethyl)phenyl) piperidine ~1—carbonyl) —6,7—dihydro~1H—pyrazolo[4,3~c]pyridine— 5(4H)— carbo- nitrile as a white solid (95 mg, quant.): No clear melt observed; 1H NMR (500 MHz, DMSO—da 5 13.115 (s, 1H), 7.833—7.627 (m, 1H), 7.627— 7.409 (m, 1H), 5.188 — — 5.067 (m, 1H), 4.558 4.469 (m, 1H), 4.374 (s, 2H), 3.538—3.404 (m, 2H), 3.074—2.98 (br s, 2H), 2.877—2.805 (m, 2H), 1.801—1.694 (br s, 4H); E51 M5 m/z 440 [M + H]+.

Example 34: Preparation of (4-(3,4—difluoro—2(trifluoromethyl)phenyl) piperidin-l—yl)(5—ethyl-1,4,5,6-tetrahydropyrrolo[3,4—c]pyrazol—3- yl)methanone (96) Step A: Following general procedure GP—Jl, (4—(3,4—difluoro-2* uoromethyl)phenyl)piperidin—1—yl)(1,4,5,6-tetrahydropyrrolo [3,4~c]pyrazol—3—yl)methanone (38) and acetaldehyde were converted to (4-(3,4—difluoro—2—(trifluoromethyl)phenyl)piperidin—1-yl)(5-ethyl— 1,4,5,6—tetrahydropyrrolo[3,4—c]pyrazolyl)methanone as a white solid (36 mg, 76%): No clear melt observed; 1H NMR (500 MHz, DMSO-da 5 13.140 * 12.832 (m, 1H), 7.879~7.669 (m, 1H), 7.669 — 7.408 (m, 1H), .271—3.901 (m, 2H), 3.901—3.559 (m, 4H), 3.216—3.013 (m, 2H), 2.960- 2.684 (m, 3H), 1.854~1.569 (m, 4H), 1.162 — 1.005 (m, 3H); ESI MS m/z 429.2 [M + H]+.

Example 35: Preparation of (5-(cyclopropylmethyl)-1,4,5,6-tetrahydro pyrrolo[3,4-c]pyrazol-3~yl)(4—(3,4-dif1uoro—2-(trifluoromethyl) phenyl)piperidin-l—yl)methanone (97) Step A: Following general ure GP-Jl, (4-(3,4—difluoro—2— (trifluoromethyl) phenyl)piperidin—1—yl)(1,4,5,6—tetrahydropyrrolo [3,4*c]pyrazol—3—yl)methanone (38) and cyclopropropane carboxaldehyde were converted to ((5—(cyclopropylmethyl)—1,4,5,6—tetrahydropyrrolo [3,4«c]pyrazol—3—yl) (4~(3,4-difluoro—2—(trifluoromethyl) phenyl) piperidin—1~yl)methanone as a white solid (36 mg, 76%): No clear melt observed; 1H NMR (500 MHz, DMSO—dg) 5 13.101 — 12.818 (m, 1H), 7.887— 7.665 (m, 1H), 7.665 ~ 7.423 (m, 1H), 5.223~3.923 (m, 2H), 3.923—3.594 (m, 4H), 3.258a3.667 (m, 3H), 2.667~2.533 (m, 2H), 1.827—1.606 (m, 4H), 0.988 ~ 0.793 (m, 1H), 0.598 — 0.417 (m, 2H), 0.235 — 0.087 (m, 2H); ESI MS m/z 455.1 [M + H]+.

Example 36: Preparation of (5—(cyclopropylmethyl)~1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl)(4~(3,4-difluoro (trifluoromethyl)phenyl)piperidin-l—yl)methanone (98) Step A: Following general procedure GP—Jl, 4—difluoro-2— uoromethyl) phenyl) piperidin-1~yl)(1,4,5,6-tetrahydropyrrolo ]pyrazol—3—yl)methanone (38) and anone were converted to (4—(3,4—difluoro~2—(trifluoromethyl)phenyl) piperidin—l—yl) (5— (oxetan—3—yl)—l,4,5,6—tetrahydropyrrolo[3,4—c]pyrazolyl) methanone as a white solid (39 mg, 74%): No clear melt observed; 1H NMR (500 MHz, DMSO—dm 5 13.105 — 12.925 (m, 1H), 7.874—7.65l (m, 1H), 7.602 — 7.442 (m, 1H), 5.250—4.509 (m, 1H), 4.245»3.601 (m, 5H), 3.221—3.074 (m, 1H), 3.016— 2.723 (m, 3H), 2.596—2.518 (m, 2H), 1.854 ~ 1.610 (m, 4H); ESI MS m/z 457.1 [M + H]+.

Example 37: Preparation of (4-(3,4-dif1uoro-2—(trifluoromethyl) phenyl) din-l- yl)(5-neopenty1—1,4,5,6-tetrahydropyrrolo[3,4— c]pyrazoly1)methanone (99) Step A: Following general ure GP~Jl, (4~(3,4—difluoro—2— (trifluoromethyl) ) piperidin~l~yl)(1,4,5,6~tetrahydropyrrolo [3,4~c]pyrazol—3—yl)methanone (38) and pivaldehyde were converted to (4~(3,4-difluoro—2—(trifluoromethyl)phenyl)piperidin—l-yl)(5— tyl —1,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol—3—yl)methanone as a white solid (25 mg, 46%): No clear melt observed; 1H NMR (500 MHz, DMSO~da 8 13.060—12.840 (m, 1H), 7.440 (m, 2H), 5.315‘4.473 (m, 1H), 4.210—3.642 (m, 5H), 3.272~2.728 (m, 3H), 2.555 (s, 2H), 1.867— 1.597 (m, 4H), 0.905 (s, 9H); ESI MS m/z 471.2 [M + H]+.

Example 38: Preparation of 3-(4-(3,4-dif1uoro—2-(trifluoromethyl) phenyl)piperidine—l-carbonyl)-N—methy1—4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)~carboxamide (100) Step A: Following general procedure GP-H2, (4—(3,4-difluoro—2— (trifluoromethyl)phenyl)piperidin-l—yl)(1,4,5,6—tetrahydropyrrolo ]pyrazol—3—yl)methanone (38) and methyl isocyanate were converted to 3~(4—(3,4-difluoro—2—(trifluoromethyl)phenyl) piperidine —1—carbonyl)—N—methyl—4,6—dihydropyrrolo[3,4-c]pyrazole*5(lH) carbo~ xamide as a white solid (55 mg, 53%): mp >260 °C; 1H NMR (300 MHz, DMSO—dm 5 13.449912.960 (m, 1H), 7.719—7.620 (m, 1H), 7.620—7.379 (m, 1H), 6.272 (s, 1H), 5.454—3.850 (m, 6H), 3.240—2.737 (m, 3H), 2.623 (s, 3H), 1.979— 1.523 (m, 4H; ESI MS m/z 458.1 [M + H]+.

Example 39: Preparation of methyl 3—(4-(3,4-difluoro—2- (trifluoromethyl)phenyl)piperidine—l—carbonyl)-4,6-dihydropyrrolo [3,4—c]pyrazole-5(1H)~carboxylate (101) Step A: Following general procedure GP-Hl, (4—(3,4—difluoro-2— (trifluoromethyl)phenyl)piperidin—l-yl)(1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol—3~yl)methanone (38) and methyl chloroformate were converted to methyl 3—(4~(3,4-difluoro-2—(trifluoromethyl) phenyl)piperidine—l-carbonyl)—4,6—dihydropyrrolo[3,4-c]pyrazole-5 (1H) -carboxylate as a white solid (30 mg, 55%): No clear. melt ed; WiNMR (500 MHz, DMSO—d? 8 l3.503—l3.llO (br s, 1H), 7.310— 7.721 (m, 1H), 7.587—7.47l (m, 1H), 4.808—4.53l (br s, 1H), 4.531— 4.370 (m, 4H), 3.673 (s, 3H), 3.277—3.102 (m, 2H), 2.722 (br s, 1H), 1.851—1.621 (m, 4H); ESI MS m/z 459.2 [M + H]+.

Example 40: Preparation of (5~benzoyl—1,4,5,6-tetrahydropyrrolo[3,4~ c]pyrazolyl)(4~(3,4-difluor0*2-(trifluoromethyl)phenyl)piperidin- 1-yl)methanone (102) Step A: Following general procedure GP—Hl, (4—(3,4—difluoro (trifluoromethyl) phenyl) piperidin—l—yl)(l,4,5,6—tetrahydropyrrolo 2O [3,4~c]pyrazol~3~yl)methanone (38) and l chloride were converted to (5—benzoyl-l,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol~3— yl) (4~(3,4—difluoro—2—(trifluoromethyl) ) piperidin—1~yl) methanone as a white solid (30 mg, 55%): mp >260 °C; 1H NMR (500 MHz, DMSO~da 6 —13.007 (m, 1H), 7.867~7.668 (m, 1H), 7.668~7.545 (m, 2H), 7.545—7.384 (m, 4H), 5.416—3.89l (m, 6H), 2.620 (m, 3H), l.923—l.524 (m, 4H); ESI MS m/z 505 [M + H]+.

Example 41: Preparation of (4-(3,4-difluoro-2(trifluoromethyl)phenyl) piperidin-l—yl)(5—picolinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazoly1)methanone (103) Step A: Following general procedure GP—Hl, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl)(l,4,5,6~tetrahydropyrrolo [3,4~c]pyrazol—3—yl)methanone (38) and picolinoyl chloride were converted to 4—difluoro—2—(trifluoromethyl) phenyl) piperidin— l—yl) (5—picolinoyl—l,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol—3—yl) methanone as a white solid (13 mg, 22%): No clear melt observed; 1H NMR (300 MHZ, DMSO—dd 5 13.632-13.061 (m, 1H), 8.722—8.139 (m, 1H), 7.908 (m, 1H), 7.908—7.684 (m, 2H), 7.684—7.398 (m, 2H), 5.115* 4.428 (m, 5H), 3.316—2.598 (m, 3H), 1.133 (m, 5H); ESI MS m/z 506.1 [M + H]+.

Example 42: ation of 4-difluoro(trifluoromethyl) phenyl) piperidin-l-yl)(5—nicotinoyl—1,4,5,6—tetrahydropyrrolo[3,4— c]pyrazolyl)methanone (104) Step A: Following general procedure GP—Hl, 4—difluoro~2- (trifluoromethyl)phenyl)piperidin—1—yl)(1,4,5,6—tetrahydropyrrolo [3,4—c] pyrazol~3~yl)methanone (38) and nicotinoyl chloride were converted to (4—(3,4—difluoro~2—(trifluoromethyl)phenyl)piperidin—1— yl)(5—nicotinoyl—l,4,5,6-tetrahydropyrrolo[3,4—c]pyrazol yl)methanone as a white solid (34 mg, 59%): No clear melt observed; 1H NMR (500 MHz, DMSO—ds) 5 13.589-13.123 (br s, 1H), 8.807 (s, 1H), 8.140~7.99l (m, 1H), 7.843—7.678 (m, 1H), 7.628—7.364 (m, 2H), 5.433— 3.721 (m, 6H), 2.701 (m, 3H), 1.933~1.522 (m, 4H); ESI MS m/z 506.1 [M + H]+.

Example 43: Preparation of (4-(3,4-difluoro—2(trifluoromethyl)phenyl) piperidin-l-yl)(5-isonicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4—c] pyrazol~3-yl)methanone (105) Step A: ing general procedure GP—Hl, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) (1,4,5,6—tetrahydropyrrolo [3,4—c] pyrazol—3—yl)methanone (38) and isonicotinoyl chloride were converted to (4—(3,4~difluoro—2~(trifluoromethyl)phenyl)piperidin—1~ yl) (5-isonicotinoyl—l,4,5,6*tetrahydropyrrolo [3,4~c] pyrazol—3—yl) methanone as a white solid (14 mg, 24%): mp >260 °C; 1H NMR (500 MHz, DMSO—dm 5 13.420—13.120 (m, 1H), 8.770—8.620 (m, 2H), 7.833—7.679 (m, 1H), 7.612—7.369 (m, 3H), 5.410—3.820 (m, 6H), 3.240—3.06O (m, 2H), 1.860—l.530 (m, 4H), l.290~l.190 (m, 1H); ESI MS m/z 506.1 [M + H]+.

Example 44: Preparation of (4—(3,4—difluoro—2—(trifluoromethyl) phenyl)piperidin—1-yl)(5-(pyrrolidine-l—carbonyl)-1,4,5,6— tetrahydropyrrolo [3,4—c]pyrazolyl)methanone (106) Step A: Following general procedure GP—H2, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin-l-yl) (1,4,5,6wtetrahydropyrrolo [3,4—c]pyrazole3—yl)methanone (38) and l—pyrolocarbamoyl chloride were converted to (4~(3,4—difluoro~2- (trifluoromethyl)phenyl) piperidin—l—yl)(5—(pyrrolidine—l-carbonyl)-l,4,5,6~tetrahydropyrrolo [3,4-c]pyrazol—3—yl)methanone as a white solid (22 mg, 38%): mp >260 °C; 1H NMR (500 MHz, DMSO—ds) 5 l3.389—l3.022 (m, 1H), 7.858—7.407 (m, 2H), 5.439~3.846 (m, 6H), 3.4l2—3.326 (m, 4H), 3.253—2.742 (m, 3H), l.868-l.638 (m, 8H); ESI MS m/z 498.2 [M + H]+. e 45: Preparation of 4-(3,4-difluoro(trifluoromethyl)phenyl) piperidin-l—yl)(5—(2,2,2—trifluoroethyl)~1,4,5,6-tetrahydropyrrolo ]pyrazol—3-yl)methanone(107) Step A: Following general procedure GP—J2, (4-(3,4-difluoro~2~ uoromethyl) phenyl )piperidin—l—yl) (l,4,5,6—tetrahydropyrrolo [3,4—c]pyrazol—3—yl)methanone (38) and 2,2,2—trifluoroethyl trifluoromethanesulfonate were converted to (4—(3,4—difluoro-2— (trifluoromethyl) phenyl) piperidin~l~yl) (5—(2,2,2-trifluoroethyl)— l,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol—3-yl)methanone as a white solid (16 mg, 28%): No clear melt observed; 1H NMR (500 MHz, DMSO—d? 13.274—12.902 (m, 1H), 7.343—7.681 (m, 1H), 7.441 (m, 1H), 3.811 (m, 6H), 3.695~3.52O (m, 2H), 3.273—2.7l (m, 3H), 1.906— 1.571 (m, 4H); ESI MS m/z 483.1 [M + H]+.

Example 46: Preparation of (4-(3,4—difluoro—2(trifluoromethyl)phenyl) piperidin-l—yl)(5-(3,3,3—trifluoropropyl)-1,4,5,6-tetrahydropyrrolo 3O [3,4-c]pyrazol-3—yl)methanone (108) Step A: Following general procedure GP—JZ, 4~difluoro—2— (trifluoromethyl)phenyl)piperidin~l—yl)(1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol—3—yl)methanone (38) and 1,1,l-trifluoro-3—bromopropane were converted to (4~(3,4—difluoro-2—(trifluoromethyl)phenyl) piperidin—l—yl) (5-(3,3,3-trifluoropropyl) —l,4,5,6— tetrahydro— pyrrolo[3,4—c]pyrazol~3—yl)methanone as a white solid (13 mg, 22%): No clear melt observed; 1H NMR (500 MHz, DMSO—dm 5 13.091~l2.860 (m, 1H), 7.837—7.65l (m, 1H), 7.638—7.430 (m, 1H), 5.271-4.038 (m, 7H), 3.899—3.673 (m, 4H), 3.210—3.059 (m, 2H), 2.681 (br s, 1H), 1.869-1.558 (m, 4H); ESI MS m/z 497 [M + H]+.

Example 47: Preparation of (4-(3,4-difluoro—2(trifluoromethyl)phenyl) piperidin-l-yl)(5—(2—methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4- zol—3-yl)methanone(109) Step A: Following general procedure GP-J2, (4-(3,4—difluoro—2— (trifluoromethyl) phenyl)piperidin-l~yl)(1,4,5,6-tetrahydropyrrolo [3,4—c] pyrazolyl)methanone (38) and 2—methoxy—bromoethane were converted to (4—(3,4~difluoro~2—(trifluoromethyl)phenyl)piperidin—l~ (2—methoxyethyl)—l,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol—3—yl) methanone as a white solid (14 mg, 22%): No clear melt observed; 1H NMR (300 MHz, DMSO—dm 5 —12.86O (m, 1H), 7.852—7.648 (m, 1H), 7.616—7.449 (m, 1H), 5.365—3.596 (m, 6H), 3.560—3.4l3 (m, 2H), 3.298~ 3.219 (m, 4H), 3.219'3.047 (m, 2H), 2.937—2.832 (m, 3H), 1.843~1.576 (m, 5H); ESI MS m/z 459.2 [M + H]+.

Example 48: Preparation of 3—(4—(3,4—difluoro—2—(trifluoromethyl) phenyl) piperidine-l-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole- (1H)-carbonitrile (110) Step A: Following general procedure GP—J2, (4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidin-lvyl)(1,4,5,6—tetrahydropyrrolo [3,4—c]pyrazol—3-yl)methanone (38) and cyanogen bromide were converted to —(4-(3,4—difluoro-2~(trifluoromethyl)phenyl)piperidine~ l—carbonyl)-4,6-dihydropyrrolo[3,4—c]pyrazole—5(lH)—carbonitrile as a white solid (23 mg, 79%): No clear melt observed; 1H NMR (500 MHz, DMSO—d5) 8 13.623-13.l72 (m, 1H), 7.850—7.664 (m, 1H), 7.664—7.47O (m, 1H), 3.846 (m, 6H), 3.271-2.652 (m, 3H), 2.042—l.503 (m, 4H); ESI MS m/z 426 [M + H]+.

Example 49: Preparation of (4-(3,4—Difluoro(trifluoromethyl) phenyl) piperidin—l-yl)(6-ethyl—4,5,6,7-tetrahydro—1Hrpyrazolo[3,4— c]pyridin-3—yl)methanone (111) Step A: Following general procedure GP—Gl, 4-dif1uoro—2— (trifluoromethyl) phenyl)piperidin—1—yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3~yl)methanone TFA salt (34) and acetaldehyde were converted to 4~difluoro(trifluoromethyl)phenyl) piperidin-l-yl) (6~ethyl—4,5,6,7~tetrahydro-lH—pyrazolo [3,4—c] pyridina3?yl)methanone as a white solid (13 mg, 21%): mp 207—210 °C; 1H NMR (500 MHz, DMSO—d6) 5 12.90 (br s, 0.25H), 12.71 (br s, 0.75H), 7.78—7.70 (m, 1H), 7.50~7.49 (m, 1H), .85 (m, 1H), 4.68a4.66 (m, 1H), .45 (m, 2H), 3.14~3.13 (m, 2H), 2.78~2.77 (m, 1H), .55 (m, 6H, partialy merged with DMSO peak), 1.76~1.70 (m, 4H), 1.07 (t, J = 7.0 Hz, 3H); ESI MS m/z 443 [M + H]+.

