NZ718075B2

NZ718075B2 - Compositions useful for treating disorders related to kit

Info

Publication number: NZ718075B2
Application number: NZ718075A
Authority: NZ
Inventors: Brian L Hodous; Joseph L Kim; Douglas Wilson; Kevin J Wilson; Yulian Zhang
Original assignee: Blueprint Medicines Corporation
Priority date: 2013-10-17
Filing date: 2014-10-15
Publication date: 2022-02-01

Abstract

Compounds of formula (II) and compositions useful for treating disorders related to mutant KIT are described herein.

Description

Compositions Useful for Treating Disorders Related to KIT Claim of Priority This application claims ty to N. 61/892,086 filed October 17, 2013, U.S.S.N. 61/931,204 filed January 24, 2014, and N. 61/975,229 filed April 4, 2014, the content of each of which is incorporated by reference in its entirety.

Background The invention relates to nds and compositions useful for treating disorders related to KIT and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT s receptor dimerization and activation of ream signaling pathways. KIT mutations generally occur in the DNA encoding the embrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. ons make KIT function independent of activation by SCF, leading to a high cell division rate and ly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma.

As such, there is a need for therapeutic agents that inhibit KIT, and especially agents that inhibit mutant KIT.

Platelet—derived growth factor receptors R) are cell e tyrosine kinase receptors for members of the platelet—derived growth factor (PDGF) family. PDGF subunits —A and —B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. A PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. As such, there is a need for agents that target this mutation.

Summary of the Invention The present invention features compounds and compositions for treating or preventing conditions such as mastocytosis and mast cell diseases by modulating the activity of KIT, such compounds having the structural Formula I: or a pharmaceutically acceptable salt f, wherein: W is selected from hydrogen or / wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl or cyclyl; each X and Y is independently selected from CR1 or N; Z is C1—C6 alkyl, lkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl; wherein each of C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0—5 ences of RC; L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkynylene)—, 6 alkenylene)—, — (C1—C6 haloalkylene)—, —(C1—C6 heteroalkylene)—, —(C1—C6 hydroxyalkylene)—, —C(O)—, —O—, —S—, — 3(0), soy, —N(R2)—, -O-(C1—C6 ne)—, —(C1—C6 alkylene)—O—, —N(R2)—CO—, —CO—N(R2)—, —(C1—C6 alkylene)—N(R2)—, —N(R2)—(C1—C6 alkylene)—, -CO-(C1-C6 alkylene)—, —CO— N(R2)—(C1—C6 alkylene)—, —N(R2)—SOZ—, — R2)-, —N(R2)-SOZ-(C1-C6 alkylene)—, or sog— N(R2)—(C1—C6 alkylene)—; each RA and RB is ndently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 heterocyclyl, halo, C1-C6 kyl, C1-C6 yalkyl, C1-C6 heteroalkyl, monocyclic or ic aralkyl, -N(R2)(R2), cyano, -OR2; each RC is independently selected from C1-C6 alkyl, C1-C6 alkynyl, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or ic l, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, 2, - OC(O)R2, -C(O)OR2, -SR2, -S(O)2R2, -S(O)2-N(R2)(R2), -(C1-C6 alkylene)-S(O)2-N(R2)(R2), - N(R2)(R2), -C(O)-N(R2)(R2), -N(R2)(R2)-C(O)R2, -(C1-C6 alkylene)-N(R2)-C(O)R2, - NR2S(O)2R2, -P(O)(R2)(R2), and –OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, l, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or 2 RC together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring tuted with 0-5 occurrences of Ra; each RD and RF is, independently, en, C1-C6 alkyl, C1-C6 cycloalkyl, hydroxyl, halo, C1-C6 alkoxy, C1-C6 haloalkyl, -N(R2)(R2), or cyano; each R1 is independently ed from hydrogen, C1-C6 alkyl, monocyclic aralkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, -N(R2)(R2), -OR2; each R2 is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 thioalkyl, - NR"R", C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, wherein each of C1-C6 alkyl, cycloalkyl and heterocyclyl is independently tuted with 0-5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently hydrogen, halo, cyano, hydroxyl, C1-C6 alkoxyl, - C(O)R’, C(O)OR’, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, - NR’R’, or cycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences of R’; each R’ is hydrogen, hydroxyl, or C1-C6 alkyl; each R" is hydrogen, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C(O)-NR’R’; -C(S)-NR’R’; and m, p, and q are each independently 0, 1, 2, 3, or 4.

In a first aspect, the invention provides a compound of Formula II: A (RA)q N N (RB)p or a pharmaceutically acceptable salt thereof, n: Ring A is selected from monocyclic or bicyclic aryl, monocyclic or ic aryl, cycloalkyl and heterocyclyl; Z is selected from C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or ic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; wherein each of C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or ic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cyclyl, monocyclic and bicyclic heterocyclylalkyl is ndently substituted with 0-5 occurrences of RC; L is selected from a bond, -(C(R2)(R2))m-, -(C2-C6 alkynylene)-, -(C2-C6 alkenylene)-, - (C1-C6 haloalkylene)-, -(C1-C6 heteroalkylene)-, -(C1-C6 hydroxyalkylene)-, -C(O)-, -O-, -S-, - S(O), -S(O)2-, -N(R2)-, -O-(C1-C6 ne)-, -(C1-C6 alkylene)-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -(C1-C6 alkylene)-N(R2)-, -N(R2)-(C1-C6 alkylene)-, -N(R2)-C(O)-(C1-C6 alkylene)-, -C(O)- N(R2)-(C1-C6 alkylene)-, -N(R2)-S(O)2-, - S(O)2-N(R2)-, -N(R2)-S(O)2-(C1-C6 alkylene)-, and – S(O)2-N(R2)-(C1-C6 alkylene)-; each RA and RB is independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 heterocyclyl, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, monocyclic or bicyclic aralkyl, -N(R2)(R2), cyano, and -OR2; each RC is independently selected from C1-C6 alkyl, C1-C6 alkynyl, halo, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, -C(O)R2, - OC(O)R2, -C(O)OR2, -SR2, -S(O)2R2, -S(O)2-N(R2)(R2), 6 alkylene)-S(O)2-N(R2)(R2), - - 3a - N(R2)(R2), -C(O)-N(R2)(R2), -N(R2)(R2)-C(O)R2, -(C1-C6 ne)-N(R2)-C(O)R2, - NR2S(O)2R2, -P(O)(R2)(R2), and –OR2; wherein each of alkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or 2 RC together with the carbon ) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of Ra; each R2 is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 thioalkyl, - NR"R", C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of Rb, or 2 R2 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C6 alkoxyl, -C(O)R’, C(O)OR’, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, -NR’R’, and cycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences of each R’ is en, hydroxyl, or C1-C6 alkyl; each R" is hydrogen, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C(O)-NR’R’; or -C(S)-NR’R’; and m, p, and q are each independently 0, 1, 2, 3, or 4.

In a second aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically able carrier and a compound of the first aspect or a pharmaceutically acceptable salt thereof.

In a third aspect, the ton provides the use of a compound according to the first aspect or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating ytosis in a patient.

In a fourth aspect, the invention provides the use of a nd ing to the first aspect or a pharmaceutically acceptable salt thereof, in the cture of a medicament for treating gastrointestinal stromal tumor in a patient.

In a fifth aspect, the invention provides the use of a compound according to the first aspect or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ng acute myeloid leukemia in a t.

Any of the compounds disclosed herein may be used to treat any of the diseases disclosed herein - 3b - [Followed by page 4] Brief Description of the Drawings Figure l is a line graph ing tumor growth curves of different treatment groups: vehicle (0), Dasatinib at 25 mpk p0 bid*lO days (I), Compound 46 at 3 mpk p0 qd*lO days (—A—), nd 46 at 10 mpk p0 qd*lO days (—V—), Compound 46 at 30 mpk p0 qd*lO days (4), and Compound 46 at 100 mpk p0 qd*lO days (.).

Figure 2 is a line graph depicting the results from the body weight changes in the tumor bearing mice of different treatment groups: vehicle (4), Dasatinib at 25 mpk p0 bid*lO days (I), Compound 46 at 3 mpk p0 qd*lO days (—A—), Compound 46 at 10 mpk p0 qd*lO days (—V—), nd 46 at 30 mpk p0 qd*lO days (4), and nd 46 at 100 mpk p0 qd*lO days (.‘).

Detailed Description of the Invention "Aliphatic group" means a straight—chain, branched—chain, or cyclic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, and an l group.

"Alkylene" refers to a divalent radical of an alkyl group, 6.57., —CH2—, —CH2CH2—, and CH2CH2CH2—.

"Alkenyl" means an aliphatic group containing at least one double bond.

"Alkoxyl" or "alkoxy" means an alkyl group having an oxygen radical ed thereto.

Representative alkoxyl groups include y, ethoxy, propyloxy, tert—butoxy and the like.

The term "haloalkoxy" refers to an alkoxy in which one or more hydrogen atoms are ed by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g. , perfluoroalkoxy).

"Alkyl" refers to a monovalent radical of a saturated straight or branched hydrocarbon, such as a ht or branched group of 1—12, 1—10, or 1—6 carbon atoms, referred to herein as C1—C12 alkyl, C1—C10 alkyl, and C1—C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2—methyl—l—propyl, 2—methyl—2—propyl, 2—methyl— l —butyl, 3—methyl— l , 2—methyl—3—butyl, 2,2—dimethyl— l l, 2—methyl— l —pentyl, 3—methyl—l—pentyl, 4—methyl—l—pentyl, 2—methyl—2—pentyl, 3—methyl—2—pentyl, 4—methyl—2—pentyl, 2,2—dimethyl—l—butyl, 3,3—dimethyl—l—butyl, 2—ethyl—l—butyl, butyl, isobutyl, t—butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

"Alkenylene" refers to an l group having two connecting points. For example, ylene" represents the group —CH=CH—. Alkenylene groups can also be in an unsubstituted form or substituted form with one or more tuents.

"Alkynyl" refers to a straight or branched hydrocarbon chain containing 2— 12 carbon atoms and terized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3—hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

"Alkynylene" refers to an alkynyl having two connecting points. For example, "ethynylene" represents the group —CEC—. Alkynylene groups can also be in an unsubstituted form or substituted form with one or more tuents.

"Hydroxyalkylene" or "hydroxyalkyl" refers to an alkylene or alkyl moiety in which an alkylene or alkyl hydrogen atom is replaced by a hydroxyl group. Hydroxyalkylene or hydroxyalkyl includes groups in which more than one hydrogen atom has been replaced by a hydroxyl group.

"Aromatic ring system" is art—recognized and refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.

"Aryl" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and cenyl, and ring systems where an aromatic carbon ring is fused to one or more non—aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.

"Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2— phenylethyl, 3—phenylpropyl, 9—ﬂuorenyl, benzhydryl, and trityl groups.

"Aryloxy" refers to —O—(aryl), wherein the heteroaryl moiety is as d herein.

"Halo" refers to a radical of any n, 6.57., —F, —Cl, —Br, or —I.

"Haloalkyl" and "haloalkoxy" refers to alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For e, the terms "ﬂuoroalkyl" and "ﬂuoroalkoxy" include kyl and haloalkoxy groups, respectively, in which the halo is ﬂuorine. "Haloalkylene" refers to a divalent alkyl, e.g., —CH2—, —CH2CH2—, and —CH2CH2CH2—, in which one or more en atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo.

"Heteroalkyl" refers to an optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A cal range may be given, e.g. C1—C6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms. For example, a —CHZOCH2CH3 radical is referred to as a "C3" heteroalkyl. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain.

"Heteroalkylene" refers to a divalent optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.

"Carbocyclic ring system" refers to a clic, bicyclic or polycyclic hydrocarbon ring system, wherein each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic. cyclyl" refers to a monovalent radical of a carbocyclic ring system. entative carbocyclyl groups include cycloalkyl groups (e.g., entyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like).

"Cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non—aromatic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more tuents). The cycloalkyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl es include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbomyl.

"Cycloalkylalkyl" refers to a —(cycloalkyl)—alkyl l where cycloalkyl and alkyl are as disclosed herein. The "cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl group.

"Heteroaromatic ring system" is art—recognized and refers to monocyclic, bicyclic or polycyclic ring system wherein at least one ring is both aromatic and comprises at least one heteroatom (e.g., N, O or S); and wherein no other rings are heterocyclyl (as defined below). In certain instances, a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring atoms in such ring. oaryl" refers to a lent radical of a heteroaromatic ring system.