Example 50: Preparation of 3—(4-(3,4-Difluoro—2-(trifluoromethyl) )piperidine—l—carbonyl)-N;methyl-1,4,5,7—tetrahydro- 6prrazolo[3,4—c]pyridine—G—carboxamide (112) Step A: Following general ure GP-EZ, (4—(3,4—difluoro—2— 2O (trifluoromethyl) phenyl) piperidin-l—yl) (4,5,6,7—tetrahydro—1H- pyrazolo[3,4—c]pyridin—B—yl)methanone TFA salt (34) and isocyanatomethane were converted to 3~(4—(3,4—difluoro—2~ (trifluoromethy1)phenyl) piperidine-l—carbonyl)—NLmethyl—1,4,5,7— tetrahydro—6prrazolo[3,4—c]pyridine-6—carboxamide as an off—white solid (6 mg, 27%): mp 220*225 °C; 1H NMR (500 MHz, DMSO—d6) 5 13.05 (br s, 0.25H), 12.85 (br s, 0.75H), 7.79—7.70 (m, 1H), .48 (m, 1H), 6.61—6.60 (m, 0.75H), 6.55—6.54 (m, 0.25H), 4.86-4.84 (m, 1H), 4.68—4.65 (m, 1H), 4.47—4.42 (m, 2H), 3.54—3.50 (m, 2H), 3.l4~3.13 (m, 2H), 2.78— 2.77 (m, 1H), 2.59—2.56 (m, 5H, partialy merged with DMSO peak), 1.76—1.67 (m, 4H); ESI MS m/z 472 [M + H]+.

Example 51: Preparation of (4-(3,4—Difluoro-2—(trifluoromethyl) phenyl)piperidinyl)(6~methyl—4,5,6,7—tetrahydro-1Hapyrazolo[3,4— c]pyridin~3—yl)methanone (113) Step A: Following general procedure GP—Gl, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin~1~yl)(4,5,6,7—tetrahydro-1H— pyrazolo[3,4-c]pyridin—3—y1)methanone TFA salt (34) and formaldehyde were converted to 4—difluoro—2—(trifluoromethyl)phenyl) piperidin-l—yl) (6-methyl—4,5,6,7-tetrahydro—1Hepyrazolo [3,4-c] pyridin—3-y1)methanone as a white solid (18 mg, 55%): mp 210—211 °C; 1H NMR (500 MHz, DMSO—ds) 8 12.91 (br s, 0.25H), 12.72 (br s, 0.75H), 7.79—7.70 (m, 1H), 7.50—7.49 (m, 1H), 4.88~4.86 (m, 1H), 4.67—4.65 (m, 1H), 3.43—3.40 (m, 2H), 3.15—3.13 (m, 2H), 2.77—2.76 (m, 1H), .60 (m, 4H), 2.36 (s, 3H), 1.76—1.69 (m, 4H); E51 M5 m/z 429 [M + H]+.

Example 52: Preparation of 3—(4-(3-Fluoro(trifluoromethyl)phenyl) piperidine-l-carbonyl)-NLmethyl-6,7-dihydro-1H‘pyrazolo[4,3- c]pyridine—5(4H)-carboxamide (114) Step A: Following general procedure GP—C, (4—(3—fluoro—2- uoromethyl)phenyl)piperidin-l—yl)(4,5,6,7~tetrahydro—1H— pyrazolo[4,3—c]pyridin~3—yl)methanone hydrochloride (32) and methyl isocyanate were converted to 3—(4—(3-fluor0*2~(trifluoromethyl) phenyl)piperidine—l—carbonyl)~N¥methyl—6,7—dihydro—1Hepyrazolo[4,3— c]pyridine—5(4H)—carboxamide as a white solid (32 mg, 41%): mp 165— 170 °C; 1H NMR (500 MHz, DMSO~da 8 13.03—12.85 (m, 1H), 7.70~7.62 (m, 1H), 7.46 (d, J'= 8.0 Hz, 1H), 7.30 (dd, J'= 12.0, 8.0 Hz, 1H), 6.58— 6.49 (m, 1H), 5.19—5.06 (m, 2H), 4.76—4.62 (m, 2H), .50 (m, 2H), 3.27~3-09 (m, 2H), 2.86—2.72 (m, 1H), 2.64 (t, J'= 5.5 Hz, 2H), 2.59— 2.54 (m, 3H), .59 (m, 4H); E51 M5 m/z 454 [M + H]? Example 53: Preparation of 2—(3—(4—(3,4—Difluoro—2-(trifluoromethyl) phenyl)piperidine-l—carbonyl)—1,4,5,7—tetrahydro-6Hepyrazolo[3,4— c]pyridin—6—yl)acetic acid (115) Step A: Following general ure GP~G2, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) ,7—tetrahydro~1H— pyrazolo[3,4-c]pyridin—3—yl)methanone TFA salt (34) and tert—butyl 2~ bromoacetate were converted to provide tert—butyl 2—(3—(4—(3,4— difluoro—2—(trifluoromethyl)phenyl) piperidine-l—carbonyl)—1,4,5,7- tetrahydro—6Hepyrazolo[3,4—c]pyridin—6—yl)acetate as a clear, glassy solid (55 mg, 69%): 1H NMR (500 MHz, DMSO—d6) 5 12.94 (br s, 0.25H), 12.71 (br s, 0.75H), 7.37~7.33 (m, 1H), 7.50—7.49 (m, 1H), 4.86—4.84 (m, 1H), .66 (m, 1H), 3.67~3.63 (m, 2H), 3.34—3.30 (m, 2H, partially merged with H20 peak), 3.14—3.13 (m, 2H), 2.59—2.58 (m, 3H), 2.59—2.50 (m, 2H, lly merged with DMSO peak), 1.76—1.70 (m, 4H), 1.43 (s, 9H); ESI MS m/z 529 [M + H]+.

Step B: A on tert—butyl 2—(3-(4-(3,4—difluoro—2— (trifluoromethyl) phenyl)piperidine—l—carbonyl)~1,4,5,7—tetrahydro~ 6H—pyrazolo[3,4-c]pyridin-6—yl)acetate (53 mg, 0.10 mmol) in anhydrous CH2C12 (3 mL) was treated with TFA (3 mL) and stirred under an atmosphere of N2 at room temperature for 8 h. After this time, the mixture was concentrated to dryness under d re and solvent exchanged with CH2C12 (10 mL). The residue was diluted in anhydrous CH2C12 (10 mL), d with MP-carbonate (0.50 g) and stirred at room temperature for 15 min. After this time, the solution was filtered and the resin washed with CH2C12 (2 X 10 mL). The filtrate was concentrated to dryness under reduced pressure to e 2—(3-(4— (3,4~dif1uoro-2—(trifluoromethyl) phenyl) piperidine-l-carbony1)— 1,4,5,7—tetrahydro—6H—pyrazolo[3,4-c]pyridin—6—y1)acetic acid as an off—white solid (40 mg, 85%): mp 151-153 °C; 1H NMR (500 MHz, DMSO—dd 13.29 (br s, 0.25H), 12.89 (br s, O.75H), 7.56—7.55 (m, 1H), 7.51- 7.50 (m, 1H), 4.87—4.86 (m, 1H), 4.66e4.64 (m, 1H), 4.04—4.02 (m, 2H), 3.76—3.72 (m, 2H), 3.34—3.32 (m, 2H, partially merged with H20 peak), 3.15—3.11 (m, 4H), 2.76— 2.74 (m, 2H), 1.76~1.7O (m, 4H); ESI MS m/z 473 [M + H]+.

Example 54: Preparation of Methyl 3-(4-(3,4-difluoro (trifluoromethyl) phenyl)piperidine-l-carbonyl)-1,4,5,7-tetrahydro- 3O 6H>pyrazolo[3,4—c]pyridine—G—carboxylate (116) Step A: Following general procedure GP—El, (4—(3,4—difluoro—2* (trifluoromethyl) phenyl) piperidin—l—yl)(4,5,6,7~tetrahydro-1H- pyrazolo[3,4—c]pyridin—3—yl)methanone TFA salt (34) and methyl carbonochloridate were converted to 3—(4~(3,4—dif1uoro—2— (trifluoromethyl) phenyl) piperidine—l—carbonyl)—1,4,5,7—tetrahydro— 6prrazolo[3,4—c]pyridine—6—carboxylate as a light orange solid (30 mg, 60%): mp 0 °C; 1H NMR (500 MHZ, DMSO-dd 5 13.13 (br s, 0.25H), 12.86 (br s, 0.75H), 7.78—7.70 (m, 1H), 7.51~7.48 (m, 1H), 4.82—4.80 (m, 1H), 4.67—4.65 (m, 1H), 4.54 (s, 1.5H), 4.50 (s, 0.5H), 3.64 (s, 3H), 3.60—3.57 (m, 2H), .13 (m, 2H), 2.79—2.78 (m, 1H), 2.64— 2.59 (m, 2H), 1.76—1.68 (m, 4H); ESI MS m/z 473 [M + H]+.

Example 55: Preparation of (4—(3,4—Difluoro—2—(trifluoromethyl) )piperidin-1—yl)(6—(oxetanyl)-4,5,6,7-tetrahydro-1H— pyrazolo [3,4—c]pyridin-3—yl)methanone (117) Step A: Following general procedure GP—Gl, (4-(3,4—difluoro-2— (trifluoromethyl) phenyl) din—l-yl) (4,5,6,7~tetrahydro-1H— pyrazolo[3,4—c]pyridin—3—yl)methanone TFA salt (34) and oxetan—3—one were ted to (4*(3,4-dif1uoro—2— (trifluoromethyl)phenyl) piperidin—l—yl)(6—(oxetan-3—yl)-4,5,6,7—tetrahydro—1prrazolo[3,4—c] pyridin-3—yl)methanone as an off—white solid (32 mg, 50%): mp 206—207 °C; 1H NMR (500 MHz, DMSO—da 5 12.96 (br s, 0.25H), 12.76 (br s, 0.75H), 7.80~7.70 (m, 1H), 7.51—7.50 (m, 1H), 4.86—4.84 (m, 1H), 4.68— 4.65 (m, 1H), 4.60 (apparent t, J = 6.5 Hz, 2H), 4.50 ent t, J = 6.0 Hz, 2H), 3.71—3.64 (m, 1H), 3.43—3.38 (m, 2H), 3.15~3.13 (m, 2H), 2.78—2.77 (m, 1H), 2.64-2.60 (m, 2H), 1.79—1.68 (m, 4H), CH2 obscured by solvent peak; ESI MS m/z 471 [M + H]+.

Example 56: Preparation of (6-(Cyclopropylmethyl)-4,5,6,7-tetrahydro— alyrazolo[3,4~c]pyridinyl)(4-(3,4-difluoro~2-(trifluoromethyl) phenyl)piperidin-l-yl)methanone (118) Step A: Following general procedure GP—Gl, (4—(3,4—dif1uoro-2— (trifluoromethyl) phenyl) din—l—yl) (4,5,6,7~tetrahydro—1H~ 3O pyrazolo[3,4—c]pyridin—3—yl)methanone TFA salt (34) and cyclopropanecarbaldehyde were converted to (6—(cyclopropylmethy1)- 4,5,6,7—tetrahydro—1H-pyrazolo[3,4—C]pyridin—3—yl)(4—(3,4—difluoro— 2—(trifluoromethyl)phenyl)piperidin—1~yl)methanone as a white solid (30 mg, 58%): mp 184-185 °C; 1H NMR (500 MHz, CD3OD) 5 7.53 (dd, J = 17.5, 9.0 Hz, 1H), 7.39 (dd, J'= 9.0, 4.0 Hz, 1H), 4.83—4.82 (m, 1H, lly merged with H20 peak), .63 (m, 1H), 3.94‘3.92 (m, 2H), 3.29—3.26 (m, 2H, partially merged with CH3OH peak), 3.05—3.03 (m, 2H), .84 (m, 3H), 2.69~2.67 (m, 2H), 1.89*1.81 (m, 4H), 1.04— 1.02 (m, 1H), 0.65 (d, J = 7.0 Hz, 2H), 0.29—0.27 (m, 2H), NH proton not observed; ESI MS m/z 469 [M + H]+.

Example 57: Preparation of (4—(3,4-Difluoro-2(trifluoromethyl)phenyl) piperidin-l—yl)(6-(3,3,3-trifluoropropyl)~4,5,6,7-tetrahydro-1H— pyrazolo[3,4-c]pyridinyl)methanone (119) Step A: Following general procedure GP-Gl, (4-(3,4-difluoro~2— (trifluoromethyl) phenyl) piperidin-l—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—B—yl)methanone TFA salt (34) and 3,3,3~ trifluoropropanal were converted to (4—(3,4—difluoro—2— (trifluoromethyl)phenyl)piperidin~1~yl)(6—(3,3,3-trifluoropropyl)~ 4,5,6,7*tetrahydro—1H-pyrazolo[3,4~c]pyridin—3—yl)methanone as an off-white solid (18 mg, 36%): mp 194—195 °C; 1H NMR (500 MHz, DMSO—dd 12.94 (br s, 0.25H), 12.76 (br s, 0.75H), 7.79—7.70 (m, 1H), 7.50« 7.49 (m, 1H), 4.87—4.85 (m, 1H), 4.68-4.66 (m, 1H), 3.57—3.53 (m, 2H), 3.15—3.13 (m, 2H), 2.75 (t, J'= 7.5 Hz, 2H), 2.69~2.67 (m, 2H), 2.58— 2O 2.50 (m, 5H, partially merged with DMSO peak), 1.76~1.68 (m, 4H); ESI MS m/z 511 [M + H]+.

Example 58: Preparation of 3-(4-(3,4-Difluoro(trifluoromethyl) phenyl) piperidine-l-carbonyl)-1,4,5,7-tetrahydro-6H—pyrazolo[3,4- c]pyridine-G-carbonitrile (120) Step A: Following general procedure GP—G2, (4—(3,4—difluoro~2~ (trifluoromethyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro~1H- lo[3,4-c]pyridin~3~yl)methanone TFA salt (34) and cyanogen bromide were converted to 3—(4-(3,4—difluoro(trifluoromethyl) phenyl)piperidine-l—carbonyl)-1,4,5,7~tetrahydr0v6H>pyrazolo[3,4-c] pyridinecarbonitrile as a white solid (36 mg, 83%): mp 0 °C; 1H NMR (500 MHz, DMSO—d6) 6 13.26 (br s, 0.25H), 12.97 (br s, 0.75H), 7.78—7.75 (m, 1H), .49 (m, 1H), 4.85 (apparent d, J z 8.0 Hz, 1H), 4.68—4.66 (m, 1H), 4.47—4.40 (m, 2H), 3.43-3.40 (m, 2H), 3.16— 3.14 (m, 2H), 2.77—2.72 (m, 3H), 1.77-1.71 (m, 4H); ESI MS m/z 440 [M + H]+.

Example 59: Preparation of 1—(3-(4—(3,4-Difluoro(trifluoromethyl) phenyl)piperidine—l-carbonyl)-1,4,5,7-tetrahydro—6Hprrazolo[3,4- c]pyridinyl)~2-methylpropanone (121) Step A: ing general ure GP—El, (4—(3,4-difluoro—2— (trifluoromethyl) phenyl) piperidin-l—yl) (4,5,6,7—tetrahydro-1H— pyrazolo [3,4mc]pyridin—3—yl)methanone TFA salt (34) and isobutyryl chloride were converted to 1-(3—(4—(3,4-difluoro~2—(trifluoromethyl) phenyl)piperidineal—carbonyl)—l,4,5,7—tetrahydro-6prrazolo[3,4*c] pyridin~6-yl)—2—methylpropan—1—one as a white solid (29 mg, 62%): mp 228—229 °C; 1H NMR (500 MHz, DMSO—dd 5 13.12 (br s, , 12.87 (br s, 0.75H), 7.79—7.70 (m, 1H), 7.50*7.48 (m, 1H), 4.88~4.86 (m, 1H), 4.68—4.56 (m, 3H), 3.70 (s, 2H), 3.15—3.13 (m, 2H), 2.99—2.97 (m, 1H), 2.79—2.77 (m, 1H), 2.70—2.64 (m, 2H), 1.76— 1.68 (m, 4H), 1.04-1.01 (m, 6H); ESI MS m/z 485 [M + H]+.

Example 60: Preparation of 1-(3-(4-(3,4-Dif1uoro—2—(trifluoromethyl) ) piperidine-l—carbonyl)—1,4,5,7-tetrahydro-6Hkpyrazolo[3,4- c]pyridin-G-yl)propan-l-one (122) Step A: Following general procedure GP-El, (4—(3,4—difluoro—2— (trifluoromethyl) phenyl) piperidin~1~yl) (4,5,6,7—tetrahydro—1H— pyrazolo [3,4—c]pyridin—3—yl)methanone TFA salt (34) and nyl chloride were converted to l—(3—(4—(3,4—difluor0m2— (trifluoromethyl)phenyl)piperidine—l—carbonyl)—1,4,5,7—tetrahydro— 6prrazolo[3,4—c]pyridin—6—yl)propan—1~one as a white solid (35 mg, 63%): mp 182—187 °C; HiNMR (500 MHz, DMSO—dd 513.15—13.1O (m, 0.25H), 12.87 (br s, 0.75H), 7.76—7.72 (m, 1H), 7.51—7.49 (m, 1H), 4.85—4.83 (m, 1H), 4.68—4.57 (m, 3H), 3.69 (s, 0.5H), 3.63 (s, 1.5H), 3.15~3.13 (m, 2H), 2.79—2.77 (m, 1H), 2.68—2.55 (m, 2H, partially merged with DMSO peak), .38 (m, 2H), 1.76—1.71 (m, 4H), 1.02 (t, J = 7.5 Hz, 3H); ESI MS m/z 471 [M + H]+.

Example 61: Preparation of 1—(3-(4—(3,4-Difluoro-2— (trifluoromethyl)phenyl)piperidine-l—carbonyl)-1,4,5,7-tetrahydro- 6Hprrazolo[3,4—c]pyridin-6—yl)~3-methylbutanone (123) Step A: Following general ure GP—El, (4~(3,4~dif1uoro—2- (trifluoromethyl) phenyl) piperidin-1~y1) (4,5,6,7-tetrahydro—1H- pyrazolo[3,4*c]pyridin—3—y1)methanone TFA salt (34) and 3— methylbutanoyl chloride were converted to 1—(3—(4-(3,4-dif1uoro—2— (trifluoromethy1)pheny1)piperidine—l-carbonyl)—1,4,5,7—tetrahydro— 6prrazolo[3,4-c]pyridin—6—y1)~3~methy1butan~1~one as ea white solid (37 mg, 63%): mp 8 °C; 1H NMR (500 MHz, DMSO—de) 5 13.11 (m, 0.25H), 12.87—12.84 (m, 0.75H), 7.79—7.70 (m, 1H), 7.51—7.49 (m, 1H), 4.89—4.86 (m, 1H), 4.67~4.57 (m, 3H), 3.67—3.64 (m, 2H), 3.15— 3.13 (m, 2H), 2.79~2.77 (m, 1H), .64 (m, 2H), 2.55-2.51 (m, 1H, partially merged with DMSO peak), 2.02 (pent, J = 7.0 Hz, 1H), 1.76~ 1.70 (m, 4H), 1.26 (t, J = 7.0 Hz, 1H), 0.92—0.90 (m, 6H); ESI MS m/z 499 [M + H]+.

Example 62: Preparation of (4—(3,4—Difluoro(trifluoromethyl) phenyl)piperidinyl)(6-(2-methoxyethyl)—4,5,6,7-tetrahydro-1H— 2O pyrazolo[3,4—c]pyridinyl)methanone (124) Step A: Following general procedure GP—GZ, (4—(3,4—dif1uoro—2— (trifluoromethyl) phenyl) din—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4~c]pyridin~3~y1)methanone TFA salt (34) and 1—bromo-2— methoxyethane were ted to (4—(3,4—dif1uoro—2-(trifluoromethyl) pheny1)piperidin—1—y1) (6-(2~methoxyethy1) —4,5,6,7—tetrahydro—1H— pyrazolo[3,4—0]pyridin—3—y1)methanone as a white solid (33 mg, 48%): mp 171—173 °C; 1H NMR (500 MHz, DMSO—d@ 8 12.91 (br s, 0.25H), 12.71 (br s, 0.75H), 7.78—7.70 (m, 1H), 7.51—7.48 (m, 1H), 4.85 (apparent d, J = 11.0 Hz, 1H), 4.66 (apparent d, J = 11.0 Hz, 1H), 3.57~3.49 (m, 4H), 3.25 (s, 3H), 3.16—3.11 (m, 2H), 2.77— 2.58 (m, 7H), 1.76— 1.68 (m, 4H); ESI MS m/z 473 [M + H]+.

Example 63: Preparation of (4-(3,4-Difluoro—2-(trifluoromethyl) phenyl)piperidin-1—yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7—tetrahydro- 1H¥pyrazolo[3,4-c]pyridin—B-yl)methanone (125) Step A: Following general procedure GP—G2, (4~(3,4-difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl) ,7—tetrahydro~1H— pyrazolo [3,4-c]pyridin—3~yl)methanone TFA salt (34) and 2,2,2— trifluoroethyl trifluoromethanesulfonate were converted to (4-(3,4- difluoro—2~(trifluoromethyl) phenyl) piperidin—l-yl) (6-(2,2,2— trifluoroethyl)—4,5,6,7—tetrahydro—1H—pyrazolo[3,4—c]pyridin—3—yl) methanone as an te solid (39 mg, 72%): mp 192—193 °C; 1H NMR (500 MHz, DMSO-dw 5 13.00 (br s, 0.25H), 12.76 (br s, 0.75H), 7.80* 7.70 (m, 1H), 7.50~7.48 (m, 1H), 4.85 (apparent d, J = 11.0 Hz, 1H), 4.66 (apparent d, J = 11.0 Hz, 1H), 3.79 (s, 1.5H), 3.75 (s, 0.5H), 3.42—3.35 (m, 2H), 3.15—3.13 (m, 2H), 2.87 (t, J'= 6.0 Hz, 2H), 2.78— 2.76 (m, 1H), 2.64—2.62 (m, 2H), 1.79—1.68 (m, 4H); ESI MS m/z 497 [M + H]+.

Example 64: ation of (4—(3,4—Difluoro-2(trifluoromethyl)phenyl) piperidin-l-yl) (6-neopentyl-4,5,6,7-tetrahydro-1H—pyrazolo[3,4-c] n—3—yl)methanone (126) Step A: Following general procedure GP—Gl, (4—(3,4—difluoro—2— uoromethyl)phenyl)piperidin—1—yl)(4,5,6,7~tetrahydro-1H— pyrazolo[3,4«c]pyridine3-yl)methanone TFA salt (34) and pivalaldehyde were converted to (4—(3,4-difluoro~2~(trifluoromethy1)phenyl) piperidin-l—yl)(6—neopenty1~4,5,6,7—tetrahydro—1H—pyrazolo[3,4— c]pyridin—3—yl)methanone as a white solid (28 mg, 49%): mp 218-220 °C; 1H NMR (500 MHz, w 512.90 (br s, 0.25H), 12.67 (br s, 0.75H), 7.75~7.70 (m, 1H), 7.49 (dd, J = 8.0, 4.0 Hz, 1H), 4.88 (apparent d, J = 12.0 Hz, 1H), 4.67 (apparent d, J = 10.0 Hz, 1H), 3.61 (s, 1.5H), 3.59 (s, 0.5H), 3.15—3.13 (m, 2H), 2.78—2.76 (m, 1H), 2.71 (t, J = 5.5 Hz, 2H), 2.64—2.58 (m, 2H), 2.25 (s, 2H), 1.79—1.68 (m, 4H), 0.88 (s, 9H); ESI MS m/z 485 [M + H]+.

Example 65: Preparation of (4-(3,5—Difluoro—2—(trifluoromethyl) phenyl)piperidin—1-yl)(5—(2*methoxyethyl)-4,5,6,7-tetrahydro—1H— pyrazolo[4,3-c]pyridinyl)methanone (127) Step A: Following l procedure GP~G2, (4~(3,5-difluoro—2- (trifluoromethyl) phenyl)piperidin—1~yl)(4,5,6,7-tetrahydro-1H— pyrazolo[3,4—c]pyridin—3~y1) methanone hydrochloride (60) and bromoethylmethyl ether were converted to (4—(3,5—difluoro—2— (trifluoromethyl)phenyl)piperidinyl)(5—(2—methoxyethyl)—4,5,6,7— ydro-lH—pyrazolo[4,3-c]pyridin—3—yl)methanone as a white solid (32 mg, 41%): 1H NMR (500 MHz, e) 6 12.85 (m, 1H), 7.48 (m, 2H), .12 (m, 1H), 4.67 (m, 1H), 3.50 (m, 4H), 3.01-3.32 (m, 5H), 2.73 (m, 7H), 3.63—3.50 (m, 2H), 1.62 (m, 4H); ESI MS m/z 473 [M + H]*.

Example 66: ation of (4-(3,4-Difluoro(trifluoromethyl) phenyl)piperidin—1—yl)(5-(piperidine-l-carbonyl)-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol—3-yl)methanone (128) Step A: Following general procedure GP—HZ, (4-(3,4—difluoro—2— (trifluoromethyl)phenyl) piperidin—l—yl)(1,4,5,6—tetrahydropyrrolo [3,4—c]pyrazol—3—yl)methanone (38) and piperidine—l-carbonyl chloride were converted to (4—(3,4—difluoro—2—(trifluoromethyl) phenyl) piperidin—l—yl) (5-(piperidine—l—carbonyl)v1,4,5,6—tetrahydropyrrolo ]pyrazol—3-yl)methanone as a white solid (45 mg, 77%): mp 236— 237 0C; 1H NMR (500 MHz, DMSO—de) 6 13.26 (br s, O.6H), 13.06 (br s, 0.4H), 7.79—7.70 (m, 1H), 7.56—7.50 (m, 1H), 5.25~5.23 (m, 0.4H), 4.65—4.62 (m, O.6H), 4.57 (s, 2H), 4.47 (s, 2H), 4.17—3.91 (m, 1H), 3.26—3.03 (m, 6H), 3.01—2.73 (m, 1H), 1.80~1.71 (m, 4H), 1.53—1.49 (m, 6H); ESI MS m/z 512 [M + H]+.

Example 67: Preparation of (4—(3,5—Difluoro(trifluoromethyl) phenyl)piperidin—1-yl)(5-(3,3,3-trifluoropropyl)~4,5,6,7—tetrahydro— 1H—pyrazolo[4,3-c]pyridin—3~yl)methanone (129) Step A: Following general procedure GP—GZ, (4—(3,5—difluor0*2- (trifluoromethyl)phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro~1H— pyrazolo[3,4—c]pyridin~3~yl)methanone hloride (60) and 3— 3O bromo—l,1,1—trifluoropropane were converted to (4—(3,5—difluoro-2— (trifluoromethyl)phenyl)piperidin—l—yl)(5-(2—methoxyethyl)—4,5,6,7- tetrahydro-1H~pyrazolo[4,3—c]pyridin—3~yl)methanone as a white solid (41 mg, 51%): 1H NMR (500 MHz, DMSO—de) 6 12.83 (m, 1H), 7.43 (m, 2H), .12 (m, 1H), 4.67 (m, 1H), 3.53 (m, 2H), 2.50~3.12 (m, 11H), 1.68 (m, 4H); ESI MS m/z 511 [M + H]+.

Example 68: Preparation of Methyl 3,5-difluoro (trifluoromethyl) phenyl)piperidine-l-carbonyl)-1,4,5,7-tetrahydro- 6H>pyrazolo[3,4—c]pyridine-G-carboxylate (130) Step A: Following l procedure GP—E2, (4—(3,5—bis (trifluoromethyl) phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridine3—yl)methanone hydrochloride (52) and methyl carbonochloridate were converted to methyl 3—(4—(3,5—difluoro—2— (trifluoromethyl) phenyl) piperidine—l—carbonyl)—1,4,5,7—tetrahydro- 6H—pyrazolo[3,4—c]pyridine—6—carboxy1ate as an ite solid (7 mg, 20%): mp 253—254 °C; 1H NMR (500 MHz, DMSO-de) 6 13.12 (br s, 0.25H), 12.86 (br s, , 7.45~7.38 (m, 2H), 4.84~4.82 (m, 1H), 4.68~4.66 (m, 1H), 4.54-4.51 (m, 2H), 3.64 (s, 3H), 3.60-3.58 (m, 2H), 3.20~ 3.13 (m, 2H), 2.79—2.77 (m, 1H), 2.65~2.62 (m, 2H), .72 (m, 4H); ESI MS m/z 473 [M + H]+.

Example 69: 1-(3—(4-(3,5—Difluoro—2-(trifluoromethyl) phenyl) piperidine—l-carbonyl)-4,5—dihydro—1H—pyrazolo[3,4-c]pyridin-6(7H)— yl)ethanone (131) Step A: Following general procedure GP-El, (4—(3,5- bis(trifluoromethyl)pheny1)piperidin~1~y1)(4,5,6,7-tetrahydro—1H— pyrazolo[3,4—c]pyridin—3—y1)methanone hydrochloride (52) and acetyl chloride were converted to 1—(3—(4—(3,5—dif1uoro—2—(trifluoromethyl) phenyl)piperidine—l—carbonyl)—4,5-dihydro—1H—pyrazolo[3,4—c]pyridin— yl)ethanone as a white solid (0.087 g, 41%): 1H NMR (300 MHz, CDC13) 811.01 (hr, 1H), 6.93 (m, 1H), 6.78 (m, 1H), 4.84—4.66 (m, 4H), 3.85~3.67 (m, 2H), 3.34~2.68 (m, 5H), 2.22 and 2.19 (s, 3H), 1.89— 1.66 (m, 4H); MS (ESI+) m/z 457 [M+H]+.77 (m, 1H), 2.65~2.62 (m, 2H), 1.76—1.72 (m, 4H); ESI MS m/z 473 [M + H]+.

Example 70: 3-(4—(3,5-Difluoro-2—(trifluoromethyl)phenyl)piperidine— 1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-G-carbonitrile (132) Step A: To a solution of tert~buty1 4—(3,5—dif1uoro~2— (trifluoromethyl)phenyl)piperidine—1~carboxy1ate (0.246 g, 0.675 mmol) in dichloromethane (5 mL) was added HCl (2 M in ether, 10 mL).

The mixture was stirred for 6 h and evaporated to afford a solid that was dissolved in DMF (4 mL). In a separate flask, to a solution of ethyl 6-bromo—[1,2,4]triazolo[4,3—a]pyridine—3—carboxylate (0.182 g, 0.675 mmol) in THF (5 mL) was added a solution of m hydroxide hydrate (0.028 g, 0.675 mmol) in water (2 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to pH 6 and evaporated to dryness.

To this residue were added benzotriazole-1—yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (0.448 g, 1.01 mmol), N,N~ diisopropylethylamine (0.349 g, 2.70 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was ted with ethyl acetate and the organic layer was washed with brine for three times, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting e was chromatographed over silica gel (0—60% EtOAc in hexanes) to give (6—bromo-[1,2,4]triazolo[4,3- a]pyridin—3—yl)(4~(3,5~difluoro—2—(trifluoromethyl)phenyl)piperidin— 1-yl)methanone as an off—white solid (0.115 g, 34%): 1H NMR (300 MHz, CDC13) 59.37 (m, 1H), 7.79 (dd, J = 9.6, 0.9 Hz, 1H), 7.50 (dd, J = 9.6, 1.7 Hz, 1H), 6.96 (d, J = 9.7 Hz, 1H), 6.84—6.77 (m, 1H), 5.77— .72 (m, 1H), 5.00— 4.95 (m, 1H), 3.44—3.29 (m, 2H), 3.01—2.92 (m, 1H), 2.01—1.69 (m, 4H); MS (ESI+) m/z 489 [M+H]+.

Step B: A e of (6-bromo—[1,2,4]triazolo[4,3—a]pyridin—3—yl)(4— (3,5~difluoro—2~(trifluoromethyl)phenyl)piperidin~1~yl) methanone (0.115 g, 0.235 mmol), zinc cyanide (0.055 g, 0.470 mmol), tetrakis(triphenylphosphine)palladium (0.027 g, 0.0235 mmol), and DMF (4 mL) was heated under ave irradiation at 130 °C for 30 min.

After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL). The extract was washed with brine (2 x 80 mL), dried (Nazson, ed, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-50% EtOAc in hexanes) to give 3—(4*(3,5-difluoro—2~ (trifluoromethyl)phenyl)piperidine—l~carbonyl)—[1,2,4]triazolo[4,3— a]pyridine-6— carbonitrile as a white solid (0.050 g, 49%): 1H NMR (300 MHZ, CDC13) 59.71 (m, 1H), 7.98 (dd, J = 9.5, 1.0 Hz, 1H), 7.51 (dd, J = 9.5, 1.6 Hz, 1H), 6.95 (d, J = 9.5 Hz, 1H), 6.84‘6.77 (m, 1H), 5.76 (m, 1H), 5.01-4.96 (m, 1H), 3.46~3.31 (m, 2H), .94 (m, 1H), 2.07~1.70 (m, 4H); MS (ESI+) m/Z 436 [M+H]+.

Example 71: Preparation of (4—(3,5—dif1uoro—2-(trifluoromethyl) phenyl)piperidinyl)(5-ethyl~4,5,6,7-tetrahydro—1H—pyrazolo[4,3— c]pyridinyl)methanone (133) Step A: Following general procedure GP-Gl, (4—(3,5~bis (trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (52) and acetaldehyde were converted to (4—(3,5-difluoro—2—(trifluoromethyl) pheny1)piperidin—1—yl)(5—ethy1—4,5,6,7-tetrahydro—1H—pyrazolo[4,3— c]pyridin—3—yl)methanone as a white solid (29 mg, 67%): mp 149 — 155 °C; 1H NMR (500 MHz, DMSO—de) 5 12.766 (s, 1H), 7.481—7.353 (m, 1H), .049 (m, 1H), 4.765a4.569 (m, 1H), 3.558—3.378 (m, 2H), 3.263— 3.048 (m, 2H), 2.850—2.715 (m, 1H), 2.664 (s, 4H), 2.575—2.515 (m, 2H), 1.858~1.606 (br s, 4H), 1.121 — 1.018 (m, 4H); ESI MS m/z 443.2 [M + H]+.

Example 72: Preparation of (5—(cyclopropylmethyl)—4,5,6,7-tetrahydro— 1H-pyrazolo[4,3-c]pyridin-3—yl)(4-(3,5—difluoro—2-(trifluoromethyl) phenyl)piperidin—1—yl)methanone (134) Step A: Following general procedure GP—Gl, (4—(3,5—bis (trifluoromethyl) phenyl) piperidin—l-yl) (4,5,6,7—tetrahydro—1H— lo [3,4—c]pyridin—3—yl)methanone hydrochloride (52) and cyclopropyl acetaldehyde were converted to (5—(cyclopropylmethyl)w 7—tetrahydro—1H—pyrazolo[4,3-c] pyridin—3—yl) 5- difluoro— 2—(trifluoromethyl)phenyl)piperidin~1—yl)methanone as a white solid (29 mg, 67%): No clear melt observed; 1H NMR (500 MHz, DMSO—da 5 12.764 (s, 1H), 7.522—7.347 (m, 2H), 5.016 (br s, 1H), 4.766—4.580 (br s, 1H), 3.673~3.444 (m, 2H), 3.258—3.034 (m, 2H), 2.868—2.601 (m, 5H), 2.443~2.334 (m, 2H), 1.858—1.620 (br s, 4H), 0.995- 0.829 (m, 1H), 0.551 — 0.410 (m, 2H), 0.195 - 0.075 (m, 2H); ESI MS m/z 469.1 [M + H]+.

Example 73: Preparation of (4—(3,5—dif1uoro(trifluoromethyl) phenyl)piperidin-1—yl)(5—(oxetanyl)-4,5,6,7-tetrahydro-1H- lo[4,3-c]pyridinyl)methanone (135) Step A: Following general procedure GP—Gl, (4-(3,5— bis(trifluoromethyl)phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro~1H— pyrazolo[3,4—c]pyridin-3~yl)methanone hydrochloride (52) and 3— oxetanone were converted to (4-(3,5—difluoro—2~(trifluoromethyl) phenyl)piperidin-1—yl)(5—(oxetan—3~yl)-4,5,6,7—tetrahydro—1H— pyrazolo[4,3~c]pyridin—3—yl)methanone as a white solid (35 mg, 67%): No clear melt observed; 1H NMR (300 MHz, DMSO-de) 5 12.843 (s, 1H), 7.483~7.346 (m, 1H), 5.234—5.065 (br s, 1H), 4.731~4.627 (br s, 1H), 4.627 — 4.562 (m, 2H), 4.562—4.452 (m, 2H), 3.714—3.643 (m, 1H), 3_473-3_337 (br s, 2H), 3.260—3.058 (m, 2H), 2.724 (m, 1H), 2.724 ~ 2.658 (m, 2H), 2.582 — 2.516 (m, 2H), 1.876 — 1.586 (br s, 4H); ESI MS m/z 471 [M + H]+. e 74: Preparation of 3—(4~(3,5-difluoro—2-(trifluoromethyl) phenyl)piperidine-l—carbonyl)-6,7-dihydro-1H-pyrazolo[4,3- c]pyridine~5(4H)—carbonitrile (136) Step A: Following general procedure GP—G2, (4—(3,5— bis(trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro-1H— lo[3,4—c]pyridin—3—yl)methanone hydrochloride (52) and cyanogen bromide were converted to 3—(4—(3,5—difluoro~2—(trifluoromethyl) phenyl) dine—l-carbonyl) —6,7—dihydro—1H—pyrazolo[4,3—c] pyridine—5(4H)—carbonitrile as a white solid (16 mg, 55%): No clear melt observed; 1H NMR (500 MHz, DMSO—dm 5 13.146—13.060 (m, 1H), 7.508—7.356 (m, 2H), 5.402— 4.584 (m, 2H), 4.433-4.327 (m, 2H), 3.536— 3.412 (m, 2H), 3.092 (m, 2H), 2.905~2.728 (m, 3H), 1.884—1.608 (m, 4H); ESI MS m/z 440 [M + H]+.

Example 75: Preparation of (4-(3,5-difluoro-2—(trifluoromethyl) phenyl)piperidinyl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro— lH-pyrazolo[4,3-c]pyridin-3—yl)methanone (137) Step A: Following general procedure GP-G2, (4—(3,5—bis (trifluoromethyl) phenyl)piperidin—1—yl)(4,5,6,7—tetrahydro—1H— pyrazolo [3,4-c]pyridin—3—yl)methanone hydrochloride (52) and 2,2,2— trifluoroethyl trifluoromethanesulfonate were converted to (4-(3,5— difluoro-2—(trifluoromethyl) phenyl) piperidin—l-yl) (5—(2,2,2— trifluoroethyl)—4,5,6,7—tetrahydro—lH—pyrazolo[4,3—c]pyridin—3—yl) methanone as a white solid (16 mg, 55%): No clear melt observed; 1H NMR (500 MHz, DMSO’de) 6 l3.033—l2.768 (m, 1H), 7.506—7.333 (m, 2H), .290—4.578 (m, 2H), 3.894~3.657 (m, 2H), 3.447—3.32O (m, 2H), 3.256— 3.037 (m, 2H), 2.937 (s, 2H),2.709 (s, 3H), l.605 (br s, 4H); ESI MS m/z 497 [M + H]+.