Representative aryl groups include ring systems where (i) each ring comprises a atom and is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, nyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl, benzothienyl, benzofuranyl, ofuranyl, lyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3—b]—l,4—oxazin—3— (4H)—one, 5,6,7,8—tetrahydroquinolinyl and 5,6,7,8—tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H—quinolizinyl.

"Heterocyclic ring system" refers to clic, bicyclic and clic ring systems Where at least one ring is saturated or partially unsaturated (but not ic) and comprises at least one heteroatom. A heterocyclic ring system can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.

"Heterocyclyl" refers to a monovalent radical of a heterocyclic ring system.

Representative heterocyclyls include ring systems in which (i) every ring is non—aromatic and at least one ring ses a atom, e.g., tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is omatic and ses a heteroatom and at least one other ring is an aromatic carbon ring, 6.57., l,2,3,4—tetrahydroquinolinyl, l,2,3,4—tetrahydroisoquinolinyl; and (iii) at least one ring is non—aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, e.g., 3,4—dihydro—lH—pyrano[4,3—c]pyridine, and 4—tetrahydro—2,6—naphthyridine. In some embodiments, heterocyclyl can include: ‘3; \7LLLs_ , _§_l\ -§—l: OHN \ // HN '/ NH _§_|\'/ N H K/o ’ ’ ‘ET/l\ 3|":o |\ NH, _§T/ NH. ocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group.

"Cyano" refers to a —CN radical.

"Nitro" refers to —N02.

"Hydroxy" or "hydroxyl" refers to —OH.

"Hydroxyalkylene" refers to a divalent alkyl, e.g., —CH2—, —CH2CH2—, and —CH2CH2CH2—, in which one or more hydrogen atoms are replaced by a hydroxy, and includes alkyl es in which all hydrogens have been replaced by hydroxy.

"Substituted", whether preceded by the term nally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable on of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the ion of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in n embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

As used herein, the tion of each sion, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition ere in the same ure.

Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, ing cis— and trans—isomers, R— and S—enantiomers, diastereomers, (D)—isomers, (L)—isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be ed in this invention.

If, for instance, a ular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the le contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an riate optically—active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the chemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof.

The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below a composition ns 90% of one enantiomer, 6.57., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee 2 (90—lO)/100 = 80%.

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

The compounds or compositions described herein may contain an enantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one form of the compound, e.g., the S—enantiomer. In other words such compounds or itions contain an enantiomeric excess of the S enantiomer over the R enantiomer.

The compounds described herein may also n unnatural proportions of atomic isotopes at one or more of the atoms that constitute such nds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example deuterium (2H), tritium (3H), carbon—l3 (13C), or carbon—l4 (14C). All isotopic ions of the compounds disclosed herein, whether ctive or not, are ed to be encompassed within the scope of the present invention. In addition, all tautomeric forms of the nds bed herein are intended to be within the scope of the invention.

The compound can be useful as the free base or as a salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, e, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, te, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1— 19.) n compounds disclosed herein can exist in ated forms as well as solvated forms, including hydrated forms. The term "hydrate" or "hydrated" as used herein, refers to a compound formed by the union of water with the parent compound.

In general, the solvated forms are equivalent to unsolvated forms and are encompassed Within the scope of the present invention. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are ed to be Within the scope of the t invention.

As used herein, the term "patient" refers to sms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g. murines, simians, s, bovines, porcines, canines, felines, and the like), and most ably includes humans.

As used herein, the term tive amount" refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or s and is not intended to be limited to a particular formulation or administration route. As used herein, the term "treating" includes any effect, e.g., lessening, reducing, modulating, rating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

Compounds In one embodiment, the invention provides a compound having structural Formula I or a pharmaceutically acceptable salt thereof, wherein: "‘11.

W is selected from hydrogen and / wherein Ring A is selected from clic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl; each X and Y is independently selected from CR1 and N; Z is C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl; n each of C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0—5 occurrences of RC; L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkynylene)—, —(C2—C6 alkenylene)—, — (C1—C6 haloalkylene)—, —(C1—C6 alkylene)—, —(C1—C6 hydroxyalkylene)—, , —O—, —S—, — 3(0), —soz—, —N(R2)—, -O-(C1—C6 alkylene)—, —(C1—C6 alkylene)—O—, —N(R2)—CO—, —CO—N(R2)—, —(C1—C6 alkylene)—N(R2)—, —N(R2)—(C1—C6 alkylene)—, -N(R2)-CO-(C1-C6 alkylene)—, —CO— N(R2)—(C1—C6 ne)—, —N(R2)—SOz—, — SOg-N(R2)-, —SOz—(C1-C6 ne)—, and sog— (C1—C6 alkylene)—; each RA and RB is independently selected from C1—C6 alkyl, C1—C6 cycloalkyl, C1—C6 heterocyclyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, monocyclic or bicyclic l, —N(R2)(R2), cyano, and —OR2; each RC is independently selected from C1—C6 alkyl, C1—C6 alkynyl, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, clic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R2, — OC(O)R2, —C(O)OR2, —SR2, —S(O)2R2, —S(O)2—N(R2)(R2), —(C1—C6 alkylene)—S(0)2—N(R2)(R2), — N(R2)(R2), —C(O)—N(R2)(R2), (R2)—C(O)R2, —(C1—C6 alkylene)—N(R2)—C(O)R2, — NRZS(O)2R2, -P(O)(R2)(R2), and —OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, l, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0—5 occurrences of Ra; or 2 RC together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0—5 occurrences of Ra; each RD and RF is independently selected from en, C1—C6 alkyl, C1—C6 cycloalkyl, yl, halo, C1—C6 alkoxy, C1—C6 haloalkyl, -N(R2)(R2), and cyano; each R1 is independently selected from hydrogen, C1—C6 alkyl, monocyclic aralkyl, C1—C6 hydroxyalkyl, halo, C1—C6 haloalkyl, -N(R2)(R2), and -OR2; each R2 is ndently selected from hydrogen, hydroxyl, halo, thiol, C1—C6 thioalkyl, — NR"R", C1—C6 alkyl, C1—C6 alkoxy, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and cyclylalkyl, wherein each of C1—C6 alkyl, cycloalkyl and heterocyclyl is independently substituted with 0—5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently selected from en, halo, cyano, hydroxyl, C1—C6 alkoxyl, -C(O)R’, C(O)OR’, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 yalkyl, —NR’R’, and cycloalkyl, wherein cycloalkyl is substituted with 0—5 occurrences of each R’ is hydrogen, yl, or C1—C6 alkyl; each R" is hydrogen, C1—C6 alkyl, —C(O)—C1—C6 alkyl, NR’R’; or —C(S)—NR’R’; and m, p, and q are each ndently 0, l, 2, 3, or 4.

In some embodiments, W is H. In some embodiments, W is / . In some embodiments, Ring A is monocyclic or bicyclic aryl substituted with 0, l, 2 or 3 RA. In some embodiments, Ring A is phenyl. In some ments, Ring A is phenyl substituted with halo.

In some embodiments, Ring A is phenyl substituted with ﬂuoro or chloro. In some embodiments, Ring A is 4—ﬂuorophenyl. In some embodiments, Ring A is 2,4—diﬂuorophenyl.

In some embodiments, Ring A is 2, 4, 6—triﬂuorophenyl. In some embodiments, Ring A is 4— chlorophenyl.

In some embodiments, each RA is independently selected from C1—C6 alkyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, —N(R2)(R2), cyano, and —OR2. In some embodiments, RA is independently selected from C1—C6 alkyl and halo. In some embodiments, RA is independently selected from ﬂuoro, chloro and methyl. In some embodiments, RA is independently selected from ﬂuoro and chloro. In some embodiments, RA is . In some embodiments, RA is ﬂuoro and q is l, 2, or 3. In some embodiments, RA is chloro and ﬂuoro and q is 2. In some ments, RA is methyl and ﬂuoro and q is 2.

In some embodiments, each RB is independently selected from C1—C6 alkyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, —N(R2)(R2), cyano and —OR2. In some embodiments, RB is C1— WO 57873 C6 alkyl or C1—C6 hydroxyalkyl. In some embodiments, RB is , ethyl, or hydroxymethyl.

In some ments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, at least one of X and Y is N. In some embodiments, X and Y are both N. In some embodiments, X and Y are both CR1. In some embodiments, X and Y are both In some embodiments, Z is monocyclic or bicyclic aryl. In some embodiments, Z is monocyclic or ic aryl. In some embodiments, Z is monocyclic or bicyclic heterocyclyl. In some embodiments, Z is monocyclic heteroaryl. In some embodiments, Z is selected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl. In some embodiments, Z is substituted with 0, l or 2 occurrences of RC. In some embodiments, Z is substituted with 0 or 1 occurrences of RC.

In some embodiments, RC is independently selected from cyano, C1—C6 alkyl, C1—C6 l, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or ic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, — C(O)R2, —OC(O)R2, —C(O)OR2, (R2), —C(O)—N(R2)(R2), and —OR2. In some embodiments, RC is independently selected from cyano, C1—C6 alkyl, halo, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R2, — C(O)OR2, (R2), —C(O)—N(R2)(R2), and —OR2. In some embodiments, each RC is independently selected from C1—C6 alkyl, halo, monocyclic and bicyclic heterocyclyl.

In some embodiments, RD is hydrogen, C1—C6 alkyl, C1—C6 alkoxy, C1—C6 haloalkyl, — N(R2)(R2), or cyano. In some embodiments, RD is en or —N(R2)(R2). In some embodiments, RD is hydrogen or —NH2.

In some embodiments, RF is hydrogen or halo, e.g., chloro or ﬂuoro. In some embodiments, RF is hydrogen. In some embodiments, RF is chloro or ﬂuoro.

In some embodiments, L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkenylene)—, — (C1—C6 haloalkylene)—, —(C1—C6 hydroxyalkylene)—, —S—, —S(O), —SOz—, and —N(R2)—. In some embodiments, L is selected from a bond, )(R2))m—, —S—, and —SOZ—. In some embodiments, L is —(C(R2)(R2))m—. In some embodiments, L is a bond or CH2. In some embodiments, L is — (R2))m—, wherein each R2 is independently selected from hydrogen, hydroxyl, —NR"R", C1— C6 alkyl, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, and cycloalkyl; and m is 1.

In some embodiments, each R2 is independently selected from hydrogen, yl, halo, —NR"R", C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, and cycloalkyl, wherein each of C1— C6 alkyl and cycloalkyl is independently substituted with 0—5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or heterocyclyl ring. In some embodiments, each R2 is independently ed from halo, hydrogen, hydroxyl, — NR"R", and C1—C6 alkyl wherein C1—C6 alkyl is independently substituted with 0—5 occurrences of Rb. In some embodiments, Rb is independently hydrogen, halo or hydroxyl. In some embodiments, L is —NR"R". In some embodiments, R" is hydrogen or C1—C6 alkyl. In some embodiments, R" is hydrogen. In some embodiments, L is —S—. In some embodiments, L is — CH2: In some embodiments, m is 0, l or 2. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, p is 0 or 1.

In some embodiments, q is 0, l, 2 or 3. In some embodiments, q is 0. In some ments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

In r embodiment, the invention features a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein: N/ / kw / Z Ring A is ed from monocyclic or ic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl; Z is selected from C1—C6 alkyl, cycloalkyl, clic or ic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; wherein each of C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or ic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0—5 occurrences of RC; L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkynylene)—, —(C2—C6 alkenylene)—, — (C1—C6 kylene)—, —(C1—C6 heteroalkylene)—, —(C1—C6 hydroxyalkylene)—, —C(O)—, —O—, —S—, — 3(0), —soz—, —N(R2)—, —C6 alkylene)—, —(C1—C6 alkylene)—O—, —N(R2)—CO—, —CO—N(R2)—, —(C1—C6 alkylene)—N(R2)—, —N(R2)—(C1—C6 alkylene)—, -N(R2)-CO-(C1-C6 alkylene)—, —CO— N(R2)—(C1—C6 alkylene)—, —N(R2)—SOz—, — SOg-N(R2)-, -N(R2)—SOz—(C1-C6 alkylene)—, and sog— N(R2)—(C1—C6 ne)—; each RA and RB is independently selected from C1—C6 alkyl, C1—C6 cycloalkyl, C1—C6 heterocyclyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, monocyclic or bicyclic aralkyl, —N(R2)(R2), cyano, and —OR2; each RC is independently selected from C1—C6 alkyl, C1—C6 alkynyl, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or ic heterocyclyl, monocyclic or ic heterocyclylalkyl, nitro, cyano, 2, — OC(O)R2, —C(O)OR2, —SR2, —S(O)2R2, —S(O)2—N(R2)(R2), —(C1—C6 alkylene)—S(O)2—N(R2)(R2), — N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R2, —(C1—C6 ne)—N(R2)—C(O)R2, — )2R2, -P(O)(R2)(R2), and —OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, lkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0—5 occurrences of Ra; or 2 RC together with the carbon atom(s) to which they are attached form a cycloalkyl or cyclyl ring substituted with 0—5 occurrences of Ra; each R2 is independently selected from hydrogen, hydroxyl, halo, thiol, C1—C6 thioalkyl, — NR"R", C1—C6 alkyl, C1—C6 alkoxy, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1—C6 alkyl, cycloalkyl and heterocyclyl is independently substituted with 0—5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are ed form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently selected from hydrogen, halo, cyano, hydroxyl, C1—C6 alkoxyl, —C(O)R’, C(O)OR’, C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 heteroalkyl, C1—C6 yalkyl, —NR’R’, and cycloalkyl, wherein cycloalkyl is tuted with 0—5 occurrences of each R’ is hydrogen, hydroxyl, or C1—C6 alkyl; each R" is hydrogen, C1—C6 alkyl, —C(O)—C1—C6 alkyl, —C(O)—NR’R’; —C(S)—NR’R’; and m, p, and q are each independently 0, l, 2, 3, or 4.