Example 76: Preparation of Methyl 3—(4—(3,5-difluoro—2—(trifluoro- methyl)phenyl)piperidine—l—carbonyl)-6,7—dihydro—1H-pyrazolo[4,3—c] ne-5(4H)-carboxylate (138) Step A: Following general procedure GP—B2, (4-(3,5—difluoro—2— (trifluoromethyl) phenyl) piperidin—l—yl)(4,5,6,7—tetrahydro—lH~ pyrazolo[3,4-c]pyridin—3—yl)methanone hydrochloride (60) and methyl formate were converted to methyl 3—(4—(3,5—difluoro—2- (trifluoromethyl) phenyl) piperidine-l-carbonyl)-6,7-dihydro—lH— pyrazolo[4,3—c]pyridine—5(4H)~carboxylate as a white solid (16 mg, 55%): 1H NMR (300 MHz, DMSO-de) 6 12.93 (m, 1H), 7.56—7.32 (m, 2H), 5.40—5.16 (m, 1H), .59 (m, 1H), 4.59—4.40 (m, 2H), 3.64 (s, 5H), 3.28—3.03 (br s, 2H), 2.89—2.62 (m, 3H), 1.94—1.61 (br s, 4H); ESI MS m/z 472 [M + H]*.

Example 77: Preparation of 3-(4-(3,5-difluoro—2—(trifluoromethyl) phenyl)piperidine—l-carbonyl)-N~methyl-6,7—dihydro—1H-pyrazolo[4,3— c]pyridine-5(4H)-carboxamide (139) Step A: Following general procedure GP-E2, (4—(3,5-bis (trifluoromethyl) phenyl)piperidin-l—yl)(4,5,6,7~tetrahydro~lH- 3O pyrazolo[3,4~c]pyridin—3—yl)methanone hydrochloride (52) and methyl isocyanate were converted to 3,5—difluoro—2~(trifluoromethyl) ) piperidine—l-carbonyl)~N-methyl—6,7—dihydro—1prrazolo[4,3~ c] pyridine—5(4H)—carboxamide as a white solid (16 mg, 55%): No clearmelt; 1H NMR (500 MHz, DMSO—de) 5 13.043—12.777 (m, 1H), 7.523— 7.348 (m, 2H), 6.536 (s, 1H), 5.275—4.595 (m, 2H), 4.536—4.296 (m, 2H), 3.561 (S, 2H), 3.076 (m, 2H), 2.891—2.706 (br s, 1H), 2.706—2.614 (m, 2H), 2.576 (s, 3H), 1.906— 1.585 (m, 4H); ESI MS m/z 472 [M + H]+.

Example 78: Preparation of 4-(5-f1uoro(trifluoromethyl) phenyl)piperidine-l-carbonyl)-4,5-dihydro-1H>pyrazolo[3,4-c]pyridin- 6(7H)—y1)ethanone (140) Step A: Following general procedure GP—El, fluoro—2— (trifluoromethyl) phenyl) piperidin—l-yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3—yl)methanone hydrochloride (44) and acetyl chloride were converted to 1—(3—(4—(5—fluoro—2—(trifluoromethyl) phenyl) dine—l—carbonyl)—4,5—dihydro—1H—pyrazolo[3,4—c] pyridine —6(7H)—y1)ethanone as a white solid (27 mg, 41%): mp 190—195 °C; 1H NMR (500 MHz, DMSO—dw 6 13.17—12.85 (m, 1H), 7.79—7.73 (m, 1H), 7.57—7.52 (m, 1H), 7.30—7.22 (m, 1H), 4.94—4.77 (m, 1H), 4.74— 4.63 (m, 1H), 4.62—4.51 (m, 2H), 3.73—3.56 (m, 2H), 3.19—3.06 (m, 2H), 2.83—2.53 (m, 3H), 2.14—2.05 (m, 3H), 1.80—1.64 (m, 4H); ESI MS m/z 439 [M + H]+. 2O e 79: Preparation of (4-(5-f1uoro-2—(trifluoromethy1)pheny1) piperidin—l-yl)(5-(methylsulfonyl)-4,5,6,7—tetrahydro-1H- pyrazolo[4,3-c]pyridin—3—y1)methanone (141) Step A: Following general procedure GP—C, (4—(5—f1uoro—2— (trifluoromethyl) pheny1)piperidin—1—y1)(4,5,6,7—tetrahydro—1H— lo[4,3—c]pyridin—3—y1)methanone hydrochloride (46) and methane sulfonyl chloride were converted to (4—(5—f1uoro—2— (trifluoromethy1)pheny1)piperidin—l—yl)(5—(methylsulfony1)—4,5,6,7— tetrahydro—lH—pyrazolo[4,3—c]pyridin—3—y1)methanone as a white solid (105 mg, 60%): mp > 260 °C; 1H NMR (500 MHz, DMSO—dm 5 13.03 (s, 1H), 7.76 (dd, J'= 9.0, 6.0 Hz, 1H), 7.55 (dd, J'= 10.5, 2.5 Hz, 1H), 7.28— 7.21 (m, 1H), 5.34—5.23 (m, 1H), 4.72—4.64 (m, 1H), 4.43—4.26 (m, 2H), 3.54—3.39 (m, 2H), 3.22—3.09 (m, 2H), 2.94 (s, 3H), 2.86—2.72 (m, 3H), 1.83—1.67 (m, 4H); ESI MS m/z 475 [M + H]+.

Example 80: Preparation of 3—(4—(5—fluoro—2—(trifluoromethyl) phenyl)piperidine-l—carbonyl)—[1,2,4]triazolo[4,3-a]pyridine—6- carbonitrile (142) Step A: To a solution of ethyl 6—brom0*[1,2,4]triazolo[4,3—a]pyridine— 3—carboxylate (85 mg, 0.32 mmol) in THE (2.6 mL) was added a solution of LiOH monohydrate (15 mg, 0.35 mmol) in H20 (1.8 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.0 mL) under an here of N2. To this mixture was added 4—(5-fluoro—2—trifluoromethyl)phenylpiperidine hydrochloride (11, 89 mg, 0.32 mmol), benzotriazole—1—yl-oxy—tris—(dimethylamino)— phosphonium hexafluorophosphate (280 mg, 0.63 mmol), and diisopropylethylamine (0.17 mL, 0.95 mmol). The mixture was d at ambient temperature for 18 h. The resulting mixture was diluted with H20 (20 mL). The solution was extracted with EtOAc (3 x 20 mL).

The ed organic layers were washed with a saturated brine solution (3 x 20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 50% EtOAc in hexanes) to provide 2O to provide (6~bromo—[1,2,4]triazolo[4,3—a]pyridin—3-yl)(4~(5—fluoro~ 2-(trifluoromethyl)phenyl)piperidin—l—yl)methanone as a white solid (97 mg, 65%): 1H NMR (500 MHz, DMSO-de) 5 9.16~9.l4 (m, 1H), 7.98 (dd, J'= 10.0, 1.0 Hz, 1H), 7.77 (dd, J = 8.5, 5.5 Hz, 1H), 7.72 (dd, J = 9.5, 1.5 Hz, 1H), 7.52 (dd, J = 11.0, 3.5Hz, 1H), 7.29~7.23 (m, 1H), .24 (m, 1H), .70 (m, 1H), 3.42-3.32 (m, 1H), 3.27~3.19 (m, 1H), 3.06~2.96 (m, 1H), 1.98~1.75 (m, 4H).

Step B: A solution of (6—bromo—[1,2,4]triazolo[4,3--a]pyridin-—3——yl)(4-~ (5—fluoro—2—(trifluoromethyl)phenyl)piperidin—l—yl)methanone (97 mg, 0.21 mmol) in DMF (2.2 mL) was sparged with Ar for 20 min. Zinc cyanide (48 0.41 mmol) was added and the on sparged with Ar for 10 min. To the solution was added Pd(PPh?4 (24 mg, 0.021 mmol) and the vessel was sealed and heated to 130 °C with microwaves for 30 min.

The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4 x 30 mL). The ed c extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 50% EtOAc in hexanes) and freeze dried to give 3-(4—(5~fluoro~2-(trifluoromethyl)phenyl)piperidine~1— carbonyl)-[1,2,4]triazolo[4,3—a]pyridine—6—carbonitrile as a white solid (35 mg, 41%): mp 190—197 °C; 1H NMR (500 MHz, DMSO—de) 5 9.54~ 9.53 (m, 1H), 8.14 (dd, J = 9.5, 1.5 Hz, 1H), 7.82 (d, J = 9.5, 1.5 Hz, 1H), 7.78 (dd, J = 9.0, 6.0 Hz, 1H), 7.56 (dd, J = 10.5, 2.5 Hz, 1H), 7.30—7.24 (m, 1H), 5.20—5.10 (m, 1H), 4.73~4.71 (m, 1H), 3.43— 3.34 (m, 1H), 3.29~ 3.20 (m, 1H), .00 (m, 1H), 1.99—1.77 (m, 4H); E51 M5 m/Z 418 [M + H]+.

Example 81: Preparation of 1—(3—(4-(2—chloro—5-fluorophenyl) piperidine-l-carbonyl)-4,5-dihydro-1H—pyrazolo[3,4-c]pyridin-6(7H)— yl)ethanone (143) Step A: Following general procedure GP—El, ((4*(2—chloro—5— phenyl)piperidin~1—yl)(4,5,6,7—tetrahydro—1H—pyrazolo[3,4—c] pyridinyl)methanone hydrochloride (48) and acetyl chloride were converted to l—(3—(4—(2—chloro—5—fluorophenyl)piperidine-l~carbonyl) —4,5—dihydro~lH—pyrazolo[3,4—c]pyridin—6(7H)-yl)ethanone as a. white 2O solid (27 mg, 63%): 1H NMR (500 MHz, DMSO—de) 5 13.99—12.18 (m, 1H), 7.48 (dd, J = 9.0, 5.5 Hz, 1H), 7.72 (dd, J = 10.5, 3.5 Hz, 1H), 7.15— 7.08 (m, 1H), 4.90~4.74 (m, 1H), 4.73- 4.53 (m, 3H), 3.71—3.55 (m, 2H), 3.28—3.10 (m, 2H), 2.87—2.50 (m, 3H, overlaps with solvent), .04 (m, 3H), 1.91—1.71 (m, 2H), .52 (m, 2H); ESI MS m/z 405 [M + H]+.

Example 82: Preparation of (4—(2—chloro-5—fluorophenyl)piperidin-l- yl)(5~(methylsulfonyl)—4,5,6,7—tetrahydro-1H—pyrazolo[4,3-c]pyridin- 3-yl)methanone (144) 3O Step A: Following general ure GP—C, (4-(2-chloro—5~ fluorophenyl)piperidin~l—yl)(4,5,6,7—tetrahydro—lHepyrazolo[4,3— c]pyridin~3~yl)methanone hydrochloride (50) and methane sulfonyl chloride were converted to (4—(2—chloro-5‘fluorophenyl)piperidin—l— yl)(5-(methylsulfonyl)—4,5,6,7—tetrahydro—lH—pyrazolo[4,3—c]pyridin— 3~yl)methanone as a white solid (36 mg, 51%): mp 260~267 °C; 1H NMR WO 68286 2015/028293 (500 MHz, DMSO-de) 5 13.03 (s, 1H), 7.48 (dd, J = 8.5, 5.0 Hz, 1H), 7.28 (dd, J'= 10.5, 3.5 Hz, 1H), 7.13—7.08 (m, 1H), 5.30-5.20 (m, 1H), 4.72—4.63 (m, 1H), 4.41~4.24 (m, 2H), 3.53-3.40 (m, 2H), 3.28-3.13 (m, 2H), 2.93 (S, 3H), 2.89—2.73 (m, 3H), 1.90~1.74 (m, 2H), 1.70- 1.51 (m, 2H); ESI MS m/z 441 [M + H]+. e 83: Preparation of 3-(4-(2—Chlorofluorophenyl)piperidinel-carbonyl )—[1,2,4]triazolo[4,3-a]pyridine-G—carbonitrile (145) Step A: To a solution of ethyl 6~bromo~[1,2,4]triazolo[4,3—a]pyridine~ 3—carboxylate (73 mg, 0.27 mmol) in THE (2.2 mL) was added a solution of LiOH monohydrate (13 mg, 0.30 mmol) in H20 (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.9 mL) under an atmosphere of N2. To this mixture was added 4—(2—chloro-5—fluorophenyl)piperidine hydrochloride (17, 68 mg, 0.27 mmol), benzotriazole—l~yl—oxy—tris—(dimethylamino)—phosphonium hexafluorophosphate (240 mg, 0.54 mmol), and diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H20 (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were tographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo— [1,2,4]triazolo[4,3—a]pyridin—3—yl)(4—(2—chloro—5—fluorophenyl) piperidin—l—yl)methanone as a white solid (50 mg, 42%): 1H NMR (500 MHz, e) 5 9.13—9.11 (m, 1H), 7.98 (dd, J = 9.5, 1.0 Hz, 1H), 7.71 (dd, J = 9.5, 1.5 Hz, 1H), 7.50 (dd, J = 9.0, 5.5 Hz, 1H), 7.28 (dd, J = 25, 3.0 Hz, 1H), 7.15—7.10 (m, 1H), 5.28~5.20 (m, 1H), 4.76— 4.70 (m, 1H), 3.42—3.29 (m, 2H, overlaps with H20), 3.07~2.98 (m, 1H), 1.96—1.65 (m, 4H).

Step B: A solution of (6-bromo—[1,2,4]triazolo[4,3—a]pyridin-3~yl)(4~ (2~chloro—5-fluorophenyl)piperidin—l—yl)methanone (50 mg, 0.21 mmol) in DMF (2.0 mL) zinc cyanide (48 mg, 0.41 mmol) was d with Ar for 20 min. To the solution was added Pd(PPh?4 (13 mg, 0.011 mmol) and the vessel was sealed and heated to 130 °C with microwaves for 30 min. The e was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4 x 30 mL). The combined c extracts were concentrated to dryness under d pressure.

The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) and freeze dried to give 2—chlorofluorophenyl)piperidine—l- carbonyl)-[1,2,4]triazolo[4,3-a]pyridine—6—carbonitrile as a white solid (21 mg, 54%): mp 211-214 °C; 1H NMR (500 MHz, DMSO-ds) 8 9.52— 9.50 (m, 1H), 8.13 (dd, J = 9.5, 1.0 Hz, 1H), 7.81 (dd, J = 9.5, 1.5 Hz, 1H), 7.50 (dd, J = 9.0, 5.5 Hz, 1H), 7.28 (dd, J = 10.5, 3.5 Hz, 1H), 7.16—7.11 (m, 1H), 5.16—5.11 (m, 1H), 4.78—4.71 (m, 1H), 3.46— 3.30 (m, 2H, overlaps with H20), 3.11—3.01 (m, 1H), 1.99—1.70 (m, 4H); ESI MS m/z 384 [M + H]+.

Example 84: Preparation of (4-(2-chloro-3—(fluorophenyl)piperidin—l— yl)(6-cyclopropylmethyl)-4,5,6,7-tetrhydro-1Hprrazolo[3,4- c]pyridineyl)methanone (146) Step A: Following general procedure GP—G2, (4—(2—chloro—3- fluorophenyl)piperidin~1~yl) (4,5,6,7—tetrahydro—1Hepyrazolo[4,3— 2O c]pyridin—3—yl)methanone hydrochloride (40) and cyclopropane carbaldehyde were converted to (4—(2—chloro—3-(fluorophenyl) piperidine—l—yl)(6—cyclopropylmethyl)—4,5,6,7—tetrhydro~1H>pyrazolo [3,4—c]pyridine—3—yl)methanone as a white solid (21 mg, 36%): mp 187~ 191 °C; 1H NMR (300 MHz, DMSO—da 8 12.74 (br s, 1H), 7.38—7.24 (m, 3H), 4.96—4.55 (m, 2H), 3.57 (s, 2H), 3.28—3.17 (m, 2H), .38 (m, 7H), 1.91—1.79 (m, 2H), 1.64—1.56 (m, 2H), 0.92—0.85 (m, 1H), 0.52—0.48 (m, 2H), 0.16—0.08 (m, 2H); ESI MS m/z 417 [M + H]+.

Example 85: Preparation of Methyl 2—chloro—3— fluorophenyl)piperidine—l—carbonyl)-4,5-dihydro—1H—pyrazolo[3,4— c]pyridine-6(7H)—carboxylate (147) Step A: Following general procedure GP—El, (4—(2—chloro-3— fluorophenyl)piperidin-l—yl)(4,5,6,7—tetrahydro—1H~pyrazolo[4,3—c] pyridin—3—yl)methanone hydrochloride (40) and methyl chloroformate were converted to methyl 3-(4—(2—chloro-3—fluorophenyl)piperidine—l— carbonyl)—4,5-dihydro~1H?pyrazolo[3,4~c]pyridine—6(7H)-carboxylate as a white solid (30 mg, 65%): mp 182—185 °C; 1H NMR (300 MHz, DMSO— d5) 5 12.88 (br s, 1H), 7.39—7.24 (m, 3H), 4.85-4.61 (m, 2H), 4.54— 4.49 (m, 2H), 3.64~3.56 (m, 5H), 3.28—3.12 (m, 2H), 2.93—2.75 (m, 1H), 2.61-2.55 (m, 2H), 1.91-1.78 (m, 2H), 1.64—1.55 (m, 2H); ESI MS m/Z 421 [M + H]+.

Example 86: Preparation of 3-(4—(2-chloro-3—f1uoropheny1)piperidine— ony1)-4,5-dihydro-1Hprrazolo[3,4-c]pyridine—6(7H)- carbonitrile (148) Step A: Following general ure GP—G2, (4-(2—chloro fluorophenyl)piperidin—l—yl)(4,5,6,7—tetrahydro—lH—pyrazolo[4,3— c]pyridin-3—yl)methanone hydrochloride (40) and cyanogen bromide were converted to 3—(4‘(2—chloro—3—fluorophenyl)piperidine-l-carbonyl)- 4,5~dihydro-1H~pyrazolo[3,4~c]pyridine*6(7H)—carbonitrile as a white solid (19mg, 35%): mp 182~185 PC; 1H NMR (300 MHz, DMSO-de) 5 12.98 (br s, 1H), 7.37— 7.24 (m, 3H), 4.91-4.65 (m, 2H), 4.47—4.40 (m, 2H), .12 (m, 4H), 2.93~2.69 (m, 3H), .78 (m, 2H), 1.76—1.55 (m, 2H); ESI MS m/z 388 [M + H]+.

Example 87: Preparation of (4-(2—chloro—3-(fluorophenyl)piperidin-l- yl)(6—oxetan—3—y1)—4,5,6,7-tetrhydro-1?hpyrazolo[3,4-c]pyridine—3- hanone (149) Step A: Following l procedure GP-Gl, (4-(2—chloro-3~ fluorophenyl)piperidin—l-yl)(4,5,6,7—tetrahydro—lH—pyrazolo[4,3—c] pyridin-3—yl)methanone hydrochloride (40) and oxetan—3‘one were converted to (4-(2vchloro—3—(fluorophenyl)piperidine-l—yl)(6—oxetan— 3*yl)—4,5,6,7—tetrhydro—lH—pyrazolo[3,4—c]pyridineyl)methanone as a white solid (17 mg, 31%): 1H NMR (300 MHZ, DMSO—dg) 6 12.77 (br s, 1H), 7.37—7.24 (m, 3H), 4.91~4.47 (m, 6H), 3.71—3.61 (m, 1H), 3.47~ 3.12 (m, 4H), 2.93—2.78 (m, 1H), 2.74—2.53(m, 4H), 1.91—1.78 (m, 2H), 1.76—1.55 (m, 2H); ESI MS m/z 419 [M + H]+.

Example 88: ation of 1~(3-(4-(2-chlorofluorophenyl) piperidine-l-carbonyl)-4,5-dihydro-1H¥pyrazolo [3,4—c]pyridin-6(7H)~ yl)ethanone (150) Step A: Following general procedure GP—El, (4‘(2—chlor0*3- fluorophenyl)piperidin—l—yl)(4,5,6,7-tetrahydro—lH—pyrazolo[4,3—c] pyridin—3~yl)methanone hydrochloride (40) and acetyl chloride were converted to l~(3-(4—(2—chloro—3—fluorophenyl)piperidine—l—carbonyl) ihydro-lH—pyrazolo[3,4—c]pyridin—6(7H)~yl)ethanone as (a white solid (14 mg, 25%): 1H NMR (500 MHz, DMSO—dw 5 l3.18~12.83 (m, 1H), 7.41—7.31 (m, 1H), 7.30~7.22 (m, 2H), 4.87—4.74 (m, 1H), 4.73—4.63 (m, 1H), 4.62-4.53 (m, 2H), 3.71—3.58 (m, 2H), 3.31—3.24 (m, 1H, overlaps with H20), 3.20-3.12 (m, 1H), 2.90—2.76 (m, 1H), 2.74—2.52 (m, 2H), 2.11—2.07 (m, 3H), 1.89~1.72 (m, 2H), 1.65—1.52 (m, 2H); ESI MS m/z 405 [M + H]+; HPLC >99% purity (Method H). (m, 3H), 4.91—4.47 (m, 6H), 3.71—3.61 (m, 1H), .12 (m, 4H), 2.93—2.78 (m, 1H), 2.74—2.53(m, 4H), 1.9l*1.78 (m, 2H), 1.76—1.55 (m, 2H); ESI MS m/Z 419 [M + H]+.

Example 89: Preparation of (4-(2-chloro—3—fluorophenyl)piperidin-l- yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1Hepyrazolo[4,3-c]pyridin- 3-ylmethanone (151) Step A: ing general procedure GP-C, ((4—(2—chloro—3— fluorophenyl)piperidin—l—yl)(4,5,6,7—tetrahydro-1H~pyrazolo[4,3- c]pyridin—3—yl)methanone hydrochloride (40) and methanesulfonyl chloride were converted to 1—(3—(4—(2—chloro—3—fluorophenyl) piperidine—l—carbonyl)—4,5~dihydro~1H~pyrazolo[3,4«c(4-(2—chloro~3— fluorophenyl)piperidin—l—yl)(5-(methylsulfonyl)*4,5,6,7—tetrahydro— 1H—pyrazolo[4,3-c]pyridin—3—ylmethanone as a white solid (21 mg, 34%): mp 247—253 °C .; 1H NMR (500 MHZ, DMSO~dd 5 13.03 (br s, 1H), 7.39—7.31 (m, lH), 7.29—7.22 (m, 2H), 5.28—5.19 (m, 1H), 4.72—4.63 (m, 1H), 4.39—4.28 (m, 2H), 3.50—3.14 (m, 7H, overlaps with Hx?, 2.86—2.79 (m, 3H), 1.91-1.76 (m, 2H), 1.69—1.53 (m, 2H); ESI MS m/z 441 [M + H]+.

Example 90: ation of (6—bromo-[1,2,4]triazolo[4,3—a]pyridin-3— yl)(4-(2-chloro—3-fluorophenyl)piperidin—l-yl)methanone (152) Step A: To a on of ethyl 6—bromo-[1,2,4]triazolo[4,3-a]pyridine- 3—carboxylate (102 mg, 0.38 mmol) in THE (3.1 mL) was added a solution of LiOH monohydrate (16 mg, 0.38 mmol) in H20 (2.0 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained e was diluted in DMF (4.0 mL) under an atmosphere of N2. To this e was added 4—(2—chloro—3—fluorophenyl)piperidine hydrochloride (14, 94 mg, 0.38 mmol), benzotriazole-1—yl—oxy—tris—(dimethylamino)—phosphonium hexafluorophosphate (334 mg, 0.76 mmol), and diisopropylethylamine (0.20 mL, 1.1 mmol). The mixture was stirred at ambient temperature for 18 h. The ing mixture was diluted with H20 (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g p column, 0 to 50% EtOAc in hexanes) to provide (6—bromo—[1,2,4] triazolo [4,3—a]pyridin~3—yl) (4—(2—chloro—3-fluorophenyl) piperidin— 1—yl)methanone as a white solid (80 mg, 48%): 1H NMR (300 MHz, DMSO— dd 5 9.11 (br s, 1H), 8.03—7.95 (m, 1H), 7.71 (dd, J = 9.6, 1.8 Hz, 2O 1H), 7.43~7.23 (m, 3H), 5.27—5.17 (m, 1H), 4.80-4.69 (m, 1H), 3.48— 3.34 (m, 2H), 3.12" 2.96 (m, 1H), 2.02~l.59 (m, 4H); ESI MS m/z 438 [M + H]+.

Step B: A solution of (6~bromo—[1,2,4]triazolo[4,3-a]pyridin~3—yl)(4— (2—chloro—3-fluorophenyl)piperidin—l—yl)methanone (80 mg, 0.18 mmol) in DMF (2.0 mL) with zinc cyanide (43 mg, 0.65 mmol) was sparged with Ar for 20 min. To the solution was added Pd(PPh?4 (21 mg, 0.018 mmol) and the vessel was sealed and heated to 130 °C with microwaves for 30 min. The mixture was diluted with H20 (10 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g p column, 0% to 60% EtOAc in s) and freeze dried to give 3—(4-(2—chloro-3— fluorophenyl)piperidine—l—carbonyl)-[1,2,4]triazolo[4,3—a]pyridine- 6-carbonitrile as a white solid (38 mg, 55%): mp 158—163 °C; 1H NMR (500 MHz, DMSO~d6) 5 9.51—9.50 (m, 1H), 8.12 (dd, J = 9.5, 1.0 Hz, 1H), 7.81 (dd, J = 9.5, 1.5 Hz, 1H), .34 (m, 1H), 7.31—7.24 (m, 2H), 5.16—5.09 (m, 1H), 4.78—4.71 (m, 1H), 3.47—3.37 (m, 2H), 3.12~ 3.03 (m, 1H), 2.00—1.64 (m, 4H); ESI MS m/z 384 [M + H]+.

Example 91: Preparation of 1—(3-(4-(3,5—bis(trifluoromethyl) phenyl)piperidine-l-carbonyl)-4,5-dihydro—1H9pyrazolo[3,4—c]pyridin— 6(7H)—y1)ethanone (153) Step A: Following l procedure GP—El, 4~(3,5~bis (trifluoromethyl) ) piperidin-l—yl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin-3—yl)methanone hydrochloride (52) and acetyl chloride were ted to l—(3-(4—(3,5—bis(trifluoromethyl)phenyl) piperidine—l—carbonyl)—4,5—dihydro—lHepyrazolo[3,4—c]pyridin—6(7H)— yl) ethanone as a white solid (33 mg, 50%): mp 204—205 °C; 1H NMR (500 MHz, DMSO—dw 5 13.13—12.82 (m, 1H), 8.01-7.97 (m, 2H), 7.96—7.90 (m, 92—4.79 (m, 1H), 4.75—4.63 (m, 1H), 4.62~4.53 (m, 2H), 3.72— 3.58 (m, 2H), 3.18~3.05 (m, 2H), 2.84~2.48 (m, 3H, overlaps with solvent), 2.12-2.05 (m, 3H), 1.97~1.78 (m, 2H), 1.76~1.61 (m, 2H); ESI MS m/Z 489 [M + H]+.

Example 92: Preparation of (4-(3,5-bis(trifluoromethyl)phenyl) piperidin—l-yl)(5-(methylsulfonyl)-4,5,6,7—tetrahydro—1H‘pyrazolo [4,3—c]pyridinyl)methanone (154) Step A: Following general procedure GP—C, 5— bis(trifluoromethyl)phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H- pyrazolo[4,3~c]pyridin—3—yl) methanone hydrochloride (52) and methanesulfonyl chloride were converted to (4—(3,5—bis (trifluoromethyl)phenyl) piperidin-l—yl—(S—(methylsulfonyl)—4,5,6,7— tetrahydro—lH—pyrazolo[4,3—C]pyridin—3—yl)methanone as a white solid 3O (25 mg, 37%): 1H NMR (500 MHz, DMSO—da 5 13.02 (s, 1H), 8.01—7.98 (m, 2H), 7.94—7.91 (m, 1H), 5.31—5.24 (m, 1H), 4.73—4.63 (m, 1H), 4.40— 4.26 (m, 2H), 3.51—3.41 (m, 2H), 3.21—3.06 (m, 2H), 2.93(s, 3H), 2.85— 2.74 (m, 3H), 1.96—1.80 (m, 2H), 1.79—1.64 (m, 2H); ESI MS m/z 525 [M + H]+. e 93: Preparation of (4—(3,5~bis(trifluoromethyl) phenyl)piperidin—1—yl)(5-(methylsulfonyl)-4,5,6,7~tetrahydro—1H- pyrazolo[4,3-c]pyridin-B—yl)methanone (155) Step A: To a solution of ethyl 6—methoxy—[1,2,4]triazolo[4,3— a]pyridine-3—carboxylate (66 mg, 0.30 mmol) in THE (2.5 mL) was added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H20 (1.6 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The e was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.3 mL) under an atmosphere of N2. To this mixture was added 4-(3,5—bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), benzotriazole—1-yl—oxy—tris—(dimethylamino)— phosphonium hexafluorophosphate (266 mg, 0.60 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol). The mixture was stirred at ambient ature for 18 h. The ing mixture was diluted with H20 (20 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with a saturated brine solution (3 x 30 ml) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep , 0% to 2% MeOH in CH2Clz with 0.1% NH4OH in CH2C12). The obtained residue was dissolved in CHHHQ (10 mL) and s (100 mL). The solution was partially concentrated and the resulting solids were collected by filtration to provide 5~bis(trifluoromethyl) phenyl)piperidin—1—yl)(6—methoxy—[1,2,4]triazolo[4,3-a]pyridin-3—yl) methanone as an off- white solid (80 mg, 56%): mp 146—149 °C; 1H NMR (500 MHz, DMSO—da 5 8.55 (d, J': 2.0 Hz, 1H), 8.03 (s, 2H), 7.95—7.89 (m, 2H), 7.38 (dd, J = 10, 2.5 Hz, 1H), 5.40—5.33 (m, 1H), 4.81~4.73 (m, 1H), 3.85 (s, 3H), 3.39~3.3l (m, 1H, overlaps with H20), 3.26~3.l6 (m, 1H), 3.02—2.93 (m, 1H), 2.03—1.77 (m, 4H); ESI MS m/z 473 [M + Example 94: ation of 1-(3-(4—(2-fluoro(trifluoromethyl) phenyl)piperidine-l-carbonyl)-4,5-dihydro-1H;pyrazolo[3,4-c]pyridin- 6(7H)-yl)ethanone (156) Step A: Following general procedure GP-El, (4—(2—fluoro—6- (trifluoromethyl) phenyl) piperidin—lwyl) (4,5,6,7—tetrahydro—1H— pyrazolo[3,4—c]pyridin—3-yl)methanone hydrochloride (56) and acetyl chloride were converted to 4—(2»fluoro—6—(trifluoromethyl) phenyl)piperidine-l-carbonyl)—4,5-dihydro-1H~pyrazolo[3,4—c]pyridin— 6(7H)~yl)ethanone as a white solid (33 mg, 43%): 1H NMR (500 MHz, DMSO—da 5 13.26-12.80 (m, 1H), 7.61~7.56 (m, 1H), 7.56-7.47 (m, 2H), 4.87—4.49 (m, 4H), 3.72—3.56 (m, 2H), 3.25—3.04 (m, 2H), 2.84—2.53 (m, 3H), 2.07—1.89 (m, 5H), 1.79—1.64 (m, 2H); ESI MS m/z 439 [M + Example 95: Preparation of 3-(4—(2—f1uoro-6—(trifluoromethy1)phenyl) piperidine-l—carbonyl)-[1,2,4]triazolo[4,3—a]pyridine-G-carbonitrile (157) Step A: To a solution of ethyl 6—bromo—[1,2,4]triazolo[4,3—a]pyridine— 3-carboxylate (72 mg, 0.27 mmol) in THE (2.2 mL) was added a solution of LiOH monohydrate (12 mg, 0.29 mmol) in Ha) (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.8 mL) under an here of N2. To this mixture was added 4—(2—fluoro~6~(trifluoromethyl)phenyl)piperidine hydrochloride (23, 75 mg, 0.27 mmol), riazole-l—yl-oxy—tris—(dimethylamino)— phosphonium hexafluorophosphate (236 mg, 0.53 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol). The mixture was stirred at ambient ature for 18 h. The resulting e was diluted with H30 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated brine solution (30 mL) and concentrated under d pressure. The obtained e was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo- [1,2,4]triazolo[4,3*a]pyridin—3—yl)(4—(2~fluoro—6- (trifluoromethyl)phenyl)piperidin—l—yl)methanone as a light orange 3O film (80 mg, 64%):\ 1H NMR (300 MHz, DMSO—dg) 6 9.12-9.10 (m, 1H), 8.00~ 7.95 (m, 1H), 7.74—7.68 (m, 1H), 7.65—7.50 (m, 3H), 5.29—5.15 (m, 1H), .68 (m, 1H), 3.41—3.19 (m, 2H, overlaps with H20), 3.07—2.97 (m, 1H), 2.34~2.19 (m, 1H), 2.15—2.02 (m, 1H), 1.93—1.75 (m, 2H); ESI MS m/z 472 [M + H]+.] Step B: A solution of (6—bromo—[1,2,4]triazolo[4,3—a]pyridin—3—yl)(4— (2—fluoro-6—(trifluoromethyl)phenyl)piperidin—l—yl)methanone (80 mg, 0.17 mmol) in DMF (2.0 mL) with zinc cyanide (40 mg, 0.34 mmol) was sparged with Ar for 15 min. To the solution was added Pd(PPh?4 (19 mg, 0.017 mmol) and the vessel was sealed and heated to 130 °C with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate on (20 mL) and extracted with EtOAc (3 x 30 mL).

The combined organic extracts were washed with a saturated brine solution (2 x 30 mL) and concentrated to dryness under reduced pressure. The ing residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g p column, 0% to 50% EtOAc in hexanes) followed by HPLC (Phenomenex Luna C18 (2), 250.0 X 50.0 mm, micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) and was washed with saturated sodium bicarbonate solution, and freeze dried to give 3~(4—(2—fluoro—6—(trifluoromethyl)phenyl)piperidine—1~carbonyl)— [1,2,4]triazolo[4,3—a]pyridine-6— itrile as a white solid (23 mg, 33%): 1H NMR (500 MHz, DMSO-dm 5 9.54—9.52 (m, 1H), 8.14—8.11 (m, 1H), 7.82—7.78 (m, 1H), 7.64~7.59 (m, 1H), .50 (m, 2H), 5.17— .10 (m, 1H), 4.79—4.72 (m, 1H), 3.40~3.24 (m, 2H, overlaps with H20), 3.07—2.98 127 (m, 1H), 2.30—2.19 (m, 1H), 2.14~2.03 (m, 1H), 1.91— 1.79 (m, 2H); ESI MS m/z 418 [M + H]+. e 96: ation of 1—(3-(4—(4ef1uoro—2—(trifluoromethyl) )piperidine-l-carbonyl)—4,5—dihydro-1H;pyrazolo[3,4—c1pyridin— 6(7H)-yl)ethanone (158) Step A: A on of tert—butyl 4—(((trifluoromethyl)sulfonyl)oxy)— ,6—dihydropyridine—l(2H)—carboxylate (1.50 g, 4.53 mmol) in 1,2— dimethoxyethane (25 mL) was sparged with N2 for 30 min. 4-Fluoro—(2— trifluoromethyl)phenyl boronic acid (1.13 g, 5.43 mmol) was added followed by a 2 M solution of sodium carbonate (2.9 mL). The resulting mixture was sparged with N2 for 10 min. Pd(PPh?4 (260 mg, 0.225 mmol) was added and the resulting mixture was heated to 80 °C under an atmosphere of N2. After 72 h, the resulting solution was cooled to ambient temperature and diluted with 5% lithium chloride solution (100 mL). The solution was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated brine (2 x 50 mL) and concentrated to dryness under reduced re. The residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert—butyl 4—(4~ fluoro—Z—(trifluoromethyl) phenyl) -5,6~ dihydropyridine—1(2H)- carboxylate as a brown oil (1.29 g, 83%): 1H NMR (300 MHz, CDCl3) 8 7.37w7.08 (m, 3H), 5.57 (br s, 1H), 4.02—3.99 (m, 2H), .58 (m, 2H), 2.32 (br s, 2H), 1.46 (s, 9H).

Step B: A solution of tert—butyl luoro~2—(trifluoromethyl) phenyl)—5,6—dihydropyridine—1(2H)—carboxylate (1.29 g, 3.74 mmol) in ethyl acetate (20 mL) andacetic acid (0.22 mL) was sparged with Nb Platinum dioxide (84 mg) was added and the resulting sion was sparged with N2 for 5 min. The mixture was placed under an Hzatmosphere at 1 atm. After 18 h the reaction was sparged with N2 for 15 min, filtered through a diatomaceous earth pad, recharged with platinum dioxide (100 mg) and stirred under a 1 atm hydrogen atmosphere. The filtration and recharging of the reaction was repeated thrice over the next 64 h. The reaction was filtered through diatomaceous earth.

The obtained filtrate was washed with sodium bicarbonate solution, dried (Nagson and concentrated under reduced pressure. The residue was tographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert—butyl 4— oro~2—(trifluoromethyl)phenyl)piperidine—l—carboxylate as a yellow oil (0.8l3 g, 63%): 1H NMR (300 MHZ, CDCl? 5 7.37-7.20 (m, 3H), 4.27—4.22 (m, 2H), 3.07—2.99 (m, 1H), .75 (m, 2H), .46 (m, 13H).

Step C: To a solution of utyl 4—(4—fluoro—2— (trifluoromethyl)phenyl)piperidine—l—carboxylate (0.813 g, 2.34 mmol) in diethyl ether (6 mL) was added 2 M HCl in diethyl ether (10 mL).

The mixture stirred for 18 11 at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether (10 mL). The solids were collected by filtration to give 4—(4—fluoro-2~(trifluoromethyl)phenylpiperidine hydrochloride as a white solid (0.244 g, 37%): 1H NMR (300 MHz, CDCl? 9.79 (br s, 1H), 7.59—7.54 (m, 1H), .24 (m, 2H), .64 (m, 2H), 3.27—3.03 (m, 4H), 2.39—2.27 (m, 2H), 2.01—1.96 (m, 2H); ESI MS m/z 248 [M + H]+.

Step D: To a on of 4—(4~fluoro—2-trifluoromethyl) phenylpiperidine hydrochloride (75 mg, 0.26 mmol), t— butoxycarbonyl)—4,5,6,7—tetrahydro—1H—pyrazolo[3,4-c]pyridine—3— carboxylic acid (75 mg, 0.29 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (3 mL) under an atmosphere of N2 was added EDC (70 mg, 0.37 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with rho (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (1 x 20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 100% ethyl acetate in hexanes) to provide tert— butyl 3—(4—(4—fluoro—2— (trifluoromethyl)phenyl)piperidine—1— carbonyl)—4,5~dihydro—1H—pyrazolo[3,4vc]pyridine—6(7H)—carboxylate as a white solid (75 mg, 58%): 1H NMR (300 MHz, DMSO—de) 6 12.04 (br s, 1H), 7.72—7.68 (m, 1H), .49 (m, 2H), 4.84—4.64 (m, 1H), 4.49— 4.45 (m, 2H), 3.56—3.53 (m, 2H), 3.08 (br s, 2H), 2.78—2.50 (m, 4H), 1.75 (br s, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + H]+.