In some ments, A is monocyclic or bicyclic aryl. In some embodiments, Ring A is monocyclic or bicyclic aryl substituted with 0, l, 2 or 3 RA. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is phenyl substituted with halo. In some embodiments, Ring A is phenyl substituted with ﬂuoro or chloro. In some embodiments, Ring A is 4— ﬂuorophenyl. In some embodiments, Ring A is 2,4—diﬂuorophenyl. In some embodiments, Ring A is 2, 4, uorophenyl. In some embodiments, Ring A is 4—chlorophenyl.

In some embodiments, each RA is independently selected from C1—C6 alkyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, (R2), cyano, and —OR2. In some embodiments, RA is independently selected from C1—C6 alkyl and halo. In some embodiments, RA is independently selected from ﬂuoro, chloro and methyl. In some embodiments, RA is independently selected from ﬂuoro and chloro. In some embodiments, RA is methyl. In some embodiments, RA is ﬂuoro and q is l, 2, or 3. In some embodiments, RA is chloro and ﬂuoro and q is 2. In some embodiments, RA is methyl and ﬂuoro and q is 2.

In some embodiments, each RB is independently ed from C1—C6 alkyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, —N(R2)(R2), cyano and —OR2. In some embodiments, RB is C1— C6 alkyl or C1—C6 hydroxyalkyl. In some embodiments, RB is methyl, ethyl, or hydroxymethyl.

In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, Z is monocyclic or ic aryl. In some embodiments, Z is monocyclic or bicyclic heteroaryl. In some embodiments, Z is monocyclic or bicyclic heterocyclyl. In some embodiments, Z is clic heteroaryl. In some embodiments, Z is ed from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl. In some embodiments, Z is substituted with 0, l or 2 occurrences of RC. In some embodiments, Z is tuted with 0 or 1 occurrences of RC.

In some embodiments, RC is independently selected from cyano, C1—C6 alkyl, C1—C6 alkynyl, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic heterocyclyl, clic or bicyclic heterocyclylalkyl, — C(O)R2, —OC(O)R2, —C(O)OR2, —N(R2)(R2), —C(O)—N(R2)(R2), and —OR2. In some embodiments, RC is independently ed from cyano, C1—C6 alkyl, halo, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, 2, — C(O)OR2, —N(R2)(R2), —C(O)—N(R2)(R2), and —OR2. In some embodiments, each RC is independently selected from C1—C6 alkyl, halo, monocyclic or bicyclic heterocyclyl. —l6— In some ments, RD is hydrogen, C1—C6 alkyl, C1—C6 alkoxy, C1—C6 haloalkyl, — N(R2)(R2), or cyano. In some embodiments, RD is hydrogen or —N(R2)(R2). In some embodiments, RD is hydrogen or —NH2.

In some embodiments, RF is hydrogen or halo, e.g., chloro or ﬂuoro. In some ments, RF is hydrogen. In some embodiments, RF is chloro or ﬂuoro.

In some embodiments, L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkenylene)—, — (C1—C6 haloalkylene)—, —(C1—C6 hydroxyalkylene)—, —S—, —S(O), —SOZ—, and —. In some embodiments, L is selected from a bond, —(C(R2)(R2))m—, —S—, and —SOZ—. In some embodiments, L is —(C(R2)(R2))m—. In some embodiments, L is a bond or CH2. In some embodiments, L is — (R2))m—, wherein each R2 is independently selected from hydrogen, yl, —NR"R", C1— C6 alkyl, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, and lkyl; and m is 1.

In some embodiments, each R2 is independently selected from hydrogen, hydroxyl, halo, —NR"R", C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, cycloalkyl, wherein each of C1—C6 alkyl and lkyl is independently substituted with 0—5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are attached form a lkyl or heterocyclyl ring. In some embodiments, each R2 is independently selected from halo, hydrogen, hydroxyl, — NR"R", C1—C6 alkyl wherein C1—C6 alkyl is independently substituted with 0—5 occurrences of Rb.

In some embodiments, Rb is ndently hydrogen, halo or hydroxyl. In some embodiments, L is —NR"R". In some embodiments, R" is hydrogen or C1—C6 alkyl. In some embodiments, R" is hydrogen. In some ments, L is —S—. In some embodiments, L is —CH2—.

In some embodiments, m is 0, l or 2. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, p is 0 or 1.

In some embodiments, q is 0, l, 2 or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

In another embodiment, the invention features a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein: WO 57873 Z is selected from C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic l, clic or ic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; n each of C1—C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, clic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0—5 occurrences of RC; L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkynylene)—, —(C2—C6 alkenylene)—, — (C1—C6 haloalkylene)—, —(C1—C6 heteroalkylene)—, —(C1—C6 hydroxyalkylene)—, —C(O)—, —O—, —S—, — 3(0), —soz—, —N(R2)—, -O-(C1—C6 alkylene)—, —(C1—C6 alkylene)—O—, —N(R2)—CO—, —CO—N(R2)—, —(C1—C6 alkylene)—N(R2)—, —N(R2)—(C1—C6 alkylene)—, -CO-(C1-C6 alkylene)—, —CO— N(R2)—(C1—C6 alkylene)—, —N(R2)—SOz—, — SOg-N(R2)-, -N(R2)—SOz—(C1-C6 alkylene)—, and sog— N(R2)—(C1—C6 alkylene)—; each RA and RB is independently selected from C1—C6 alkyl, C1—C6 cycloalkyl, C1—C6 heterocyclyl, halo, C1—C6 kyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, monocyclic or bicyclic aralkyl, —N(R2)(R2), cyano, and —OR2; each RC is independently selected from C1—C6 alkyl, C1—C6 alkynyl, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or ic aryl, monocyclic or bicyclic y, monocyclic or bicyclic aralkyl, monocyclic or ic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R2, — OC(O)R2, —C(O)OR2, —SR2, —S(O)2R2, —S(O)2—N(R2)(R2), —(C1—C6 ne)—S(O)2—N(R2)(R2), — N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R2, —(C1—C6 alkylene)—N(R2)—C(O)R2, — NRZS(O)2R2, -P(O)(R2)(R2), and —OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, —18— alkyl, alkynyl, cycloalkyl, aryl, y, l, heterocyclyl, heterocyclylalkyl is independently substituted with 0—5 occurrences of Ra; or 2 RC together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring tuted with 0—5 occurrences of Ra; each R2 is independently selected from hydrogen, hydroxyl, halo, thiol, C1—C6 thioalkyl, — NR"R", C1—C6 alkyl, C1—C6 alkoxy, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1—C6 alkyl, cycloalkyl and heterocyclyl is independently substituted with 0—5 occurrences of Rb, or 2 R2 together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently selected from hydrogen, halo, cyano, hydroxyl, C1—C6 l, -C(O)R’, C(O)OR’, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, —NR’R’, and cycloalkyl, wherein lkyl is substituted with 0—5 occurrences of each R’ is en, hydroxyl, or C1—C6 alkyl; each R" is hydrogen, C1—C6 alkyl, —C(O)—C1—C6 alkyl, NR’R’; —C(S)—NR’R’; and m, p, and q are each independently 0, l, 2, 3, or 4.

In some embodiments, each RA is independently selected from C1—C6 alkyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, —N(R2)(R2), cyano, and —OR2. In some embodiments, each RA is independently ed from C1—C6 alkyl, halo, C1—C6 haloalkyl, C1—C6 hydroxyalkyl, —N(R2)(R2), cyano, —OR2. In some embodiments, RA is independently selected from C1—C6 alkyl and halo. In some embodiments, RA is independently selected from ﬂuoro, chloro and methyl. In some embodiments, RA is halo. In some embodiments, RA is independently selected from ﬂuoro and chloro. In some embodiments, RA is methyl. In some embodiments, RA is ﬂuoro and q is l, 2, or 3. In some embodiments, RA is chloro and ﬂuoro and q is 2. In some embodiments, RA is methyl and ﬂuoro and q is 2.

In some embodiments, Z is monocyclic or bicyclic aryl. In some embodiments, Z is monocyclic or bicyclic heteroaryl. In some embodiments, Z is monocyclic or bicyclic cyclyl. In some embodiments, Z is monocyclic heteroaryl. In some embodiments, Z is selected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl. In some embodiments, Z is tuted with 0, l or 2 occurrences of RC. In some embodiments, Z is substituted with 0 or 1 ences of RC.

In some embodiments, each RB is independently selected from C1—C6 alkyl, C1—C6 hydroxyalkyl, C1—C6 heteroalkyl, —N(R2)(R2), cyano and —OR2. In some embodiments, RB is C1— C6 alkyl or C1—C6 hydroxyalkyl. In some embodiments, RB is methyl, ethyl, or hydroxymethyl.

In some embodiments, p is 0 or 1. In some ments, p is 0. In some embodiments, p is 1.

In some embodiments, RC is ndently selected from cyano, C1—C6 alkyl, C1—C6 alkynyl, halo, C1—C6 heteroalkyl, C1—C6 haloalkyl, C1—C6 koxy, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or ic heterocyclylalkyl, — C(O)R2, —OC(O)R2, —C(O)OR2, —N(R2)(R2), —C(O)—N(R2)(R2), and —OR2. In some embodiments, RC is independently selected from cyano, C1—C6 alkyl, halo, C1—C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R2, — C(O)OR2, —N(R2)(R2), —C(O)—N(R2)(R2), and —OR2. In some ments, each RC is independently selected from C1—C6 alkyl, halo, monocyclic or ic heterocyclyl.

In some embodiments, L is selected from a bond, —(C(R2)(R2))m—, —(C2—C6 alkenylene)—, — (C1—C6 kylene)—, —(C1—C6 hydroxyalkylene)—, —S—, —S(O), —SOZ—, and —N(R2)—. In some embodiments, L is selected from a bond, —(C(R2)(R2))m—, —S—, and —SOz—. In some embodiments, L is —(C(R2)(R2))m—. In some embodiments, L is a bond or CH2. In some embodiments, L is — (C(R2)(R2))m—, wherein each R2 is independently selected from hydrogen, hydroxyl, —NR"R", C1— C6 alkyl, C1—C6 kyl, C1—C6 hydroxyalkyl, and cycloalkyl; and m is 1.

In some embodiments, q is 0, l, 2 or 3. In some embodiments, q is l, 2 or 3.

The invention also features pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any nd of Formulas I—III.

The table below shows the structures of compounds described herein.

Compound Structure Number Q’ ‘ N I" N N \_/ N, WO 57873 N N N N N N N N N N N N N N HO N N N N N N N NH N N N N N NH2 N N H2N N N H N N N N N H N N N N N N N nues on page 23] - 22a - / N\ H _N w "N,N / N\ H N/ _N w "N,N / // \N_N NVIM \N \ __N 16 NIAW N/_W 17 \\ _N H FRWHHHM \ /NH N w \NN\NJ N\ANn.N KNN \ / 18 N.\VWN/ 2014/060746 /_\ \N C§{% \ /—\ N—\\ —N>—N\_/\ ’N /— /—\_—l-II|©‘F N U \\ OH /—N /—\ N— N‘/ \ N N—<\:/>—l-m© N 47 N\ U OH WO 57873 N-QF OH N //_N /—\ N— — N‘ \ N N_<\ / --II\ / F N\ \—/ N OH N 54 ‘\ 55 \\ N /—\ N\ F s{ \)—N N \ N —N NJ 2014/060746 N\//_N /—\ — \ N N—<\ :/>—l-III©‘F N \_/ \ OH 60 \ WO 57873 WO 57873 2014/060746 WW"340-;QF r" /—\ N— N\ \ N N—<\ / ; F N\ \—./ N (3H 76 \ WO 57873 2014/060746 /—N /—\ N— N/ \ N \N \—/N—<\:/>—1--u©‘c| \ OH /_N /—\ N— \N : \ OH /—N /—\ N— N\/ \ N UN—<\:/>—l-m©‘l: N\ N NH2 85 \ /—N /—\ N— N\ N NH2 86 \ /—N /—\ N— N\ \_/ N 6H 87 ‘\ /—N /—\ N— \ ~\ MN-QF N\ N OH 88 '\ —36— 2014/060746 rN /—\ N— N \ N N—<\ / F \N\ V 89 \ F //—N _ Nx \FHN-QF N \_/ \ OH 90 \ F N//—\N 91 \\ /—N /—\ N— N\/ \ N\ ,—<\ / \ OH FN /—\ N \ N l \ /_<\N 3— / >3 : 93 \\ ZOl4/060746 //—N /—\ N— N \ N ,—<\N , / 95 \ /_N _ \ "HM-cw N \_/ \ OH 96 \ r" ’ N \ N N F \N\ ‘ ,4 :>—/ N\//—N /—\ \ N N—<\:>—l....©‘,:N— 94 \ FN \/ N\ NJ 98 \ Y —38— WO 57873 100 N\ N N-NH /—N /—\ N— N/ \ N N—<\ / .... F ‘N \—/ \ OH 101 \ N/ w HMQF/—N /—\ N— ‘N \—/ \ OH /—N /—\ N— N\ U N OH 103 \ /—N /—\ N— N/ w Hﬂ-QF ‘N \—/ \ OH 104 \ WO 57873 WO 57873 /—N /—\ N— N/ \ N N—<\ ---- F \N U / N OH 110 \ F F rN /_\ N_ N\ \ N N—<\ U / N\ N ....©F 111 \ F F rN N_ ~\ \Mﬂ—QF N\ N NH2 112 \ N//—\N 113 \\ //—N /—\ N— N \ N N—<\ / .... F \N U N NH 114 \ 2 \\ F WO 57873 N//—\N 115 \\ FN /—\ N— N\ \ N N_<\ / --II F N N O" 116 \ \ F F F rN /—\ N_ N\ \ N N_<\ U / N N "HQ—F \ OH 117 \ F F rN N_ ~x \ WmM N \—/ N OH 118 \ \ \> 119 (—NN) N———< F \ /N \ OH WO 57873 N\/ /—\ N— \ N N—<\ :/>—l-III©‘F N \_/ \ OH 124 / Synthesis Compounds of the invention, including salts and N —oxides thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below. The ons for preparing compounds of the invention can be carried out in suitable ts which can be readily selected by one of skill in the art of c sis. Suitable solvents can be substantially non—reactive with the starting materials ants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable ts for a ular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate ting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by oscopic means, such as nuclear ic resonance (NMR) oscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV—visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

Indications The compounds described herein can be useful for treating ions associated with aberrant KIT activity, in humans or non—humans. Activating mutations in KIT are found in le indications, including systemic mastocytosis, GIST (gastrointestinal stromal ), AML (acute myeloid leukemia), melanoma, seminoma, intercranial germ cell tumors, and mediastinal B—cell lymphoma.

Mastocytosis refers to a group of disorders characterized by excessive mast cell accumulation in one tissue, or in multiple tissues. Mastocytosis is subdivided into two groups of disorders: (1) cutaneous mastocytosis (CM) describes forms that are limited to the skin; and (2) systemic mastocytosis (SM) describes forms in which mast cells infiltrate extracutaneous organs, with or without skin involvement. SM is r subdivided into five forms: indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hemotologic non—mast cell lineage disease (SM—AHNMD), and mast cell leukemia (MCL).

Diagnosis of systemic mastocytosis is based in part on histological and cytological studies of bone marrow showing infiltration by mast cells of frequently atypical morphology, which frequently abnormally express non—mast cell s (CD25 and/or CD2). Diagnosis of SM is confirmed when bone marrow mast cell infiltration occurs in the context of one of the following: (1) abnormal mast cell morphology (spindle—shaped ; (2) elevated level of serum tryptase above 20 ng/mL; or (3) the presence of the activating KIT D816V mutation.

Activating ons at the D816 position are found in the vast majority of mastocytosis cases (90—98%), with the most common mutations being D816V and D816H, and D816Y. The D816V mutation is found in the tion loop of the kinase domain, and leads to constitutive activation of KIT kinase.

The compounds described herein may also be useful to treat GIST. Complete surgical resection s the principal treatment of choice for patients with a primary GIST. Surgery is effective in approximately 50% of patients with GIST; of the remaining patients, tumor recurrence is frequent. Primary treatment with a KIT tor such as imatinib has also been shown to be sufficient for initial ent. However, resistance to imatinib occurs within months through somatic mutation. These secondary imatinib resistant mutations are most frequently located on Exon 11, 13, 14, 17 or 18. Sunitinib is the standard of care second line ent for most ib ant tumors and is effective for those containing mutations in exons 11, 13 and 14. However, secondary KIT mutations in exons 17 and 18 are resistant to sunitinib treatment and rmore, tumors ning tertiary resistance mutations in exon 17 and 18 emerge several months after sunitinib treatment. Regorafenib has shown promising results in a phase 3 clinical trial of imatinib, sunitinib resistant GISTs with activity against l but not all exon 17 and 18 mutations, of which D816 is one. Thus, there is a need for therapeutic agents to treat GIST patients with exon 17 mutations not addressed by fenib.

In addition to the use of the compounds bed herein as single agents in the refractory GIST setting, the use of combinations of imatinib, sunitinib and/or regorafenib with the compounds disclosed herein may allow for the prevention of emergence of resistance to exon 17 ons.

There is a subset of GIST patients with a D842V mutation in PDGFROL; this subgroup of GIST patients can be stratified by identifying this mutation. This subset of patients is refractory to all tyrosine kinase inhibitors currently available. The compounds described herein, due to their activity against PDGFROL D842V, can be useful in treating these patients.

The nds described herein may also be useful in treating AML. AML ts harbor KIT mutations as well, with the majority of these mutations at the D816 position.

In addition, mutations in KIT have been linked to Ewing’s sarcoma, DLBCL (diffuse large B cell lymphoma), minoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK/T—cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain cancers.

The compounds disclosed herein may be used to treat conditions associated with the KIT mutations in Exon 9, Exon 11, Exon 13, Exon 14, Exon 17 and/or Exon 18. They may also be used to treat conditions associated with ype KIT. The compounds described herein may be used as single agents to treat the conditions described herein, or they may be used in combination with other therapeutic agents, ing, without limitation, imatinib, sunitinib and regorafenib.

Other agents include the compounds described in and WC 2014/100620.

Compounds described herein can be active against one or more KIT mutations in Exon 17 (e.g., D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D820A, D820E, D820G, N822K, N822H, Y823D, and A829P), and much less active t wild—type KIT. These compounds can be administered in ation with an agent that is (a) active against other activating mutations of KIT, such as Exon 9 and 11 ons, but (b) not active against the Exon 17 mutations. Such agents include imatinib, sunitinib, and regorafenib. The combination of the compound and the agent will thus inhibit Exon 17 mutant KIT, as well as inhibiting Exon 9/11 mutant KIT. The compound and agent can be co—administered, or administered in an —46— alternating regimen. That is, the Exon 17 mutant KIT inhibitor can be administered alone for a period of time; then the Exon 9/11 mutant KIT inhibitor can be administered alone for a period of time following. This cycle may then be repeated. It is ed that such a regimen could slow the development of resistance to the Exon 17 mutant KIT inhibitor and/or the Exon 9/11 mutant KIT inhibitor.

In addition, compounds described herein that can be ive for Exon 17 KIT mutations can be administered with agents that are active against Exon 9/11 mutations, in combination with a third agent that covers mutations that are missed with the two—way combo. The combination of the three agents could inhibit a spectrum of KIT mutations, as well as wild—type KIT in some instances. The agents could be administered aneously, or in an alternating n. They can be administered one at a time, or two agents can be administered together for a period of time; then the third agent can be administered alone for a following period of time. It is believed that such a regimen could slow the development of resistance to the mutant KIT inhibitors.

Pharmaceutical Compositions While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the nd is combined with one or more pharmaceutically able excipients or carriers. The compounds disclosed herein may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the nd included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound l nt, suitable for use in contact with the s of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safﬂower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering , such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen—free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as ol®; and (22) other non—toxic compatible substances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) water e antioxidants, such as ic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil—soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha—tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) s or extenders, such as starches, lactose, e, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, n, nyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as gar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium ate; (5) solution retarding , such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid hylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, ons, suspensions, syrups and elixirs. In addition to the active ient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl l, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3—butylene glycol, oils (in particular, cottonseed, nut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, hylene glycols and fatty acid esters of sorbitan, and es thereof. —48— sions, in addition to the active compounds, may contain suspending agents as, for example, lated isostearyl alcohols, polyoxyethylene sorbitol and an , microcrystalline cellulose, um metahydroxide, bentonite, gar and tragacanth, and es thereof.

Ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, ents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide , or mixtures of these substances. Sprays can additionally contain customary propellants, such as chloroﬂuorohydrocarbons and volatile unsubstituted arbons, such as butane and propane.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier al to produce a single dosage form will generally be that amount of the nd which produces a therapeutic .

Dosage forms for the topical or ermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

When the compounds disclosed herein are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

Dosages Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the t.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound sed herein employed, or the ester, salt or amide thereof, the route of administration, the time of stration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, ion, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A ian or veterinarian having ry skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is ed.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, enous, intracerebroventricular and subcutaneous doses of the compounds of this ion for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound may be stered as two, three, four, five, six or more sub—doses administered separately at appropriate intervals hout the day, optionally, in unit dosage forms. In some embodiments, the dose for humans will be 0 mg, or 200—300 mg, administered twice daily; or 400—700 mg, or 500—600 mg, administered once daily.

EXAMPLES The following examples are intended to be illustrative, and are not meant in any way to be limiting.

The below Schemes are meant to provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to e various compounds of the invention.

S nthetic ol 1 q(RA) ,N q(RA) H / N \d Q92 N [1 / [N ,N 1)Pd mediated q(RA) N N \ N \ j: Nuceop noaromalc| h'l' t' LG2 // jNH COUPIIngreactIon. . // [N] substitution reaction + N —> jN I" \I'v X /Y 2fcirmationggLeavin rou \ O p LG2 [H [\l‘ L XfY (RA)q The otriazinone can be coupled (LG2 can be, 6.57., Cl, Br, or I) to a boron, tin or zinc aryl, heteroaryl, alkenyl, alkyl reagent via a palladium—mediated coupling reaction, e.g., Suzuki, , Negishi coupling, to provide an intermediate with a new carbon—carbon bond formed after subsequent leaving group formation (via POCl3 or other similar reagents). The resulting pyrrolotriazine can be substituted with an amine under nucleophilic ic substitution reaction conditions using a base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solvent such as dioxane to provide the piperazine—substituted otriazine. As shown below, Compounds 9, 10, and 107 were ed using Synthetic Protocol 1.

Example 1 Synthesis of (R)—6—(l—methyl— lH—pyrazol—4—yl)—4— (l—phenylethyl)pyrimidin—2—yl) piperazin—l—yl)pyrrolo[1,2—f][l,2,4]triazine and (S)—6—( 1 —methyl— lH—pyrazol—4—yl)—4— (4—(5—(l— phenylethyl)pyrimidin—2—yl)piperazin—l—yl)pyrrolo[1,2—ﬂ[1,2,4]triazine (Compounds 9 and 10) 00 ZI r (E U \_/ E N Zn,TMSCI, . . A BrCHzCHzBr N hos)C|2 2\ 2\ chlralseparatlon —> + A —> N N + N N —> IN + THF, 70 °C, 1 h / THF, 70 0C, O. N. I I N \ \ NJ\N E J + \H" \ / N’Nﬁ —>DIPEA N | N\ / /N dioxane \ N27" DIPEA dioxane Step 1: sis of (l—phenylethyl)zinc(ll) bromide: Zn TMSCI BrCHzCHzBr THF 70°C 1h ZnBr To a sion mixture of zinc powder (active, 5.1 g, 80.0 mmol) in dry THF (20 mL) was added dropwise l,2—dibromoethane (0.28 mL, 5.7 mmol) at 70 0C under nitrogen atmosphere, followed by the addition of chlorotrimethylsilane (1.2 mL, 10.6 mmol). Subsequently, (l— bromoethyl)benzene (3.7 g, 20 mmol) was added dropwise. The resultant suspension was stirred at 70 0C for another 1 h. The reaction mixture was cooled to RT and directly used for the next step.