Step E: To a solution of tert—butyl 3—(4—(4~fluoro~2- (trifluoromethyl)phenyl)piperidine-l-carbonyl)—4,5-dihydro—1H— pyrazolo [3,4—c]pyridine—6(7H)~carboxylate (74 mg, 0.15 mmol) in CH2Cl2 (3 mL) and methanol (1 mL) was added 2 N HCl (2 mL, 2M in Etgo).

The mixture stirred for 4 11 at ambient temperature. The reaction mixture was diluted with Eth (30 mL) and the resulting solids were collected. by filtration to give (4—(4— f1uoro—2—(trifluoromethyl) phenyl)piperidin‘1~yl)(4,5,6,7~tetrahydro~1Hprrazolo ] pyridin~3—yl)methanone hydrochloride as a white solid (64 mg, 98%): 1H NMR (300 MHz, d 6 13.14 (s, 1H), 9.16 (br s, 2H), 7.73—7.68 (m, 1H), 7.59—7.50 (m, 2H), 4.84—4.69 (m, 1H), 4.32—4.25 (m, 2H), 3.26—3.03 (mwaH), 2.89—2.81 (m, 2H), 2.68-2.48 (m, 4H), 1.73 (m, 4H); ESI MS m/z 397 [M + H]+.

Step F: To a solution of (4-(4-fluoro—2—(trifluoromethyl) phenyl)piperidin*1-yl)(4,5,6,7—tetrahydro-1H—pyrazolo[3,4—c]pyridin- ethanone hydrochloride (63 mg, 0.15 mmol) and diisopropylethylamine (70 uL, 0.40 mmol) in DMF (3.0 mL) was added acetyl chloride (11 uL, 0.15 mmol). The mixture was d for 16 hour. The solvent was removed under reduced pressure and the residue was diluted with H20 (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with saturated brine (1 x 20 mL), dried over NagSO4 and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 100% (10% CH30H in CH2C12 with 0.01% NH4OH) in CH2C12) and further purified by reverse phase chromatography (Isco CombiFlash Rf unit, 12 g Redisep c18 gold column, 0% to 100% acetonitrile in water) to give 1—(3~(4~(4—fluoro— 2—(trifluoromethyl)phenyl)piperidine—l-carbonyl) —4,5—dihydro—1H~ pyrazolo[3,4—c]pyridin—6(7H)—yl)ethanone as a white solid (20 mg, 94%): mp 176—180 °C; 1H NMR (500 MHz, e) 5 12.86 (s, 1H), 7.71— 7.68 (m, 1H), 7.56~7.49 (m, 2H), .55 (m, 3H), 3.66—3.62 (m, 2H), 3.10 (br s, 2H), 2.85—2.48 (m, 4H), 2.10—2.08 (m, 3H), 1.73 (m, 4H); ESI MS m/z 439 [M + H]+.

Example 97: Preparation of (4-(4—f1uoro(trifluoromethyl)phenyl) piperidin—l-yl)(5—(methylsu1fonyl)—4,5,6,7—tetrahydro—1H‘pyrazolo [4,3~c]pyridine—3—y1)methanone (159) Step A: To a solution of 4—(4—fluoro—Z‘trifluoromethyl) phenylpiperidine hydrochloride (75 mg, 0.26 mmol), t— butoxycarbonyl)—4,5,6,7~tetrahydro~1H—pyrazolo[4,3—c]pyridine—3— carboxylic acid (75 mg, 0.29 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (3.0 mL) under an here of N2 was added EDCI (70 mg, 0.37 mmol) and HOBt (49 mg, 0.36 mmol). The resulting on was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H20 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, % to 100% ethyl acetate in hexanes) to e tert-butyl 4—fluoro—2-(trifluoromethyl)phenyl)piperidine—1— carbonyl)-6,7—dihydro—1H—pyrazolo[4,3—c]pyridine—5(4H)—carboxylate as a white solid (109 mg, 77%): 1H NMR (300 MHz, DMSO~dw 5 12.96 (s, 1H), .68 (m, 1H), 7.57~7.49 (m, 2H), 5.32—5.13 (m, 1H), 4.74— 4.64 (m, 1H), 4.47~4.45 (m, 2H), 3.59 (br s, 2H), .10 (m, 2H), 2.82—2.50 (m, 3H), 1.73 (br s, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M + Step B: To a solution of tert—butyl 3—(4—(4—fluoro~2—(trifluoromethyl phenyl)piperidine-l—carbonyl)—4,5—dihydro—1H—pyrazolo[3,4—c]— pyridine—S(4H)-carboxylate (85 mg, 0.17 mmol) in CH??a (3 mL) and methanol (1 mL) was added 2 N HCl (2 mL, 2M in EtzO). The mixture stirred for 4 11 at ambient ature. The reaction mixture was diluted with Etzo (30 mL) and the resulting solids were collected by filtration to give (4—(4—f1uoro—2-(trifluoromethyl)phenyl)piperidin~ 1-y1)(4,5,6,7~tetrahydro~1H~pyrazolo[4,3—c]pyridin—3-y1)methanone hydrochloride as an off—white solid (78 mg, >99%): 1H NMR (300 MHz, DMSO-de) 5 13.14 (br s, 1H), 9.13 (br s, 2H), 7.73—7.67 (m, 1H), 7.58— 7.50 (m, 2H), 5.32-4.69 (m, 3H), 4.24 (s, 2H), 3.38 (br s, 2H), 3.21 3.07 (m, 2H), .72 (m, 3H), 1.75 (m, 4H); ESI MS m/z 397 [M + Step C: To a solution of (4—(4—f1uoro—2—(trifluoromethy1)pheny1) piperidin—l-yl)(4,5,6,7—tetrahydro—1H-pyrazolo[4,3—c]pyridin—3— y1)methanone hydrochloride (38 mg, 0.088 mmol) and diisopropylethylamine (35 uL, 0.20 mmol) in DMF (2.0 mL) was added methanesulfonyl chloride (9 uL, 0.12 mmol). The mixture was stirred for 16 h at ambient ature. The solvent was removed under reduced pressure and the residue diluted with H20 (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under d pressure. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep , 0% to 100% (10% CH3OH in CH2C12 with 0.01% NH4OH) in CH2C12) and freeze dried to give (4~(4-fluoro~2- (trifluoromethyl)phenyl)piperidin~1—yl)(5- (methylsulfonyl)~4,5,6,7- tetrahydro—lH—pyrazolo[4,3~c]pyridinyl)methanone as a white solid (4 mg, 10%): 1H NMR (300 MHz, DMSO—da 5 13.05 (s, 1H), 7.73~7.69 (m, 1H), 7.57—7.46 (m, 2H), 5.28—5.24 (m, 1H), 4.70—4.65 (m, 1H), 4.38— 4.33 (m, 2H), 3.51—3.45 (m, 2H), 3.22—3.10 (m, 2H), 2.94 (s, 3H), 2.84—2.70 (m, 3H), 1.73 (br s, 4H); ESI MS m/z 475 [M + H]+.

Example 98: Preparation of 3—(4-(4-fluoro(trifluoromethyl) phenyl)piperidine-l—carbonyl)—[1,2,4]triazolo[4,3-a]pyridine—6- carbonitrile (160) Step A: To a solution of ethyl 6—bromo-[1,2,4]triazolo[4,3-a]pyridine— 3—carboxylate (81 mg, 0.30 mmol) in THF (2.5 mL) was added a solution of LiOH monohydrate (14 mg, 0.30 mmol) in H20 (1.7 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The ed residue was diluted in DMF (3.2 mL) under an here of N2. To this mixture was added 4~(4—fluor0*2—(trifluoromethyl)phenyl)piperidine hydrochloride (85 2O mg, 0.30 mmol), benzotriazole-l-yl-oxy—tri5*(dimethylamino)— phosphonium uorophosphate (267 mg, 0.60 mmol), and diisopropylethylamine (0.15 mL, 0.91 mmol). The e was stirred at ambient temperature for 18 h. The resulting e was diluted with H20 (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3—a]pyridin—3—yl)(4— (4—fluoro—2—(trifluoromethyl)phenyl)piperidin—l—yl)methanone as an orange film (92 mg, 64%): 1H NMR (300 MHz, DMSO—ds) 5 9.13 (dd, J = 1.7, 0.9 Hz 1H), 7.98 (dd, J = 10, 0.9 Hz, 1H), 7.77—7.69 (m, 2H), 7.60e7.47 (m, 2H), 5.30—5.18 (m, 1H), 4.77—4.68 (m, 1H), 3.43~3.34 (m, 1H), 3.28‘3.12 (m, 1H), 3.ll~2.90 (m, 1H), 1.97—1.69 (m, 4H); ESI MS m/z 472 [M + H]+.

Step B: A solution of (6—bromo—[1,2,4]triazolo[4,3—a]pyridin~3-yl)(4— (4-fluoro-2*(trifluoromethyl)phenyl)piperidin—l-y1)methanone (90 mg, 0.19 mmol) in DMF (2.2 mL) zinc cyanide (45 mg, 0.38 mmol) was sparged with Ar for 15 min. To the solution was added Pd(PPh?4 (22 mg, 0.019 mmol) and the vessel was sealed and heated to 130 °C microwaves for min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with saturated brine solution (30 mL) and concentrated to dryness under reduced pressure. The ing residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) followed by HPLC menex Luna C18 (2), 250.0 X 50.0 mm, 15 micron, H20 with 0.05% TFA and CH3CN with 0.05% TFA) and was washed with saturated sodium bicarbonate solution (3 x30 mL) then freeze dried to e 3-(4-(4— fluoro—2-(trifluoromethyl)pheny1)piperidine—l—carbonyl)~[1,2,4] triazolo[4,3ea]pyridine—6— carbonitrile as a white solid (32 mg, 40%): mp 158—162 °C; 1H NMR (300 MHz, DMSO—ds) 8 9.53 (s, 1H), 8.14 (dd, J: 9.0, 0.9 Hz, 1H), 7.82 (dd, J = 9.6, 1.5 Hz, 1H), 7.77~7.67 (m, 1H), 7.61—7.47 (m, 2H), 5.l9~5.04 (m, 1H), .67 (m, 1H), 3.46—3.14 2O (m, 2H, overlaps with H20), 3.12~2.94 (m, 1H), 2.02—1.70 (m, 4H); ESI MS m/z 418 [M +H]+. e 99: ation of 3-(3—(4-(5—Chloro-2—(trifluoromethyl) phenyl) piperidine—l—carbonyl)-[1,2,4]triazolo[4,3-a]pyridine carbonitrile (161) Step A: A mixture of (5—chloro—2—(trifluoromethyl)pheny1)boronic acid (0.453 g, 2.02 mmol), tert—butyl 4—(((trifluoromethyl)sulfony1)oxy)— ,6edihydropyridine~1(2H)—carboxy1ate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and l,2~dimethoxyethane (10 mL) was heated at 80 °C under microwave irradiation for 1.5 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2 x 50 mL), dried over Na2504, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0—25% EtOAc in hexanes) to give utyl 4~(5-chloro—2— (trifluoromethyl)phenyl)-5,6—dihydropyridine~1(2H)—carboxylate as colorless oil (0.614 g, 84%): 1H NMR (300 MHz, CDCl3) 5 7.59 (d, J = 8.5 Hz, 1H), 7.37-7.22 (m, 1H), 7.22 (d, J = 1.68 Hz, 1H), 5.60 (br. 1H), 4.02 (br, 2H), 3.61 (br, 2H), 2.34 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.

Step B: A mixture of tert—butyl 4—(5-chloro—2~(trifluoromethy1) )-5,6—dihydropyridine—1(2H)—carboxy1ate (0.614 g, 1.70 mmol), platinum oxide (0.200 g, 0.881 mmol), acetic acid (1 mL), and ethyl acetate (15 mL) was hydrogenated using a balloon of Hg for 16 h and filtered. After concentration, the residue was chromatographed over silica gel (0~30% EtOAc in hexanes) to give tert—buty1 4—(5-chloro—2— (trifluoromethyl)pheny1)piperidine-l-carboxylate as ess thick oil (0.302 g, 48%): 1H NMR (300 MHz, CDC13) 5 7.56 (d, J = 8.5 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J = 1.3 Hz, 1H), 4.26 (br, 2H), 3.04 (m, 1H), 2.80 (m, 2H), 1.80-1.55 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.

Step C: To a solution of tert—butyl 4-(5—chloro—2— (trifluoromethyl)phenyl)piperidine—l—carboxylate (0.302 g, 0.830 mmol) in dichloromethane (5 mL) was added HCl solution (2 M in ether, mL). The mixture was stirred for 4 h and evaporated to afford a solid that was dissolved in DMF (8 mL). In a separate flask, to a solution of ethyl o~[1,2,4]triazolo[4,3~a]pyridine~3* carboxylate (0.224 g, 0.830 mmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (0.035 g, 0.830 mmol) in water (2 mL).

The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated to dryness. To this residue were added benzotriazole— 1-y1-oxytris(dimethylamino)phosphonium uorophosphate (0.550 g, 3O 1.25 mmol), N,N—diisopropylethylamine (0.646 g, 5.00 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried over NagSO4, ed, and concentrated under reduced re. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6—bromo— [1,2,4]triazolo[4,3—a]pyridin—3*yl)(4—(5—chloro-2— (trifluoromethyl) phenyl) piperidin-l—yl)methanone as a solid (0.205 g, 50%): 1H NMR (300 MHz, CDCl3) 59.38 (m, 1H), 7.79 (dd, J = 9.6, 0.9 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 9.6, 1.7 Hz, 1H), 7.42 (d, J = 1.4 Hz, 1H), 7.31 (dd, J = 8.5, 1.3 Hz, 1H), 5.76—5.71 (m, 1H), .95 (m, 1H), 3.38—3.26 (m, 2H), 3.02—2.92 (m, 1H), 2.01—1.82 (m, 4H); MS (ESI+) m/z 489 [M+H]+.

Step D: A mixture of (6—bromo—[1,2,4]triazolo[4,3-a]pyridin—3—yl)(4— (5~chloro—2-(trifluoromethyl)phenyl)piperidin-l-y1)methanone (0.205 g, 0.42 mmol), zinc cyanide(0.099 g, 0.840 mmol), is (triphenylphosphine)palladium (0.048 g, 0.042 mmol), and DMF (4 mL) was heated under microwave irradiation at 130 °C for 30 min. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2 x 80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0—60% EtOAc in hexanes) to give 3— (4*(5—chloro—2—(trifluoromethyl) ) piperidine-l-carbonyl)— [1,2,4]triazolo[4,3-a]pyridine-6—carbonitrile as a white solid (0.115 g, 63%): 1H NMR (300 MHz, CDCl3) 8 9.72 (s, 1H), 7.98 (dd, J = 9.5, 1.1 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 9.5, 1.6 Hz, 1H), 7.41 (s, 1H), 7.31 (dd, J = 8.5, 1.3 Hz, 1H), 5.77—5.72 (m, 1H), 5.02— 4.96 (m, 1H), 3.40 (m, 2H), 3.04—2.94 (m, 1H), .80 (m, 4H); MS (ESI+) m/z 434 [M+H]+.

Example 100: Preparation of 3-Chloro—2-(trifluoromethyl)phenyl) piperidine-l—carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-G-carbonitrile 3O (162) Step A: A mixture of (3—chloro~2—(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert—butyl 4-(((trifluoromethyl)sulfonyl)oxy)— ,6—dihydropyridine—1(2H)~carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2«dimethoxyethane (10 mL) was heated at 80 °C under microwave irradiation for 1 h. After cooling to t temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The t was washed with brine (2 x 50 mL), dried (Na2304), ed, and concentrated under reduced pressure.

The resulting residue was chromatographed over silica gel (0—30% EtOAc in hexanes) to give tert—butyl 4*(3—chloro-2—(trifluoromethyl) phenyl)—5,6—dihydropyridine—1(2H)-carboxylate as ess oil (0.438 g, 60%): 1H NMR (300 MHZ, CDC13) 5 7.44—7.34 (m, 2H), 7.09 (m, 1H), .49 (br. 1H), 4.01 (br, 2H), 3.60 (br, 2H), 2.30 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.

Step B: A mixture of tert—butyl 4—(3—chloro—2—(trifluoromethyl) )—5,6—dihydropyridine—1(2H)—carboxylate (0.438 g, 1.21 mmol), platinum oxide (0.082 g, 0.363 mmol), acetic acid (0.073 g, 1.21 mmol), and ethyl acetate (20 mL) was hydrogenated using a balloon for h and filtered. The material was re~submitted to hydrogenation at 80 °C for 16 h and ed. After concentration, the residue was chromatographed over silica gel (0—30% EtOAc in hexanes) to give tert— butyl 4—(3—chloro—2- (trifluoromethyl)phenyl) piperidine—l— 2O carboxylate as colorless thick oil (0.115 g, 26%): 1H NMR (300 MHz, CDC13) 57.42—7.30 (m, 3H), 4.25 (br, 2H), 3.21 (m, 1H), 2.81 (m, 2H), 1.80—1.60 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.

Step C: To a solution of tert—butyl 4~(3—chloro—2—(trifluoromethyl) phenyl)piperidine—l—carboxylate (0.115 g, 0.316 mmol) in dichloromethane (3 mL) was added HCl (2 M in ether, 3 mL). The mixture was stirred for 3 h and evaporated to afford a solid that was dissolved in DMF (3 mL). In a separate flask, to a solution of ethyl 6~bromo~ [1,2,4]triazolo[4,3—a]pyridine—3—carboxylate (0.094 g, 0.348 mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (0.015 g, 0.348 mmol) in water (1 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated. To the residue were added benzotriazole—l—yl*oxy~tris(dimethylamino)phosphonium hexa— fluorophosphate (0.210 g, 0.474 mmol), N,N—diisopropylethylamine (0.163 g, 1.26 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried (Na2SO4), filtered, and trated under reduced pressure. The ing residue was chromatographed over silica gel (0~60% EtOAc in hexanes) to give (6-bromo-[1,2,4]triazolo[4,3~a]pyridin-3~yl)(4—(3— chloro-2—(trifluoromethyl)phenyl)piperidin—l-yl)methanone as a solid (0.076 7.78 J = g, 49%): 1H NMR (300 MHz, CDCl3) 89.36 (m, 1H), (dd, 9.6, 0.9 Hz, 1H), 7.50—7.34 (m, 4H), 5.73—5.68 (m, 1H), 5.00—4.94 (m, 1H), 3.52—3.28 (m, 2H), 2.97 (m, 1H), 2.01—1.74 (m, 4H); MS (ESI+) m/z 489 .