Step 2: Synthesis of 5—(l—phenylethyl)—2— (piperazin— l—yl)pyrimidine: WO 57873 22!: N E J E J N N Pd(Amphos)C|2 + A A N N / THF, 70 °C, 0. N. | N N \ ZnBr | To a solution of tert—butyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate (4.1 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium (708 mg, 1.0 mmol) in THF (80 mL, dry) was added dropwise a solution of (1—phenylethyl)zinc(ll) bromide in THF (20 mL, 1 M, 20 mmol) under nitrogen atmosphere, and the mixture was stirred at 70 0C overnight. The reaction mixture was cooled to RT and filtered through a pad of Celite. The filtration was concentrated and purified by silica gel chromatography to give tert—butyl 4— (5—(1—phenylethyl)pyrimidin—2— yl)piperazine—1—carboxylate (1.0 g, yield 23%) as a white solid (ethyl acetate/petroleum ether 2 1/5 as elute) and 5—(1—phenylethyl)—2—(piperazin—1—yl)pyrimidine (2.4 g, 75%) as a yellow oil (methanol/dichloromethane = 1/20 as elute). MS (ES+) C16H20N4 requires: 268, found: 269 [M + H ]+.

Step 3: Chiral tion of (R)—5—(1—phenylethyl)—2—(piperazin—1—yl)pyrimidine and (S)—5—( 1 — phenylethyl)—2—(piperazin— 1—yl)pyrimidine: H H H [N] [N] [N] N2\N i i chiral separation N / IN N / I IN \ \ \ te compound 5—(1—phenylethyl)—2—(piperazin—1—yl)pyrimidine (900 mg) was separated by Chiral—HPLC under the below ions: Chiral column: AD—3 (150 * 4.6 mm 3 um) Mobile phase hexane (0.1% DEA)/EtOH (0.1% DEA) (R)—5—(1—phenylethyl)—2—(piperazin—1—yl)pyrimidine (400 mg, 44%) as a yellow oil and (S)—5—(1— phenylethyl)—2—(piperazin—1—yl)pyrimidine (350 mg, 39%) as a yellow oil were obtained.

Absolute stereochemistry was assigned randomly. MS (ES+) C16H20N4 requires: 268, found: 269 [M + H ]+.

Synthesis of 4—chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine (.3' NH20H.HC| Ph\ 0 Ph—IIDI-Ph NaOH, H20, dloxane, O_ \NH2 0C 0Pp; 0 Ph H NH2 ,N N O ' /\ \ Br //N W+ Ph\P\,ONH2 NaH, DMF | N/ H2N \0 11H 0 Ph/ 0 Br 0 180 / Br /0 C, 5 h Pd(dppf)C|2, //NN\\l COB/CNN\ N32C03 // //NNWH [\ll // //NNW NH + 110°C,12h /N / dioxane/HZO 0 CI Step 4: Synthesis of O—(diphenylphosphoryl)hydroxylamine: 93' NHZOH.HC| Ph. 0 Ph—P—Ph NaOH, H20, donane, O 0C. 0/,P\’ ‘NH2 6 Ph To a solution of hydroxylamine hydrochloride (7.3 g, 106 mmol, 2.5 eq) in water (12 mL) and e (12 mL) was added a on of NaOH (4.07 g, 102 mmol, 2.4 eq) in water (12 mL), and the mixture was cooled to —5 °C in an ice/salt bath. A solution of diphenylphosphinic chloride (10 g, 42 mmol, 1 eq) in dioxane (12 mL), precooled to below 10 0C, was rapidly added to the above solution in an ice/salt bath under Vigorous stirring. After completion of the addition, the mixture was stirred for additional 5 s in an ice/salt bath, then diluted with ice water (150 mL) and ed. The filtration cake was washed with ice water, and lyophilized to give 0— (diphenylphosphoryl)hydroxylamine (6.0 g, yield 61%) as a white solid. MS (ES+) requires: 233, found 234 [M+H]+; purity: 75%.

Step 5: sis of 1—amino—4—bromo—1H—pyrrole—2—carboxylic acid methyl ester: N 0 Ph NINHZ o W+ //\PONH NaH, DMF | 2 Br 0 Ph \\ / To a solution of o—1H—pyrrole—2—carboxylic acid methyl ester (3.5 g, 17.2 mmol, 1 eq) in DMF (120 mL) was added NaH (0.82 g, 20.6 mmol, 1.2 eq) at 0°C, and the e was stirred at 0°C for 1 h, followed by the on of o—(diphenylphosphinyl)—hydroxylamine (6 g, 25.8 mmol). The reaction e was stirred for another 1 h, then neutralized with 20% NH4Cl solution, and extracted with EA. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography on silica gel (PE/EA = 4: 1) to give 1—amino—4—bromo—1H— pyrrole—2—carboxylic acid methyl ester (2.9 g, yield 77%) as a light yellow solid. MS (ES+) requires: 218, 220, found 219, 221 [M+H]+; purity: 97%.

Step 6: Synthesis of 6—bromo—3H—pyrrolo[2,1—f][1,2,4]triazin—4—one: INH2 N/N\ N O HZNAO / Br d w / NH / 180 °c, 5 h Br o / O A on of o—4—bromo—1H—pyrrole—2—carboxylic acid methyl ester (2.9 g, 13.2 mmol) in formamide (12 mL) was heated at 180°C for 5 hrs. The mixture was diluted with ethyl acetate (300 mL), and then washed with water (100 mL * 2), brine (100 mL * 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with PE/EA (4: 1, 50 mL) to give 6—bromo—3H—pyrrolo[2,1—f][1,2,4]triazin—4—one (1.4 g, yield 50%) as yellow solid. MS (ES+) requires: 213, 215, found 214, 216 [M+H]+; purity: 92%.

Step 7: Synthesis of 6—(1—methyl—1H—pyrazol—4—yl) pyrrolo[1,2—f][1,2,4] triazin—4(3H)—one: OOBQN‘M WA;Pd(dppf)C|2, ,N / N"W / N \1 NH + /N / NH 11o°c,12h dioxane/H20 O A mixture of 6—bromo—3H—pyrrolo[2,1—f][1,2,4]triazin—4—one (2.15 g, 10 mmol), 1—methyl—4— (4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—1H—pyrazole (4.2 g, 20 mmol), CsZCO3 (9.8 g, 30 mmol), PdClgdppf (814 mg, 1 mmol), water (15 mL), ethanol (15 mL) and dioxane (70 mL) in a 250 mL ﬂask was degassed with N2 for 10 min, and then heated at 120°C under N2 atmosphere WO 57873 overnight. The mixture was cooled to RT, followed by the on of silica gel (~50 g). The residue was subjected to a silica gel column and eluted with DCM:MeOH (20:0 — 20: 1) to afford 6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazin—4(3H)—one (600 mg, 28% yield) as a yellow solid. MS (ES+) requires: 215, found 216.1 [M+H]+; : 90%.

Step 8: Synthesis of 4—chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine: N N "'1 / N \W N/ //N \ / rh / jN 0 CI 6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazin—4(3H)—one (600 mg, 2.8 mmol) was treated with phosphorus oxychloride (20 mL) under reﬂux for 3 hours. The mixture was cooled to RT, concentrated under reduced pressure and the residue was diluted with ice water (100 mL).

The mixture was extracted with dichloromethane (50 mL * 4), and the combined organic layers were dried by MgSO4, filtered, concentrated to give 4—chloro—6—(1—methyl—1H—pyrazol—4— yl)pyrrolo[1,2—f][1,2,4]triazine (600 mg, 92% yield) as a brown solid. MS (ES+) requires: 233, 235, found 234, 236 [M+H]+; purity:90%.

Step 9: Synthesis of (R)—6—(1—methyl—1H—pyrazol—4—yl)—4—(4—(5—(1—phenylethyl) din—2— yl)piperazin—1—yl)pyrrolo[1,2—f][1,2,4]triazine: \ ,N N \ / N \W 22!: N\ / /N (N) N NAN DIPEA + \N \ / N’Nﬁ [N] | N\ / /N dioxane CI | A mixture of ro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine (56 mg, 0.21 mmol), (R)—5—(1—phenylethyl)—2—(piperazin—1—yl)pyrimidine (49 mg, 0.21 mmol) and diisopropylethylamine (97 mg, 0.84 mmol) in dioxane (10 mL) was stirred at RT overnight.

LCMS monitored the reaction was completed. The reaction e was concentrated to give a residue, which was purified by Prep—HPLC to afford the title compound (45 mg, 46%) as a white solid. MS (ES+) C26H27N9 requires: 465 found: 466 [M + H] +.

Step 10: Synthesis of (S)—6—(l—methyl— l H—pyrazol—4—yl)—4— (4—(5—(l—phenylethyl)pyrimidin—2—yl) zin— l —yl)pyrrolo[ l ,2—f] [ l ,2,4]triazine: N \ ,N E j N \ / N \W N\ / /N j: \ "N N DIPEA N N/ N + lil\ / \W N\ / /N dioxane [1 CI 1 N/ N A mixture of 4—chloro—6—(l—methyl—lH—pyrazol—4—yl)pyrrolo[l,2—f][l,2,4]triazine (56 mg, 0.21 mmol), (S)—5—(l—phenylethyl)—2—(piperazin—l—yl)pyrimidine (49 mg, 0.21 mmol) and diisopropylethylamine (97 mg, 0.84 mmol) in dioxane (10 mL) was stirred at RT overnight.

LCMS monitored the reaction was completed. The reaction mixture was concentrated to give a residue, which was ed by Prep—HPLC to afford the title compound (43 mg, 44%) as a white solid. MS (ES+) C26H27N9 requires: 465 found: 466 [M + H] +.

Example 2: sis of (S)— l—(2— (4— (5 —chloro—6—( 1 —methyl— lH—pyrazol—4—yl)pyrrolo[ l ,2— f] [ l ,2,4] triazin—4—yl)piperazin— l—yl)pyrimidin—5—yl)— l — (4—ﬂuorophenyl)ethanol (Compound 107) H \ H ,NH2 EN>_ N\ CI O NCS N N 0 NaOMe,MeOH N | 00/ 2NHC| , CI / | / | CCI4, reflux CI CI O / /0 WC CI CI CI / ,N m/ ,N H2N/§O / N \j NBS Pool3 /N ‘o / N B r N’Nﬁ \j / NH N// /N / 1800c THF,MeOH / NH 0' C' 0 CI o \ , H N \ / \W N N\ / /N N// //N \j N DIPEA,dioxane /N IN /N \ RT Jr: N/ IN Step 1: Synthesis of methyl 3—chloro—lH—pyrrole—2—carboxylate: H \ H 6‘ O N08 N\ C'CI N N NaOMe,MeOH 2NHC| I 00/ / I / CCI4, reflux CI CI O 0 / / CI CI CI To a solution of 5—methyl—3,4—dihydro—2H—pyrrole (2.50 g, 30.0 mmol) in CCl4 (100 mL) was added N—chlorosuccinimide (32.00 g, 240 mmol), and the mixture was then heated to reﬂux for 72 hours. The reaction mixture was cooled to 0 0C. The formed precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was ved in methanol (100 mL), followed by the addition of sodium methoxide (9.80 g, 180 mmol). The resulting sion was heated to reﬂux and stirred for 1.5 h. The solvent was evaporated, and the residue was suspended in ether. The solid was ed off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and 2 M HCI (100 mL).

The ic solution was stirred for 10 min. The c layer was separated, dried over MgSO4, filtered and evaporated. The crude oil was subjected to chromatography purification on silica gel eluting with EtOAc and Hexanes to afford the title compound (2.5 g, 52%) as an orange solid. MS (ES+) C6H6ClN02 requires: 159, found: 160 [M+H]+.

Step 2: Synthesis of methyl l—amino—3—chloro—lH—pyrrole—2—carboxylate: —58— H 5""2 NaH, DMF N 0 CI / To a suspension of sodium hydride (60 percent, 1.5 g, 37.5 mmol) in DMF (250 mL) was added methyl 3—chloro—1H—pyrrole—2—carboxylate (5.0 g, 31.3 mmol) at 0 OC, and the mixture was stirred for 25 min, followed by the addition of O—(diphenylphosphoryl)hydroxylamine (10.0 g, 43.75 mmol). The on mixture was stirred at RT for 4 h and quenched by aq. NagSO3 on. After stirred for r 5 min, the mixture was extracted with EtOAc (3 x 300 mL).