Step D: A mixture of (6—bromo—[1,2,4]triazolo[4,3—a]pyridin—3—yl)(4— (3—chloro~2—(trifluoromethyl)phenyl)piperidin—l—yl)methanone (0.076 g, 0.156 mmol), zinc cyanide (0.037 g, 0.312 mmol), ium tetrakis(triphenylphosphine) (0.018 g, 0.0156 mmol), and DMF (2 mL) was heated under microwave irradiation at 130 °C for 30 min. After cooling to t temperature, the e was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The extract was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0—60% EtOAc in hexanes) to give 3— (4—(3—chlor0*2—(trifluoromethyl) phenyl) piperidine—l—carbonyl)- [1,2,4] triazolo[4,3—a]pyridine—6* carbonitrile as a white solid (0.026 38%): 1H NMR (300 MHz, CDCl3) 89.70 (s, 1H), 7.97 (dd, J = 9.5, 1.0 Hz, 1H), 7.52—7.32 (m, 4H), 5.74—5.69 (m, 1H), 5.00—4.95 (m, 1H), 3.52—3.31 (m, 2H), 2.99 (m, 1H), 2.06—1.75 (m, 4H); MS (ESI+) m/z 434 [M+H]+. 3O Example 101: Preparation of (4—(2—Chlorofluorophenyl)piperidin-l— yl)(5-ethyl—4,5,6,7~tetrahydro-1H—pyrazolo[4,3—c]pyridin-3— yl)methanone (163) Step A: Following general procedure GP—Dl, (4—(2~chloro-3— fluorophenyl)piperidin—l—yl)(4,5,6,7—tetrahydro—1H—pyrazolo[4,3~ c]pyridin-3—yl)methanone hydrochloride (42) and formaldehyde were converted to (4—(2-Chlorofluoropheny1)piperidin—l—yl)(5—ethyl— 4,5,6,7—tetrahydro—1H~pyrazolo[4,3—c]pyridin—3—yl)methanone as a white solid (25 mg, 32%): 1H NMR (300 MHz, e) 5 12.93 (m, 1H), 7.56—7.32 (m, 3H), 5.16 (m, 1H), 4.81 (m, 1H), 2.61—3.42 (m, 9H), 1.94—1.61 (m, 4H); ESI MS m/z 391 [M + HJ? Example 102: Preparation of (4—(2—Chlorofluorophenyl) piperidin— l-yl)(5—(cyclopropylmethyl)-4,5,6,7—tetrahydro-1H-pyrazolo[4,3- c]pyridinyl)methanone (164) Step A: Following general procedure GP-Dl, (4—(2—chloro-3— fluorophenyl) piperidin—l—yl) (4,5,6,7—tetrahydro—1H4pyrazolo[4,3— c]pyridin—3-yl)methanone hydrochloride (42) and cyclopropyl— carboxaldehyde were converted to (4—(2~chloro«3-fluoropheny1) piperidin—l—yl)(5—(cyclopropylmethyl)—4,5,6,7—tetrahydro—1H—pyrazolo [4,3—c]pyridin-3—yl)methanone as a white solid (41 mg, 65%): 1H NMR (300 MHz, DMSO—de) 5 12.91 (m, 1H), 7.56—7.39 (m, 3H), 5.15 (m, 1H), 4.85 (m, 1H), 3.53 (m, 2H), 3.12 (m, 1H), 2.62—2.35 (m, 5H), 2.43 (m, 2H), 1.87 (m, 2H), 1.63 (m, 2H), 0.98 (m, 1H), 0.55 (m, 2H), 0.021 (m, 2H); ESI MS m/z 417 [M + H]+.

Example 103: Preparation of (4-(2—Chloro-3—fluorophenyl) piperidin- 1-yl)(5—(oxetan—3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin- 3—yl)methanone (165) Step A: Following general procedure GP—Dl, chloro—3~ fluorophenyl) piperidin—l—yl) ,7—tetrahydro-1Hepyrazolo[4,3— c]pyridin*3-yl)methanone hydrochloride (42) and 3—oxetanone were ted to (4-(2—chloro—3~fluoropheny1) piperidin—l—yl)(5—(oxetan— 3—yl)—4,5,6,7—tetrahydro—1H-pyrazolo[4,3—c]pyridin—3—yl)methanone as a white solid (53 mg, 62%): 1H NMR (300 MHz, DMSO—dg) 5 12.91 (m, 1H), 3O 7.56—7.39 (m, 3H), 5.15 (m, 1H), 4.52—4.85 (m, 5H), 3.53 (m, 1H), 3.12—3.40 (m, 3H), 65 (m, 3H), 1.72 (m, 2H), 1.53 (m, 2H); ESI MS m/z 419 [M + H]K e 104: Preparation of (4—(2-Chloro—3-fluorophenyl) piperidin- l-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7—tetrahydro-1H—pyrazolo[4,3— c]pyridin—3-yl)methanone (166) Step A: Following general procedure GP—D2, (4—(2-chloro—3~ f1uoropheny1) piperidin—lwyl) (4,5,6,7—tetrahydro-1H—pyrazolo[4,3— c]pyridin—3—y1)methanone hydrochloride (42) and trif1uoroethy1 oromethanesulfonate were converted to chloro—3— fluorophenyl) piperidin—1~y1) (5—(2,2,2—trif1uoroethy1)—4,5,6,7— ydro—lH—pyrazolo[4,3—c]pyridin-3—y1)methanone as a white solid (56 mg, 62%): 1H NMR (300 MHz, DMSO—de) 5 12.91 (m, 1H), 7.56—7.39 (m, 3H), 5.15 (m, 1H), 4.73 (m, 1H), 3.82 (m, 2H), 3.32 (m, 1H), 2.89 (m, 2H),2.65 (m, 2H), 1.89 (m, 2H), 1.56 (m, 2H); ESI MS m/z 445 [M + H]K Example 105: Preparation of (4—(2-Chlorofluorophenyl)piperidin—l— yl)(5—(3,3,3-trifluoropropyl)—4,5,6,7-tetrahydro—1H—pyrazolo[4,3— c]pyridinyl)methanone (167) Step A: Following general procedure GP—D2, (4—(2—chloro—3~ fluorophenyl)piperidin—l—yl) (4,5,6,7-tetrahydro—1H—pyrazolo [4,3— c]pyridin—3-yl)methanone hydrochloride (42) 3—bromo—l,1,1— trifluoropropane were converted to (4—(2—chloro—3~f1uoropheny1) piperidin—l—yl) (5-(3,3,3—trif1uoropropy1)—4,5,6,7—tetrahydro~lH- pyrazolo[4,3-c]pyridin~3—y1)methanone as a white solid (36 mg, 43%): 1H NMR (300 MHz, DMSO—de) 6 13.01 (m, 1H), 7.56—7.39 (m, 3H), 5.15 (m, 1H), 4.52 (m, 2H), 3.41 (m, 2H), 2.82 (m, 3H), 1.89 (m, 2H), 1.56 (m, 2H); ESI MS m/z 459 [M + H]? e 106: Preparation of (4-(2—Chloro—3—fluorophenyl) piperidin— 1-yl)(5—(2-methoxyethyl)~4,5,6,7-tetrahydro—1H-pyrazolo[4,3— c]pyridin~3-yl)methanone (168) Step A: Following general procedure GP—D2, (4—(2—chloro—3- phenyl) piperidin—l—yl) (4,5,6,7—tetrahydro-1H-pyrazolo[4,3— c]pyridin—3-y1)methanone hydrochloride (42) bromoethylmethyl ether 3O were converted to (4—(2—chloro—3~fluoropheny1)piperidin—l—yl)(5~(2— methoxyethyl)—4,5,6,7—tetrahydro~1H—pyrazolo[4,3—c] pyridinw3—y1) methanone as a white solid (53 mg, 45%): 1H NMR (300 MHz, DMSO—de) 5 12.89 (m, 1H), 7.56—7.39 (m, 3H), 5.15 (m, 1H), 4.52 (m, 2H), 3.51 (m, 4H), 3.23 (m, 4H), 2.72 (m, 6H), 1.89 (m, 2H), 1.56 (m, 2H); ESI MS m/z 421 [M + H]? Example 1072 Preparation of (4—(3,4-Difluoro~2—(trifluoromethyl) phenyl)piperidin—1—yl)(5-(piperazine—l-carbonyl)~1,4,5,6— tetrahydropyrrolo[3,4-c1pyrazol—3-yl)methanone (169) Step A: A solution of tert—butyl piperazine—l—carboxylate (210 mg, 1.13 mmol) and pyridine (137 mg, 1.73 mmol) in ous CH2C12 (2 mL) was cooled to 0 DC under an atmosphere of N2, treated with a solution of triphosgene (402 mg, 1.35 mmol) in anhydrous CH??g (2 mL) and stirred at 0 DC for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 1 h. After this time, the mixture was diluted with 1 M hydrochloric acid (25 mL) and extracted with CH2C12 (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2804 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure to provide tert~butyl 4-(chlorocarbonyl)piperazine— oxylate as a white solid (280 mg, 100%): 1H NMR (500 MHz, CDCl? 6 10.76 (br s, 1H), 7.33 (dd, J = 17.0, 9.0 Hz, 1H), 7.11 (dd, J = 9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J'= 4.5 Hz, 4H), 3.32 (apparent t, J'= 4.5 Hz, 4H), 3.25 (apparent t, J = 12.5 Hz, 1H), 3.14—2.88 (m, 2H), 1.94 (d, J = 12.5 Hz, 2H), 1.72—1.66 (m, 2H), 1.48 (s, 9H).

Step B: A solution of (4—(3,4—difluoro—2—(trifluoromethyl) phenyl)piperidin~1-yl)(l,4,5,6~tetrahydropyrrolo[3,4—c]pyrazol—3—yl) methanone hydrochloride salt (50 mg, 0.11 mmol), N,N,N— diisopropylethylamine (0.05 mL, 0.3 mmol) and DMAP (0.5 mg, 0.004 mmol) in anhydrous CH2C12 (1 mL) was cooled to 0 DC under an here of N2, treated with tert—butyl 4-(chlorocarbonyl)piperazine~1~ carboxylate (30 mg, 0.12 mmol) and stirred at 0 °C for 1 h. The cooling bath was then d and the reaction d at room 3O temperature for a further 4 IL After this time, the mixture was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g p gold column, % to 10% CH30H in CHZClg) to e tert~butyl 4~(3—(4- (3,4—difluoro—2—(trifluoromethyl)phenyl)piperidine—l—carbonyl)— 1,4,5,6—tetrahydropyrrolo[3,4—c]pyrazole-5—carbonyl)piperazine—l— carboxylate as a white solid (48 mg, 71%): 1H NMR (500 MHz, CDC13) 5 .76 (br s, 1H), 7.33 (dd, J": 17.0, 9.0 Hz, 1H), 7.11 (dd, J": 9.0, 4.0 Hz, 1H), 4.88—4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J'= 4.5 Hz, 4H), 3.32 (apparent t, J'= 4.5 Hz, 4H), 3.25 (apparent t, J = 12.5 Hz, 1H), .88 (m, 2H), 1.94 (d, J = 12.5 Hz, 2H), 1.72—1.66 (m, 2H), 1.48 (s, 9H).

Step C: A solution of tert—butyl 4—(3—(4—(3,4-difluoro—2-(trifluoro— methyl)phenyl)piperidine-l—carbonyl)—1,4,5,6-tetrahydro—pyrrolo[3,4— zole-5—carbonyl)piperazine—l-carboxylate (47 mg, 0.077 mmol) in anhydrous CH2C12 (1.5 mL) was cooled to 0 °C under an atmosphere of N2 and treated with TFA (1.5 mL). When the addition was te, the cooling bath was removed and the reaction stirred at room temperature for 1 h. After this time, the e was concentrated to dryness under reduced pressure, diluted in CH2C12 (100 mL) and washed with 2 M aqueous NaOH (2 x 50 mL). The organic layer was dried over Na2504 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the resulting residue chromatographed over silica gel (Isco CombiFlash Rf unit, 120 g Redisep column, 0% to 40% CH??i in CHgCl?. The combined column fractions were concentrated to dryness under reduced pressure and found to n residual TFA (~17%). The resulting residue (21 mg) was diluted in a mixture of CH2C12 (5 mL) and CH3OH (1 mL), treated with MP~carbonate and stirred at room temperature for 2 h. After this time the mixture was filtered and the filtrate concentrated to s under reduced pressure to provide (4—(3,4—difluoro~2~ (trifluoromethyl)phenyl)piperidin—1—yl)(5—(piperazine-l—carbonyl)- 1,4,5,6—tetrahydropyrrolo[3,4—c]pyrazol—3—yl)methanone as a white solid (13 mg, 33%): mp 153~155 °C; 1H NMR (500 MHz, 6) 5 13.20 (br s, 1H), 7.75 (dd, J = 18.0, 9.0 Hz, 1H), 7.55—7.52 (m, 1H), 4.65— 4.51 (m, 6H), 3.24~3.22 (m, 2H), 3.14 (t, J = 5.0 Hz, 4H), 2.96‘2.80 3O (m, 1H), 2.70—2.68 (m, 3H), 2.32—2.22 (m, 1H), 1.79—1.70 (m, 4H), 1 proton not readily observed; ESI MS m/z 513 [M + H]? Example 108: RPB4 binding of Substituted Piperidine Compounds The compounds listed in Table 1 were tested in two in vitro assays, RBP4 g (SPA) and retinol—dependent RBP4-TTR interaction (HTRF).

The compounds binded to RBP4 and/or antagonized retinol~dependent RBP4~TTR ction (Table 2). This activity indicated that the compounds reduce the levels of serum RBP4 and retinol.

TABLE 1 .

Compound Structure F F 145 ON N , o?N / 146 j TABLE 2 .

SPA binding assay HTRF assay for for RBP4: ICso (pM) antagonists of RBP4—TTR ction: IC5° (11M) _32 0.062512598 0.244123897 3 4 0.020741511 0 053147107 3 6 0.010869769 0.291188749 8 0.026852208 0.200234283 " 0.014037221 0 084919195 76 0.007397337 0.019662328 77 0 007956596 0 - 139 77 0 002879752 0 ‘ 692 -78 0.009495365 0 - 015829707 —81 0 . 006035222 0 . 013874989 —Bl 0.005257865 0 - 009751259 81 . ——_83 -_ 0 9 0 - 014933765 004188677 -_ 10 0 - 015640938 0015420503 111 0.00688552 0.022103363 I‘I'I‘I‘ I—‘i—‘I—‘H 01me 0.011482219 0.027454866 0.008568525 0.029698246 0.010291162 0.040803422 0.018874475 0.109320347 ’_l O'\ 0.011433337 0.023664257 I I_I \l 0.005480892 I 0.037691094 I |—‘ CD 87053 0.014204672 I‘I‘I‘I‘l| NNNNH (AND—‘00 0.010706312 28773 0.003446949 0.021028771 40985 0.031786798 0.027657766 0.052167868 :24 000 000 I'l‘l‘ .5014 moo Ib- mwoo mom oov—lr—I Ago 0.024895781 ;25 0 0:4989926 0.062101253 :26 0.0:6994001 0.16972172 :27 0 0:5876357 0 017030219 :28 0 0:8381483 0 032415479 :30 0.0:2836331 0 tT_—"f§f""‘_T:___ 01491032 0.006360993 0 010914335 ;3 0.006750411 0.010485373 I 35 0.016415973 0.021040669 [_ ;36 0.016716286 0 012001451 ;37 1::;* 0.018357352 0.02416484 :38 0.010124856 0 67 ;39 0.017844788 0.022818173 0.009283295 0.021890308 0.004882652 0.023217801 :43 0.008830797 0 371 " 0.006170928 12083 :45 0.007565936 0.066971574 :46 0.015873944 0.036497073 :48 0.005121182 0 007411947 :48 < 0 742 < 0.000169 _49 0.005905695 0.023421638 :50 0.004841961 F" 0 023730312 :51 0.010266809 0.067747522 :52 0.003104118 0.027843193 [::j ;53 _l‘ 0.149436EEEA 0.833441155 —.—_.:__ 0.150196791 0.384932114 0.02162571 0.186360166 0.01944249 0.247762562 0.005840561 0.09202995 32683 0.036829287 0.008056546 80303 0.009062711 0.019772679 0.005742747 0.025784179 0.00482477 0.01068914 0.015294165 0.055271368 0.013574829 0.074955125 0.01557141 0.064787312 0.012173811 17945 0.011715962 22888 0.015544906 0.081261949 0.033042848 0.055813322 Example 109: RPB4 binding of Additional Substituted Piperidine Compounds An additional aspect of the invention provides analogs of the compounds of Table 1 that are active as RBP4 antagonists. These analogs n a di- or tri—substituted phenyl ring located at the 4~position of the dine core. The analogs of Compounds 63—162 described herein analogously bind to RBP4 and antagonize retinol—dependent RBP4— TTR interaction.

Additional piperidine compounds, which are s of those described in Table l, are tested in two in vitro , RBP4 binding (SPA) and retinol—dependent RBP4~TTR interaction (HTRF). These piperidine compounds bind to RBP4 and antagonize retinol—dependent RBP4—TTR interaction. This activity indicates that the compounds reduce the level of serum RBP4 and retinol.

Example 110: Efficacy in a Mammalian Model The effectiveness of the compounds listed in Table 1 are tested in wild—type and Abca4—/— mice. The Abca4-/— mouse model manifests accelerated accumulation of lipofuscin in the RPE and is considered a pre—clinical efficacy model for a drug reducing lipofuscin accumulation. Compounds are orally dosed for 3 weeks at 30 mg/kg.

There is a reduction in the serum RBP4 level in treated animals. The levels of A2E/isoA2E and other bisretinoids are reduced in treated mice. The levels of A2-DHP-PE and atRAL di-PE are also reduced.

The effectiveness of additional piperidine compounds, which are analogs of those bed in Table 1, are tested in wild-type and Abca4—/- mice. The Abca4—/- mouse model manifests accelerated accumulation of scin in the RPE and is considered a pre—clinical efficacy model for a drug reducing lipofuscin accumulation. Compounds are orally dosed for 3 weeks at 30 mg/kg. There is a reduction in the serum RBP4 level in treated animals. The levels of A2E/isoA2E and other bisretinoids are reduced in treated mice. The levels of A2—DHP— PE and atRAL di—PE are also reduced.

Example 111: Efficacy of Compound 81 in a Mammalian Model Compound 81 inhibited bisretinoid accumulation in Abca4—/— mouse model. Abca4—/— mice have A2E levels in the ~15—19 /eye range at 17 weeks old. Mice, starting at 17 weeks old, were treated with 25 mg/kg of Compound 81 for 12 weeks. There was a 53% reduction in bisretinoid content in the Compound 81—treated mice versus the vehiclewtreated controls (Figure 8). This data was consistent with complete arrest of bisretinoid sis from the start of the dosing regiment. Reduced inoid accumulation resulted in significant serum RBP4 reduction in the Compound 81—treated mice (Figure 9). e 112: Efficacy of Additional Compounds in a Mammalian Model Compounds 34, 36, and 38 inhibit bisretinoid accumulation in /— mouse model. Mice, ng at 17 weeks old, are treated with 25 mg/kg 3O of Compounds 34, 36, or 38 for 12 weeks. There is a reduction in bisretinoid content in the treated mice versus the e-treated controls. This data is consistent with complete arrest of bisretinoid synthesis from the start of the dosing regiment. Reduced bisretinoid accumulation results in significant serum RBP4 ion in the treated mice.

Compounds 30, 40, and 42 inhibit bisretinoid accumulation in /— mouse model. Mice, ng at 17 weeks old, are treated with 25 mg/kg of Compounds 30, 40, or 42 for 12 weeks. There is a reduction in bisretinoid t in the treated mice versus the vehicle—treated controls. This data is consistent with complete arrest of bisretinoid synthesis from the start of the dosing regiment. Reduced bisretinoid accumulation results in significant serum RBP4 reduction in the treated mice.

Each of Compounds 63-80 or 82—169 inhibit bisretinoid accumulation in Abca4-/~ mouse model. Mice, starting at 17 weeks old, are treated with mg/kg any one of Compounds 63-80 or 82-169 for 12 weeks. There is a reduction in bisretinoid content in the treated mice versus the e—treated controls. This data is consistent with complete arrest of bisretinoid synthesis from the start of the dosing regiment.

Reduced bisretinoid accumulation results in significant serum RBP4 reduction in the treated mice.

Example 113. Administration to a Subject 2O An amount of a compound 81 is administered to the eye of a subject afflicted with AMD. The amount of the compound is ive to treat the subject.

An amount of a compound 81 is administered to the eye of a subject afflicted with Stargardt disease. The amount of the compound is ive to treat the subject.

An amount of any one of compounds 63—80 or 82—169 is administered to the eye of a subject afflicted with AMD. The amount of the compound is effective to treat the subject.

An amount of any one of compounds 63—80 or 82-169 is stered to the eye of a subject afflicted with Stargardt disease. The amount of the compound is effective to treat the subject.

Discussion Age—related r degeneration (AMD) is the g cause of blindness in developed countries. Its prevalence is higher than that of mer's disease. There is no treatment for the most common dry form of AMD. Dry AMD is triggered by abnormalities in the retinal t epithelium (RPE) that lies beneath the photoreceptor cells and provides critical metabolic t to these light—sensing cells.

RPE dysfunction induces secondary degeneration of photoreceptors in the central part of the retina called the macula. Experimental data indicate that high levels of lipofuscin induce degeneration of RPE and the adjacent photoreceptors in ic AMD retinas. In addition to AMD, dramatic accumulation of lipofuscin is the hallmark of Stargardt’s disease (STGD), an inherited form of juvenile onset macular degeneration. The major cytotoxic component of RPE scin is a pyridinium bisretinoid A2E. A2E formation occurs in the retina in a non-enzymatic manner and can be considered a by—product of a properly functioning visual cycle. Given the established cytotoxic affects of A2E on RPE and photoreceptors, inhibition of A2E formation could lead to delay in visual loss in patients with dry AMD and STGD.

It was suggested that small molecule visual cycle inhibitors may reduce the formation of A2E in the retina and prolong RPE and photoreceptor survival in patients with dry AMD and STGD. Rates of the visual cycle and A2E production in the retina depend on the influx of ans l from serum to the RPE. RPE retinol uptake depends on serum retinol concentrations. cological downregulation of serum retinol is a valid treatment strategy for dry AMD and STGD.

Serum retinol is maintained in circulation as a tertiary complex with retinol—binding protein (RBP4) and transthyretin (TTR). Without interacting with TTR, the RBP4‘retinol complex is rapidly cleared due 3O to glomerular filtration. Retinol binding to RBP4 is ed for formation of the RBP4—TTR complex; apo-RBP4 does not interact with TTR. Importantly, the retinol—binding site on RBP4 is sterically proximal to the interface mediating the RBP4—TTR interaction. Without wishing to be bound by any scientific theory, the data herein show that small le RBP4 antagonists displacing retinol from RBP4 and disrupting the RBP4—TTR interaction will reduce serum retinol concentration, inhibit retinol uptake into the retina and act as indirect visual cycle inhibitors reducing formation of cytotoxic A2E.

Serum RBP4 as a drug target for cological inhibition of the visual cycle As rates of the visual cycle and A2E production in the retina depend on the influx of all—trans retinol from serum to the RPE (Figure 4), it has been suggested that partial pharmacological down—regulation of serum retinol may represent a target area in dry AMD treatment (11).

Serum l is bound to retinol~binding protein (RBP4) and maintained in circulation as a tertiary complex with RBP4 and hyretin (TTR) (Figure 5). Without interacting with TTR, the RBP4—retinol complex is rapidly cleared from circulation due to glomerular filtration. Additionally, formation of the RBP4—TTR— retinol complex is required for receptor—mediated all—trans l uptake from serum to the retina.

Without wishing to be bound by any scientific , visual cycle inhibitors may reduce the formation of toxic bisretinoids and g RPE and photoreceptor survival in dry AMD. Rates of the visual cycle and A2E production depend on the influx of all—trans retinol from serum to the RPE. Formation of the tertiary retinol—binding protein 4 (RBP4)—transthyretin (TTR)—retinol complex in serum is required for retinol uptake from circulation to the RPE. Retinol-binding site on RBP4 is sterically proximal to the interface ing the RBP4—TTR interaction. RBP4 antagonists that compete with serum retinol for binding to RBP4 while blocking the RBP4-TTR ction would reduce serum l, slow down the visual cycle, and t formation of cytotoxic bisretinoids.

RBP4 represents an attractive drug target for indirect pharmacological inhibition of the visual cycle and A2E formation. The retinol—binding site on RBP4 is sterically proximal to the interface mediating the RBP4—TTR interaction. Retinol nists competing with serum retinol for binding to RBP4 while blocking the RBP4—TTR interaction would reduce serum RBP4 and retinol levels which would lead to reduced uptake of retinol to the . The outcome would be visual cycle inhibition with subsequent ion in the A2E sis.

A synthetic retinoid called fenretinide [N—(4—hydroxy— phenyl)retinamide, 4HRP] (Figure 6) previously considered as a cancer treatment (29) was found to bind to RBP4, displace all—trans retinol from RBP4 (13), and disrupt the RBP4—TTR interaction (13,14). inide was shown to reduce serum RBP4 and retinol (15), inhibit ocular all—trans retinol uptake and slow down the visual cycle (11).

Importantly, fenretinide administration reduced A2E tion in an animal model of excessive bisretinoid accumulation, Abca4 -/- mice (11). Pre—clinical experiments with fenretinide validated RBP4 as a drug target for dry AMD. r, fenretinide is non—selective and toxic. ndent of its activity as an antagonist of retinol binding to RBP4, fenretinide is an extremely active inducer of apoptosis in many cell types (16—19), including the retinal pigment epithelium cells (20). It has been suggested that fenretinide’s adverse effects are mediated by its action as a ligand of a nuclear receptor RAR (21— 24). Additionally, similar to other retinoids, inide is reported to stimulate formation of hemangiosarcomas in mice. Moreover, inide is teratogenic, which makes its use problematic in Stargardt disease patients of childbearing age.

As fenretinide’s safety profile may be incompatible with erm dosing in individuals with blinding but non—life threatening conditions, identification of new classes of RBP4 antagonists is of icant importance. The compounds of the present invention displace retinol from RBP4, disrupt retinol—induced RBP4—TTR interaction, and. reduce SGIUHI REBP4 levels. The compounds of the present invention inhibit bisretinoid lation in the Abca4 —/— mouse model of excessive lipofuscinogenesis which indicates usefulness a treatment for dry AMD and Stargardt disease.

The present ion relates to small les for ent of macular degeneration and Stargardt Disease. Disclosed herein is the ophthalmic use of the small molecules as non-retinoid RBP4 antagonists. The compound listed in Table 2 have been shown to bind RBP4 in vitro and/or to antagonize RBP4-TTR interaction in vitro at biologically significant concentrations. Additional compounds described herein, which are analogs of compound listed in Table 2 analogously bind RBP4 in vitro and antagonize RBP4-TTR interaction in vitro at biologically significant concentrations.

Currently, there is no FDA-approved treatment for dry AMD or Stargardt disease, which s millions of patients. An over the counter, non FDA-approved cocktail of antioxidant vitamins and zinc (AREDS formula) is claimed to be beneficial in a subset of dry AMD patients. There are no treatments for Stargardt e. The present ion identified non-retinoid RBP4 antagonists that are useful for the treatment of dry AMD and other conditions characterized by excessive accumulation of lipofuscin. Without wishing to be bound by any scientific theory, as lation of lipofuscin seems to be a direct cause of RPE and photoreceoptor demise in AMD and STGD retina, the nds described herein are disease-modifying agents since they directly address the root cause of these diseases. The present invention provides novel methods of treatment that will preserve vision in AMD and Stargardt disease patients, and patients’ suffereing from conditions characterized by excessive accumulation of scin, or at least provides the public with a useful choice.

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Claims (33)

What is claimed is:

1. A compound having the structure: R4 R2 R5 R1 O B wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than R6 is H, OH, or halogen; and B has the structure: X Q ? d Z2 , wherein a, ß, ?,and d are each ndently absent or present, and when present each is a bond; X is C or N; Z1 is N; Z2 is N or NR7, wherein R7 is H, C1-C4 alkyl, or oxetane; and Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure, wherein the substituent in Q when present is H, halogen, CN, CF3, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)-(C1-C6 alkyl), (C1-C6 alkyl), H2 C(O)NH-(C1-C6 alkyl), C(O)- (C6 aryl), C(O)-(C6 heteroaryl), C(O)- pyrrolidine, C(O)-piperidine, C(O)- piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)- CO2(C1-C6 alkyl) or 1-C6 alkyl), and wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than N NH , or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the ure: wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, wherein two or more of R1, R2, R3, R4, or R5 are other than R6 is H, or halogen; and B has the structure: wherein n is an r from 0-1; a, ß, ?, d, e, and f are each independently absent or present, and when present each is a bond; Z1 is N; Z2 is N or NR7; wherein R7 is H, C1-C4 alkyl, or oxetane; X is C or N; Y1, Y2, Y3, and Y4 are each independently CR8, CH2, N, or N-R9, wherein R8 is H, halogen, OCH3, CN, or CF3; and R9 is H, CN, oxetane, C1-C6 alkyl, C3- C6 lkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)-(C1-C6 alkyl), C(O)2-(C1-C6 alkyl), C(O)-NH2, C(O)NH- (C1-C6 alkyl), C(O)-(C6 aryl), C(O)- (C6 heteroaryl), C(O)-pyrrolidine, C(O)- piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2 (C1-C6 alkyl) or SO2-(C1- C6 alkyl), wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein when R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H, then B is other than N NH , or a pharmaceutically acceptable salt thereof.

4. The nd of any one of claims 1-3 having the structure: R4 R2 R5 R1 O B .

5. The compound of any one of claims 1-4, wherein R1, R2, R3, R4, R5 and R6 are each independently H, Cl, F, or CF3.

6. The compound of claim 5, wherein R1 is CF3, R2 is F, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is H, and R5 is H, or R1 is CF3, R2 is F, R3 is H, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is F, R4 is F, and R5 is H, or R1 is CF3, R2 is H, R3 is H, R4 is H, and R5 is F, or R1 is CF3, R2 is H, R3 is F, R4 is H, and R5 is H, or R1 is CF3, R2 is H, R3 is H, R4 is Cl, and R5 is H, or R1 is CF3, R2 is Cl, R3 is H, R4 is H, and R5 is H, or R1 is H, R2 is CF3, R3 is H, R4 is CF3, and R5 is H, or R1 is Cl, R2 is H, R3 is H, R4 is F, and R5 is H, or R1 is Cl, R2 is F, R3 is H, R4 is H, and R5 is H.

7. The compound of any one of claims 1-6, wherein B has the structure: X Q ? d Z2 , a, ß, ?,and d are each independently absent or present, and when present each is a bond; X is C or N; Z1 is N; Z2 is N or NR7, wherein R7 is H, C1-C4 alkyl, or oxetane; Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

8. The compound of claim 7, wherein B has the structure: X Q ? d Z2 , wherein when a is present, then Z1 and Z2 are N, X is N, ß is t, and ? and d are absent; and when a is absent, then Z1 is N, Z2 is N-R7, X is C, ß and d are present, and ? is absent.

9. The compound of claim 8, wherein B has the structure: Y1 Y2 d f Y3 Z1 Y 4 Z2 n wherein n is an integer from 0-2; a, ß, ?, d, e, and f are each independently absent or present, and when present each is a bond; Z1 is N; Z2 is N or N-R7, wherein R7 is H, C1-C10 alkyl, or oxetane; X is C or N; and Y1, Y2, Y3, and each ence of Y4 are each independently CR8, CH2, or N-R9, wherein R8 is H, halogen, OCH3, CN, or CF3; and R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)-CF3, C(O)-(C1-C6 alkyl), C(O)2-(C1-C6 alkyl), C(O)-NH2 C(O)NH-(C1-C6 alkyl), C(O)-(C6 aryl), C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 -CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2-(C1-C6 alkyl).

10. The compound of claim 9, wherein B has the structure: Y1 Y2 N Y 4 N n R7 , wherein n is 0; R7 is H, C1-C4 alkyl, or oxetane; Y1 and Y3 are each CH2; and Y2 is N-R9, wherein R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)(C3-C6 lkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)- CF3, C(O)-(C1-C6 alkyl), C(O)2-(C1-C6 alkyl), C(O)-NH2 C(O)NH-(C1-C6 , C(O)-(C6 aryl), C(O)-(C6 heteroaryl), C(O)-pyrrolidine, iperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2-(C1-C6 alkyl).

11. The compound of claim 9, n B has the structure: Y1 Y2 N Y 4 N n R7 , wherein n is 1; R7 is H, C1-C4 alkyl, or oxetane; Y1, Y2 and Y4 are each CH2; and Y3 is N-R9, wherein R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 cycloalkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)- CF3, C(O)-(C1-C6 alkyl), C(O)2-(C1-C6 alkyl), C(O)-NH2 C(O)NH-(C1-C6 alkyl), C(O)-(C6 aryl), C(O)-(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2-(C1-C6 alkyl).

12. The compound of claim 9, wherein B has the structure: Y1 Y2 N Y 4 N n R7 , wherein n is 1; R7 is H, C1-C4 alkyl, or e; Y1, Y3 and Y4 are each CH2; and Y2 is N-R9, wherein R9 is H, CN, oxetane, C1-C6 alkyl, C3-C6 lkyl, (C1-C4 alkyl)(C3-C6 cycloalkyl), (C1-C6 alkyl)-OCH3, (C1-C6 alkyl)- CF3, C(O)-(C1-C6 , C(O)2-(C1-C6 alkyl), C(O)-NH2 -(C1-C6 alkyl), C(O)-(C6 aryl), C(O)-(C6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C1-C6 alkyl)-CO2H, (C1-C6 alkyl)-CO2(C1-C6 alkyl) or SO2-(C1-C6 alkyl).

13. The compound of any one of claims 10-12, wherein B has the structure: N N N R9 N N N H , H , or H .

14. The compound of claim 13, wherein R9 is H, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, t-Bu, CH2CH(CH3)2, H3)3, CH2CF3, CH2CH2CF3, CH2OCH3, CH2CH2OCH3, O O t-Bu O OH , O , , or .

15. The compound of claim 13, wherein R9 is SO2-CH3, C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3, C(O)- CH(CH3)2, C(O)-CH2CH(CH3)2, -Bu, C(O)-OCH3, C(O)-NHCH3, O O O O N N , , , , O O N N , or .

16. The compound of any one of claims 10-12, R7 is H, CH3, CH2CH3, CH(CH3)2, or .

17. The compound of claim 9, wherein B has the structure: Y1 Y2 N Y4 wherein Y1, Y2, Y3 and Y4 are each independently CR8 or N, wherein each R8 is independently H, halogen, OCH3, CN, or

18. The compound of claim 17, wherein B has the structure: N N N N N , N , R8, or N .

19. The compound of claim 18, n each R8 is CN or OCH3.

20. The compound of claim 14 or 15 having the structure: F F F F F CF3 CF3 CF3 CF3 CF3 O O S OCH3 N N N N N N N N N N N O O H O O O N NH , N NH , N NH , N NH , N NH , F F F F CF3 CF3 CF3 CF3 CN CF3 N N N N N N N N OCH3 O O O O N NH , N NH , N NH , N NH , F F F F F CF3 CF3 CF3 CF3 CF3 N N N N N N N N CN CF3 N OCH3 N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F CF3 CF3 CF3 CF3 N O N N N N N N N O O O O N NH , N NH , N NH , N NH , F F F F F F F F F F CF3 CF3 CF3 CF3 CF3 O O O O N N N N N N N N N N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F F F F F CF3 CF3 CF3 CF3 CF3 O O OCH3 NHCH3 N N N N N N N N N N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F F F F F CF3 CF3 CF3 CF3 CF3 CF3 OCH3 N N N N N N N N N N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 O O O N N N NHCH3 N OCH3 N N N N O O O O N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 O O N O N O N N N N N N N N N O O O O N NH , N NH , N NH , N NH , F F F F F F F F F F CF3 CF3 CF3 CF3 CF3 O CF3 OCH3 N N N CF3 N N N N N N N N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F F CF3 CF3 CF3 CF3 O NHCH3 N N N N N N N NHCH3 N O O O O N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 OH O N N N O N N N OCH3 N N O O O O N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 O O N N N N N OCH3 N CN N N O O O O N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 N N N N N N CF3 N CF3 N O O O O N NH , N NH , N NH , N NH , F F F F F F F CF3 CF3 CF3 CF3 OCH3 O N O O N N N N N N N OCH3 N O O O O N NH , N NH , N NH , N NH , F F F F F F F F CF3 CF3 CF3 CF3 N N N O N N N N N CN O O O O N NH , N NH , N NH , N NH , F F F F F F F CF3 CF3 CF3 CF3 O O CF3 NHCH3 N N N N N N N N O O O O O N NH , N NH , N NH , N NH , F F F F Cl Cl Cl Cl N N N N N N N N CN O O O O N NH , N NH , N NH , N NH , F F F3C CF3 Cl Cl F CF3 O O O O S S N O N N N N N N N O O O O N NH , N NH , N NH , N NH , F F F F CF3 Cl Cl Cl Cl O O N N N N N N N N N N O O O O O N NH , N NH , N NH , N NH , N NH , F F F F F F F F Cl Cl CF3 CF3 CF3 CF3 OCH3 N N N N N N N N NH NH O O O O O N NH , N NH , N NH , N NH , N NH , F3C F F F3C F CF3 CF3 CF3 N N N N N NH N O O O N NH , N NH or N NH , or a pharmaceutically acceptable salt of the nd.

21. The compound of claim 19 having the structure: F F F F F F CF3 CF3 CF3 Cl Cl CN CN CN CN CN N N N N N O N N N N O O O O N N , N N , N N , N N , N N , F3C CF3 Cl Cl F CF3 CF3 CF3 CF3 OCH3 CN CN CN CN N N N N N N N O O N N N O O O N N , N N , N N , N N , or N N , or a pharmaceutically acceptable salt of the compound.

22. The nd of claim 1 having the structure: F F F F F F CF3 CF3 Cl Cl CF3 CF3 H H H N N N N N N N N N NH NH NH O O O O O O N NH , N NH , N NH , N NH , N NH , N NH , F F F3C CF3 F3C CF3 Cl Cl F CF3 H H H N N N N N N N N NH NH O O O O O N NH , N NH , N NH , N NH , N NH ,or F CF3 N NH , or a pharmaceutically acceptable salt of the compound.

23. The compound of claim 1 having the structure: F F F F F F F CF3 CF3 CF3 CF3 O O O CN N N N N N N O O O O N NH , N NH , N NH , N N , or F F N N , or a pharmaceutically able salt of the compound.

24. A pharmaceutical composition comprising the compound of any one of claims 1-23 and a pharmaceutically able carrier.

25. Use of the compound of any one of claims 1-23 or the ceutical composition of claim 24 in the manufacture of a medicament for treating a disease terized by excessive lipofuscin accumulation in the retina.

26. The use of claim 25, wherein the e is further characterized by bisretinoid-mediated macular degeneration.

27. The use of claim 25 or 26, wherein the amount of the compound or the pharmaceutical ition is effective to lower the serum concentration of RBP4 in the subject, or lower the retinal concentration of a bisretinoid in lipofuscin in the subject.

28. The use of claim 26 or 27, wherein the bisretinoid is A2E, isoA2E, A2-DHP-PE, or atRAL di-PE.

29. The use of any one of claims 25-28, wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Stargardt Disease, Best disease, adult vitelliform maculopathy or Stargardt-like macular dystrophy.

30. The use of any one of claims 25-29, wherein treating the disease comprises disrupting or preventing formation of a RBP4-retinol complex; or disrupting a transthyretin (TTR)/retinol binding protein 4 (RBP4)/retinol complex.

31. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim24, for use in disrupting or preventing formation of a RBP4-rentinol complex; or disrupting a transthyretin (TTR)/retinol binding protein 4 (RBP4)/retinol complex.

32. A method for the preparation of Compound 81: (Compound 81) by conversion from Compound 33: (Compound 33).

33. The compound of claim 1, substantially as herein described with reference to any one of the es and/or