The combined organic layers were washed with brine, dried over NaZSO4, filtered and concentrated to give crude product as a brown oil, which was purified by chromatography purification on silica gel (PE:EA = 4: 1) to obtain the title compound (5.00 g, 91%) as a white solid. MS (ES+) C6H7C1N202 requires: 174, 176, found: 175, 177 [M+H]+.

Step 3: sis of 5—chloropyrrolo[1,2—f][1,2,4]triazin—4(3H)—one: 1""2 N N O law/50 / N \W | / / NH 0 180°C / CI CI 0 A mixture of methyl 1—amino—3—chloro—1H—pyrrole—2—carboxylate (4.00 g, 23 mmol) and formamide (15 mL) was heated to 180 0C for 3 h. After cooled to RT, the precipitated solid was collected via filtration and washed with CHZCHZ to obtain the title compound (2.50 g, 64%) as a yellow solid. MS (ES+) C6H4C1N3O requires: 169, found: 170 [M+H]+.

Step 4: Synthesis of 6—bromo—5—chloropyrrolo[1,2—f][1,2,4]triazin—4(3H)—one: WNH N //N \ NBS / N’ \ Br j THF, MeOH / NH 0 CI 0 To a mixture of 5—chloropyrrolo[1,2—f][1,2,4]triazin—4(3H)—one ( 2.50 g, 14.7 mmol) in THF (100 mL) and MeOH (50 mL) was added N—bromosuccinimide (2.6 g, 14.7 mmol), and the mixture was stirred at RT for 2 h. The reaction was ed by water and extracted with EA.

The organic layer was dried (NazSO4), filtered and trated. The residue was purified by chromatography purification on silica gel (EA:MeOH = 10: 1) to obtain the title compound (2.00 g, 55%) as a yellow solid. MS (ES+) C6H3BrClN3O requires: 246.9, found: 247.9 [M+H]+.

Step 5: sis of 5—chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazin—4(3H)— Ol’lCI ,N N / \ ’N N \j / I}! / / 13891O / N \j Br /N / / / NH CI C' o A mixture of 6—bromo—5—chloropyrrolo[1,2—1][1,2,4]triazin—4(3H)—one (2.00 g, 8.1 mmol), 1— methyl—4—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—1H—pyrazole (2.5 g, 12.1 mmol), K3PO4 (3.4 g, 16.1 mmol) and Pd(dppf)C12 (589 mg, 0.81 mmol) in 1,4—dioxane (30 mL) and water (3 mL) was purged with N2 and then heated to 90 0C for 15 h. The reaction mixture was cooled to RT and concentrated. The residue was passed a column (silica gel, EA:DCM:MeOH = 10: 10: 1) to obtain the title compound (600 mg, 30%) as a yellow solid. MS (ES+) C10H3C1N50 requires: 249, 251, found: 250, 252 [M+H]+.

Step 6: Synthesis of 4,5—dichloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine: POCI ’ N N/ N \ /N NH /N / C' 0 CI CI A mixture of 1—methyl—4—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—1H—pyrazole (600 mg, 2.4 mmol) in POCl3 (4 mL) was heated to reﬂux for 12 h. The reaction e was cooled to RT and concentrated under reduced pressure. The residue was washed with a e of THF (20 mL) and 1,4—dioxane (10 mL) to give the title compound (450 mg, 69%) as a yellow solid. MS (ES+) C10H8C1N5O requires: 267, 269, found: 268, 270 [M + H]+.

Step 7: Synthesis of (S)—1—(2—(4—(5—chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2— f][1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)—1—(4—ﬂuorophenyl)ethanol E] W CI N N 1 U N / N’ \ . N [\l‘ N DIPEA, dloxane / // 1‘ + IN ’ A / \ RT N / CI IN CI HOn. \ H0".

To a mixture of 4,5—dichloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine (150 mg, 0.56 mmol) and (S)—1—(4—ﬂuorophenyl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol (135 mg, 0.45 mmol) in 1,4—dioxane (10 mL) was added DIPEA (361 mg, 2.8 mmol). After stirred at RT for 15 h, the mixture was concentrated under reduced re and purified by Prep—HPLC to give the title compound (40.9 mg, 17%) as a White solid. MS (ES+) C26H25C1FN90 requires: 533, found: 534 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) 5 ppm 8.41 (s, 1H), 8.39 (s, 2H), 8.13 (s, 1H), 8.09 (s, 1H), 7.48-7.44 (m, 2H), 7.22 (s, 1H), 7.14-7.10 (m, 2H), 5.91 (s, 1H), 3.95—3.89 (m, 7H), 3.71-3.68 (m, 4H), 1.82 (s, 3H). tic Protocol 2 LG2 / \j / NH H (RA) N LG2/Nﬁ q N 2/NN\j /N\ﬁ N N oz A LG2 N N \N E j . )2 /\'( Nucleophilicaromatic N Pd mediated. substitution on A coupling reaction —> A L [H \l}! —> N \N X /Y >'<' A L L (RA)q LG2 = halogen (e.g., ) Z = B or Sn group The pyrrolotriazinone can be transformed into a pyrrolotriazine via treatment with POCl3 or other similar reagents. The pyrrolotriazine can be substituted with an amine under nucleophilic aromatic substitution on conditions using an amine base such as diisopropy1ethy1amine (DIPEA) or triethy1amine (TEA) in a polar solvent such as dioxane to provide the piperazine—substituted pyrrolotriazine. The pyrrolotriazinone can be coupled (LG2 —61— can be, 6.57., Cl, Br, or I) to a boron, tin or zinc aryl, heteroaryl, alkenyl, or alkyl reagent Via a palladium—mediated coupling reaction, e.g., Suzuki, , Negishi coupling, to provide the product. As shown below, Compound 123 was prepared using Synthetic ol 2.

Example 3: Synthesis of (S)—2—((4—(4—(4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl) piperazin—l— yl)pyrrolo[l,2—f][l,2,4]triazin—6—yl)—lH—pyrazol—l—yl)methyl)morpholine und 123) /OH _/OMS Nil: 0/3 CH38020|, TEA 0/} 082003 K/NBoo "Ii/>73]: pro K/N DCIVI, 0 00, 3h HN CH3CN, 60°C 6h 0 \Boc RNo—g [BOG N F [N E j x (j/SH Cul, 1,10-Phenanthroline NJ§N HCI NJ§N NI \ N + —> —> V 052003, 1,4-dioxane v dioxane 120 °C, O/N V H HCI [N BFQY‘N/ N, \ N N / N \W 2\ D'PEA E j o N/ /O Pd dba + N + /N IN / dioxane N [l] / B\ Brett hos '0/ O \ A /NJ. 052803/dl F BCC N/ N oxane o N/ / N’ \W 0 N’ / N’ \W N N [,1 _.HCI/dioxane (,1 NAN NékN —62— Step 1: Synthesis of (S)—tert—butyl 2—((methylsulfonyloxy)methyl) morpholine—4—carboxylate : :/OH 5 o: CHgSO2CI TEA C)" O DCM 0°C 3h K/NBoc ‘Boc To a mixture of rt—butyl 2—(hydroxymethyl)morpholine—4—carboxylate (400 mg, 1.84 mmol) in 10 mL of dichloromethane was added triethylamine (372 mg, 3.68 mmol) and methanesulfonyl chloride (316 mg, 2.76 mmol) dropwise at 0 0C. The on mixture was stirred at 0 0C for 3 h, and LCMS showed the reaction was completed. The reaction solution was diluted with 20 mL of romethane, and washed with saturated aqueous NaHCO3 (30 mLx 3) and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate 2 5: 1) to afford the title product (430 mg, 79%) as a white solid. MS (ES+) C11H21NO6S requires: 295, found: 296 [M + H]+.

Step 2: Synthesis of (S)—tert—butyl 2—((4—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—1H— pyrazol—1—yl)methyl)morpholine—4—carboxylate: O/ﬁsNBocHN}B:: 26OCH3CN:0 6 hCs co -" /O {0;} E75 To a mixture of (S)—tert—butyl 2—((methylsulfonyloxy)methyl)morpholine—4—carboxylate (430 mg, 1.46 mmol) and ,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—1H—pyrazole (283 mg, 1.46 mmol) in 50 mL of acetonitrile was added cerium carbonate (1.43 g, 4.37 mmol), and the mixture was stirred at 60 0C for 3 h. TLC and LCMS showed the reaction was ted. After the solvents were removed under d pressure, the residue was diluted with 50 mL of ethyl acetate, and washed with water (50 mLx 3) and brine. The organic layer was separated, dried over sodium e, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl e 2 5: 1) to get the title product (300 mg, 52%) as colorless oil. MS (ES+) C19H32BN3O5 requires: 393, found: 394 [M + H]+.

Step 3: Synthesis of tert—butyl 4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl)piperazine—1— carboxylate: IIﬁoc [N] E F N A Cul, 1,10-Phenanthroline NJ§N N] \N + K? Cszcoa, 1,4-dioxane 120 °c, O/N V <18 Br A mixture of tert—butyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate (5.0 g, 14.6 mmol), 2—ﬂuorobenzenethiol (9.3 g, 73 mmol), 1,10—Phenanthroline (7.9 g, 43.8 mmol), copper iodide (13.9 g, 73 mmol) and cerium carbonate (28.6 g, 87.6 mmol) in e (100 mL) was reﬂuxed for 3 days. The reaction mixture was cooled to RT and trated. The residue was directly purified by silica gel chromatography to give the title compound. MS (ES+) C19H23FN402S requires: 390, found: 391 [M + H]+.

Step 4: Synthesis of 5—(2—ﬂuorophenylthio)—2—(piperazin—1—yl)pyrimidine HCl salt: BOG H HCI EN) EN] NIJ§N HCI NJ§N f/ W %l CE.

To a solution of tert—butyl 4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl)piperazine—1—carboxylate (5 g, 12.8 mmol) in dioxane (150 mL) was added HCl in dioxane (4 M, ca. 30 mL), and the mixture was stirred at 40 0C overnight. LCMS showed the reaction was completed. The reaction e was concentrated to afford 5—(2—ﬂuorophenylthio)—2—(piperazin—1—yl)pyrimidine HCl salt (3.6 g, 88%) as a solid. MS (ES+) C14H15FN4S es: 290, found: 291 [M + H]+.

Step 5: Synthesis of 6—bromo—4—(4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl) piperazin—l— yl)pyrrolo[1,2—f] [1,2,4]triazine: —64— HHCI Br //N :ﬁN [N] N / N \W + N2\N DlPEA E j / N dloxane N F A CI N/ N A mixture of o—4—chloropyrrolo[1,2—f][1,2,4]triazine (100 mg, 0.43 mmol), 5—(2— ﬂuorophenylthio)—2—(piperazin—1—yl)pyrimidine HCl salt (126 mg, 0.43 mmol) and diisopropylethylamine (280 mg, 2.15 mmol) in dioxane (5 mL) was stirred at RT ght. The reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether:ethyl acetate 2 2: 1) to afford the title compound as (100 mg, 49%) a yellow solid. MS (ES+) C20H17BrFN7S requires: 485, 487, found: 486, 488 [M + H]+.

Step 6: Synthesis of (S)—tert—butyl 2—((4— (4—(4— (5—(2—ﬂuorophenylthio)pyrimidin—2—yl)piperazin— 1—yl)pyrrolo[1,2—f] [1,2,4]triazin—6—yl)—1H—pyrazol—1—yl)methyl)morpholine—4—carboxylate: O N/ / N \ //NNT] I W BOC/Nd'ul/N:/>—<;%¢N [N]+ Pd2(dba)3 Brettphos [N] N NO,N,/3378:: Csz—>CO3/dioxane N2\N x Boc’ N/ N w. VF Sb Sb A mixture of 6—bromo—4—(4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl) piperazin—1—yl)pyrrolo[1,2— f][1,2,4]triazine (100 mg, 0.2 mmol), (S)—tert—butyl 2—((4—(4,4,5,5—tetramethyl—1,3,2— dioxaborolan—2—yl)—1H—pyrazol—1—yl)methyl)morpholine—4—carboxylate (80 mg, 0.2 mmol), Pd2(dba)3 (34 mg, 0.02 mmol), hos (40 mg,0.04 mmol) and cerium ate (260 mg, 0.4 mmol) in dioxane (5 mL) was degassed with en for three times, and then heated at 120 0C overnight. The reaction mixture was cooled to RT and concentrated to give a residue, which was purified by silica gel chromatography (dichloromethane:methanol = 15: 1) to afford the title WO 57873 compound (40 mg, 30%) as a white solid. MS (ES+) C33H37FN1003S requires: 672, found: 617 [M-56+H]+.

Step 7: Synthesis of (S)—2—((4—(4—(4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl)piperazin—l— yl)pyrrolo[ l ,2—f] [ l ,2,4]triazin—6—yl)— lH—pyrazol— l —yl)methyl)morpholine: N ,N /©-II,/N:/>—<;YNo '3’ / N" \W HO'W/N0 WV / N \d / / /N N N E j HCI/dioxane —> E j N N N2\N NAN VF o. r: r: A mixture of (S)—tert—butyl 2—((4—(4—(4—(5—(2—ﬂuorophenylthio)pyrimidin—2—yl) piperazin—l— rolo[l,2—f][l,2,4]triazin—6—yl)—lH—pyrazol—l—yl)methyl)morpholine—4—carboxylate (40 mg, 0.06 mmol) in HCl/dioxane (5 mL) was stirred at RT for 2 h. The reaction mixture was concentrated to give a residue, which was purified by PLC to afford the title compound (8.9 mg, 26%) as a yellow solid. MS (ES+) C23H29FN1008 requires: 572, found: 573 [M + H]+. 2014/060746 Synthetic Protocol 3 i w E I B (RA)q EN:1 (RAN j / N,N\j N Bng@ / / / / N /N x N N Protecting QTOUP N N NucleophHIc ic / )'<\"Y ' N IN Grignard reaction removal IY substitution reaction —* X\ N N x, Y E I x1 xi OR N N R x1 c D l A 'i / A (RA)q (R M ii 'l .N X\ Y X\ Y kyl a'k addition (RAM (RA): R= leaving group E 1 Reduction of alk=C1_e alkyl LGl= halogen N carbonyl P= protecting group (e.g., Boo) * xi: 0 o N CH2 8 | u (RAM \ Alkylation X‘ Y x:=CR13 OH NHR1 SH / N’ \j =ORl NR12SR1 a": / /N Xc em WM N / d RAlq more alkyl The piperazine carbonyl derivative, e.g., carbamoyl, (A, X and Y are each —CH—) can be coupled to the Grignard bromide (B, Ring A is aryl), to provide the ted di—substituted carbonyl (C, X1 is CH2, S, NH, or 0). When X1 is O, i.e., g a carbonyl, the carbonyl can be further reacted with an organometallic reagent such as Grignard, lithium, zinc reagents and trialkylaluminum, e.g. , trimethylaluminum, which can also deprotect the piperazine en to provide the further substituted compound (C’). Removal of the protecting group (P) from the piperazine ring of (C) can be carried out using strong acids such as 4M hydrochloric acid (HCl) in dioxane or triﬂuoroacetic acid (TFA) in a polar solvent such as methanol or dichloromethane (DCM) to afford amine (D). Pyrrolotriazine (E) can be substituted with amine (C’) or (D) under nucleophilic aromatic substitution reaction ions using an amine base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solvent such as dioxane to provide the piperazine—substituted pyrrolotriazine (F) or (F’). Reduction of —C(=X1)—, wherein X1 is CH2, S, NH, or O, 6.57., yl, of (F) can be performed using a reducing agent such as sodium borohydride to provide —C—(XH)—, 6.57., the alcohol (G). Alternatively, alkylation of X2 can be performed using alkyl halides (alternative leaving groups) to provide X3—containing analogs (G’). Enantiomeric enriched products can be ed via catalytic asymmetric 2014/060746 synthesis, chiral auxiliary based sis and resolution of a racemate. As shown below, Compounds 40 and 41 were prepared using Synthetic Protocol 3.

Example 4: Synthesis of 4— (4— (5—( l —(4—ﬂuorophenyl)propyl)pyrimidin—2—yl)piperazin— l—yl) —6—(l— methyl—lH—pyrazol—4—yl)pyrrolo[1,2—ﬂ[1,2,4]triazine (Compounds 40 and 41) E100 [i] $00 Boo N \N N N EN] \N’ \ :6| H X NaOH H para-F-CGHSMgBr NI \ N DIPEA/dioxane j: THF/MeOH/HZO [1N] N \NEDCIIHOBT/TEA/DCM THF HO o /O N o I H H [N] [N] N H N N ENj E j NIJ§N N Nl/KN EtMgBr, THF NJ§N HCI/dioxane Pd/C, MeOH —> —> —>NJ§N —> / dioxane / 0°c-RT 3h | I / R11 h / R11 h H H H [N] EN] [N] N N NJ§N l chiral HPLC NJ§N \ 1;: —> I / Step 1: Synthesis of ethyl 2—(4—(tert—butoxycarbonyl)piperazin—1—yl)pyrimidine—5—carboxylate: B ||30c Noc N i U U | H A DIPEA/dloxane 0 0 2 /\0ifO To a solution of tert—butyl piperazine—l—carboxylate (10.0 g, 53.7 mmol) and diisopropylethylamine (23.4 mL, 134.25 mmol) in dioxane (80 mL) was added ethyl 2— chloropyrimidine—5—carboxylate (10 g, 53.7 mmoL), and the reaction mixture was stirred at RT for 3 h. LCMS showed the reaction was completed. The reaction was concentrated to afford the title compound (17 g, crude), which was directly used in the next step t the further purification. MS (ES+) C16H24N4O4 requires: 336, found: 237, 281 [M —56+H]+.

Step 2: Synthesis of 2—(4—(tert—butoxycarbonyl)piperazin—1—yl)pyrimidine—5—carboxylic acid: N [E05 )\ NaOH THF/MeOH/HZO NJ§N / | /\oEo i HO O To a solution of ethyl 2—(4—(tert—butoxycarbonyl)piperazin—1—yl)pyrimidine—5—carboxylate (17 g, crude) in THF/MeOH/water (300 mL) was added sodium hydroxide (4.3 g, 107.5 mmol), and the reaction was d at 70 0C for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, ied to pH z 5—6 with 1 M HCl and filtered. The solid was collected and dried to give the title compound (16 g, 96%) as a white solid, which was directly used in the next step without further cation. MS (ES+) C14H20N4O4 requires: 308, found: 253 [M —56+ H]+.

Step 3: Synthesis of tert—butyl 4—(5—(methoxy(methyl)carbamoyl)pyrimidin—2—yl)piperazine—1— carboxylate: ||300 r") r") N H N NJ§N EDCI/HOBT/TEA/DCM Z4N HO 0 /0\r\|1 0 To a suspension of 2—(4—(tert—butoxycarbonyl)piperazin—1—yl)pyrimidine—5—carboxylic acid (13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol), and the mixture was stirred at RT for 1 h, ed by the addition of N,O—dimethylhydroxylamine (5 g, 53.7 mmol) . The reaction was stirred for another 3 h. LCMS showed the reaction was completed. The reaction e was washed with water (100 mL), and the organic layer was dried, filtered and concentrated. The residue was ed by silica gel chromatography (petroleum ether:ethyl acetate 2 1:1) to give the title compound (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351, found: 296 [M —56+ H]+.

Step 4: sis of tert—butyl 4—(5—(4—ﬂuorobenzoyl)pyrimidin—2—yl)piperazine—1—carboxylate: Boc Tee EN1 EN] para—F-C5H5MgBr j: NIJTN THF NI :N /OTN O To a solution of utyl 4—(5—(methoxy(methyl)carbamoyl)pyrimidin—2—yl)piperazine—1— carboxylate (7.8 g, 22.22 mmol) in dry THF (50 mL) was added C6H5MgFBr (1 M in THF, 50 mL) at 0 0C under nitrogen, and the mixture was stirred at RT for 3 h. LCMS showed the reaction was completed. The reaction was quenched with 1 M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 2 5:1) to give the title compound (7.2 g, 84%) as a yellow solid. MS (ES+) FN4O3 requires: 386, found: 331 [M— 56 + HT".

Step 5: Synthesis of (4—ﬂuorophenyl)(2—(piperazin—1—yl)pyrimidin—5—yl)methanone: r") r") N N NJ§N HCI NJ§N / dioxane I O O F F To a solution of tert—butyl 4—(5—(4—ﬂuorobenzoyl)pyrimidin—2—yl)piperazine—1—carboxylate (8.2 g, 21.24 mmol) in dioxane (50 mL) was added HCl in dioxane (4 M, 20 mL). The reaction mixture was d at RT overnight. LCMS showed the reaction was completed. The mixture was concentrated to get the title nd as a light yellow solid (5.5 g, 90%). MS (ES+) C15H15FN4O es: 286, found: 287 [M + H]+.

Step 6: Synthesis of 1—(4—ﬂuorophenyl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)propan—1—ol: r") r") N N NkN EtMgBr, THF NkN | ' o °C-RT, 3 h | / / F F To a solution of (4—ﬂuorophenyl)(2—(piperazin—1—yl)pyrimidin—5—yl)methanone (4.0 g, 21.84 mmol) in dry THF (150 mL) was added EtMgBr (1 M in THF, 150 mL) at 0 0C under nitrogen.

The mixture was stirred at RT for 3 h, then quenched with NH4Cl solution and extracted with ethyl acetate (200 * 3 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by combi—ﬂash with dichloromethane:methanol 2 10:1 to give the title compound (440 mg, 10%) as a yellow solid. MS (ES+) C17H21FN4O requires: 316, found: 317 [M + H]+.

Step 7: Synthesis of (E)—5—(1—(4—ﬂuorophenyl)prop—1—enyl)—2—(piperazin—1—yl)pyrimidine: H H [N] r") i N HCI/dioxane NI \N NJ§N / RT, 1 h / F F To a on of 1—(4—ﬂuorophenyl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)propan—1—ol (200 mg, 0.6 mmol) in dioxane (10 mL) was added HCl in dioxane ( 4 M, 10 mL), and the reaction was stirred at RT for 1 h. LCMS showed the reaction was completed. The mixture was concentrated to an oil, which was purified by Combiﬂash with dichloromethane:methanol 2 20:1 to give the title compound as a light yellow solid (185 mg, 98%). MS (ES+) C17H19FN4 requires: 298, found: 299 [M + H]+.

Step 8: Synthesis of 5—(1—(4—ﬂuorophenyl)propyl)—2—(piperazin—1—yl)pyrimidine [E] ("I NkN Pd/C, MeOH / RT,1h I F F To a solution of (E)—5—(1—(4—ﬂuorophenyl)prop—1—enyl)—2—(piperazin—1—yl)pyrimidine (170 mg, 0.57 mmol) in ol (10 mL) was added Pd/C (30 mg). The mixture was exposed to 1 atm hydrogen on) and stirred at RT for 1 h. The e was filtrated, and the filtrate was concentrated to an oil, which was purified by combiﬂash with dichloromethane:methanol 2 50:1 to give the title compound (racemate, 90 mg, 53%) as a yellow oil.

Step 9: Chiral separation of (R)—5—(1—(4—ﬂuorophenyl)propyl)—2—(piperazin— 1—yl)pyrimidine and (S)—5—(1—(4—ﬂuorophenyl)propyl)—2— (piperazin— 1 —yl)pyrimidine: H H H EN] EN] [N] N N NJSN NJ§N 1 chiral HPLC I + | —» N| \N / / / \\"‘ F F F The above racemate compound (90 mg) was separated by Chiral—HPLC to afford the enantiomers (35 mg). MS (ES+) C17H21FN4 requires: 300, found: 301 [M + H]+. The te stereochemistry was assigned randomly.

Chiral separation ion: Chiral column: OJ—H (250*4.6mm 5um) Mobile phase: n—Hexane(0.1%DEA):EtOH(0.1%DEA)=95:5 Step 10a: Synthesis of (R)—4—(4— (4—ﬂuorophenyl)propyl)pyrimidin—2—yl)piperazin— 1 —yl)—6— (1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine: \ ,N "H \ / N \j E I N N E J NJ§N DIPEA, dioxane + //NNW I j: / /N / N/ IN CI \ A solution of (R)—5—(1—(4—ﬂuorophenyl)propyl)—2—(piperazin—1—yl)pyrimidine 36 mg, 0.12 mmol), 4—chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine (31 mg, 0.132 mmol) and diisopropylethylamine (47 mg, 0.36 mmol) in 1,4—dioxane (5 mL) was stirred at RT for 3 h. The on mixture was concentrated, and the residue was purified by Prep—HPLC to give the title compound (21.1 mg, 35%) as a white solid. MS (ES+) C26H26FN90 requires: 497, found: 498 [M + H]+.

Step 10b: Synthesis of (S)—4—(4—(5—(1—(4—ﬂuorophenyl)propyl)pyrimidin—2—yl)piperazin— 1—yl)—6— (1—methyl—1H—pyrazol—4—yl)pyrrolo[1,2—f][1,2,4]triazine: \ ,N 'F\ Na H N\ / /N E I N N E I NJ§N DIPEA,dioxane + [\II/ / N’ij j: \\"I A mixture of (1—(4—ﬂuoropheny1)propy1)—2—(piperazin—1—y1)pyrimidine 35 mg, 0.12 mmol), 4—chloro—6—(1—methy1—1H—pyrazol—4—y1)pyrrolo[1,2—ﬂ[1,2,4]triazine (30 mg, 0.132 mmol) and diisopropylethylamine (47 mg, 0.36 mmol) in 1,4—dioxane (5 mL) was stirred at RT for 3 h. The reaction mixture was concentrated, and the residue was purified by Prep—HPLC to give the title compound (24.4 mg, 35 %) as a white solid. MS (ES+) C26H26FN90 requires: 497, found: 498 [M + HT".

Synthetic Protocol 4 q(RA) [NH] /N G—Ckr //N’N/\WN [N] sation with chiral N/N Nucleophilic aromatic ten-butanesulflnamIde. .

)'(\"Y tution reaction —> —> N/N [31:] o X\ Y >'<\ 'Y (R )q \ ,3 LG1 = halogen N *\i/ RAq) (RA)q 1) Addition of a nucleophile (Nu') 2) N-sulfinyl cleavage / N’ i 3) Chiral chromatography The piperazine shown above can be prepared using similar synthetic procedures shown in Synthetic Protocol 3. The pyrrolotriazine can be tuted with the amine of the piperazine under nucleophilic aromatic substitution reaction conditions using an amine base such as diisopropylethylamine ) or triethylamine (TEA) in a polar t such as dioxane to provide the piperazine—substituted pyrrolotriazine. Direct condensation of chiral tert— butanesulfinamide with the ketone of the piperazine— substituted pyrrolotriazine can provide the chiral inyl imine. l,2—addition of a nucleophile, such as an metallic reagent, 6.57., an alkyl Grignard, or, 6.57., an enolate, to the N—sulfinyl imine, followed by cleavage of the N— sulfinyl group under, e.g. acidic conditions, can provide the chirally enriched amine. Chirally pure amine can be obtained by chiral chromatography, e.g. , SFC or HPLC. The compounds prepared by Synthetic Protocol 4 were separated by chiral SFC using the following separation conditions: Column: ChiralPak AS—H 20 X 250 mm Mobile Phase: 45% ethanol containing 0.25% DEA in C02 Flow rate: 70 ml/min Sample: 93.7 mg racemic mixture was dissolved in 15 ml solvent consisting of methanol/ethanol = 1/1 containing 150 uL diethylamine ion: 2 mL per run Detection: 254 nm As shown below, Compounds 12, 13, 36, 43 and 44 were ed using Synthetic Protocol 4.

Example 5: Synthesis of (S)—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2, 1—ﬂ[1,2,4]triazin—4— yl)piperazin—1—yl)pyrimidin—5—yl)(phenyl)methanamine and (R)—(2— (4—(6—( 1 —methyl— 1H—pyrazol— 4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)(phenyl)methanamine (Compounds 12 and 13) E? //N j] E? //N / /71 / / N N Step 1: sis of (2—(4—(6—(1—methyl— azol—4—yl)pyrrolo[2, 1—ﬂ[1,2,4]triazin—4— yl)piperazin— 1—yl)pyrimidin—5—yl)(phenyl)methanimine: ,3? CNN] JW E j E j N N NJ\N —> NJ\N | | \ \ \N’SK NH (S,Z)—2—Methyl—N—((2—(4—(6—( 1 —methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1 —ﬂ [ 1 ,2,4] triazin—4— yl)piperazin—1—yl)pyrimidin—5—yl)(phenyl)methylene)propane—2—sulfinamide (490 mg, 0.862 mmol) was d in 4 M HCl in 1,4—dioxane (2 mL)/MeOH (2 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give (2—(4—(6—(1— methyl— 1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin— 1—yl)pyrimidin—5— yl)(phenyl)methanimine, HCl (490 mg, 0.861 mmol, 100 % yield) as a pale yellow solid, 88% by weight.

MS (ES+) C25H24N10 requires: 464, found: 465 [M + H]+.

Step 2: Synthesis of rac—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4— yl)piperazin— 1—yl)pyrimidin—5—yl)(phenyl)methanamine: N N /N:/>—<;KfNW" / N" \W /N:/>—<;YNl." / N' \W r") U NAN N I IN \\ \\ NH NH2 (2—(4—(6—(1—Methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5— yl)(phenyl)methanimine, HCl (410 mg, 0.818 mmol) was suspended in MeOH (8 mL). Sodium borohydride (40 mg, 1.057 mmol) was added in one n, producing an exotherm and forming a clear on. onal sodium borohydride (40 mg, 1.057 mmol) was added in one portion, producing an exotherm and forming a suspension. The MeOH was removed in vacuo and the residue partitioned between EtOAc—NaHCO3. The aqueous phase was ted a second time with EtOAc. The combined organic extracts were washed with brine, dried over , filtered, and concentrated in vacuo. The residue was recrystallized from EtOH to give (2—(4— (6— (1—methyl—1H—pyrazol—4—yl)pyrrolo[2, 1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5— yl)(phenyl)methanamine (182 mg, 0.390 mmol, 47.7 % yield) as an off—white solid.

MS (ES+) C25H26N10 requires: 466, found: 467 [M + H]+.

Step 3: Separation of enantiomers ,N ,N ,N 3; Ma No /N‘W / /N N; Na / / / /N /N /N /N EN] EN] [N] N N N NJ\N NJ\N NJ\N | | | \\ \ \ NH2 NH2 "’NH2 The omers of racemic (2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4— yl)piperazin—1—yl)pyrimidin—5—yl)(phenyl)methanamine (185 mg, 0.397 mmol) were separated by chiral SFC to give —(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4— yl)piperazin—1—yl)pyrimidin—5—yl)(phenyl)methanamine (74 mg, 0.159 mmol, 80.0 % yield) and (R)—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1— yl)pyrimidin—5—yl)(phenyl)methanamine (94 mg, 0.201 mmol, 100 % yield). The absolute stereochemistry was assigned randomly.

MS (ES+) C25H26N10 requires: 466, found: 467 [M + H]+.

Example 6: Synthesis of (S)—N,N—dimethyl—1—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1— ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)—1—phenylmethanamine (Compound 36): lvcﬁ lvci N N U U (S)—(2—(4—(6—(1—Methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1— yl)pyrimidin—5—yl)(phenyl)methanamine (72 mg, 0.154 mmol) and formaldehyde (125 mg, 1.543 mmol) were taken up in MeCN (1.5 mL). Sodium cyanoborohydride (25 mg, 0.398 mmol) was added, followed by acetic acid (0.02 mL, 0.349 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Saturated NaHCO3 was added and the products extracted into DCM (x2). The combined organic ts were washed with brine, dried over NagSO4, filtered, and concentrated in vacuo. Purification of the residue by MPLC (0—10% MeOH—DCM), followed by MPLC (0-10% MeOH-EtOAc), followed by MPLC (0-8% MeOH-EtOAc) gave (S)-N,N— dimethyl—1—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1— yl)pyrimidin—5—yl)—1—phenylmethanamine (15 mg, 0.030 mmol, 19.65 % .

MS (ES+) C27H30N10 es: 494, found: 495 [M + H]+.

Example 7: Synthesis of (R)—1—(4—ﬂuorophenyl)— 1—(2—(4—(6—(1—methyl—1H—pyrazol—4— yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine and (S)— 1 —(4— 2014/060746 ﬂuoropheny1)—1—(2—(4—(6—(1—methy1—1H—pyrazol—4—y1)pyrrolo[2,l—ﬂ[1,2,4]triazin—4—y1)piperazin— 1—y1)pyrimidin—5—y1)ethanamine (Compounds 43 and 44) \ ,N N\ /N\W E j N 9' N t x N U NHZ \ ’ / DIPEA, dioxane N N N x + / 4N 1 A // / / N/ N TKOEDmTHF m \\| F o N \ / N \W \N N’N\ . \ / W N\ / /N N\ / /N N N E j E j HCI,1,4-dioxane N MeMgBr, THF 1 MeOH NAI —> —> N/ IN \ \ 9 Q .+ '+ XS\N/ >r8xNH F F Step 1: Synthesis of (4—ﬂuorophenyl)(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1— f][1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)methanone: H N;>—<;\fN\ / N’Nﬁ E j N 1 N U ’ N "I N N DIPEA, dioxane / \W / 1// A /N / /N N’IN CI \ 4—Chloro—6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazine (180 mg, 0.770 mmol), (4—ﬂuorophenyl)(2—(piperazin—1—yl)pyrimidin—5—yl)methanone, HCl (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4—dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (X2). The combined c extracts were dried over NazSO4, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the e by MPLC (25—100% EtOAc—DCM) gave (4—ﬂuorophenyl)(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1— ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an ite solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.

Step 2: Synthesis of (S,Z)—N—((4—ﬂuorophenyl) (2—(4— (6—(1—methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1— 4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)methylene)—2—methylpropane—2—sulfinamide: \ ,N \ ,N N \ / N \W N \ / N \W N\ / /N N\ / /N N 9' N E j >(S‘NH2 E j l l N/ IN N/ Ti(OEt)4,THF IN \ \ o >‘/S‘N/ F F (S)—2—Methylpropane—2—sulfinamide (110 mg, 0.908 mmol), (4—ﬂuorophenyl)(2—(4—(6—(1— methyl— 1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin— 1—yl)pyrimidin—5— yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were d in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over NazSO4, filtered, and concentrated in vacuo while loading onto Celite. cation of the residue by MPLC (0—10% tOAc) gave (S,Z)—N—((4—ﬂuorophenyl)(2—(4—(6—(1—methyl— 1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)methylene)—2— methylpropane—2—sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H31FN100S requires: 586, found: 587 [M + H]+.

Step 3: Synthesis of (S)—N—( 1 orophenyl)— 1—(2—(4— (6—(1—methyl— 1H—pyrazol—4— yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethyl)—2—methylpropane—2— sulfinamide: \N \ / N’N\W \N \ / N \ | | W [N] [N] j: MeMgBr,THF j: N1" N1" \ \ 9- Q— >‘/S\N/ >‘/S\NH F F (S,Z)—N—((4—Fluorophenyl) (2— ( 1 —methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1 — ﬂ [1,2,4] triazin—4—yl)piperazin— 1—yl)pyrimidin—5—yl)methylene)—2—methylpropane—2—sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 OC. Methylmagnesium bromide (3 M solution in l ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes.

Saturated ammonium chloride was added and the ts extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over NazSO4, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0—10% MeOH—EtOAc) gave (S)—N—(1—(4—ﬂuorophenyl)— 1 —(2—(4— (6—(1—methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1— ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethyl)—2—methylpropane—2—sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) FN100S requires: 602, found: 603 [M + HT". —81— Step 4: Synthesis of 1—(4—ﬂuorophenyl)—1—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1— ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine: \ ,N \ ,N N \ / N \W N \ / N \W N\ / /N N\ / /N N N E j HCI,1,4—dioxane E j N MeOH N A —> A (S)—N—(1—(4—Fluorophenyl)— 1—(2— (4— (6—( 1 —methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1 — ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethyl)—2—methylpropane—2—sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4—dioxane (1.5 mL)/MeOH (1.5 mL) at room ature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give 1—(4—ﬂuorophenyl)— 1—(2—(4—(6—(1—methyl— 1H—pyrazol—4—yl)pyrrolo[2, 1—ﬂ[1,2,4]triazin—4— erazin—1—yl)pyrimidin—5—yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10 requires: 498, found: 482 [M—17 + H]+, 499 [M + H]+.

Step 5: Chiral separation of (R)—1—(4—ﬂuorophenyl)—1—(2—(4—(6—(1—methyl—1H—pyrazol—4— yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine and (S)— 1 —(4— ﬂuorophenyl)—1—(2—(4—(6—(1—methyl—1H—pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin— yrimidin—5—yl)ethanamine: \ ,N \ ,N \ ,N N \ / N \W N \ / N \W N \ / N \W EN] [N] N ChiralSFC N NAN NAN I I \ \ H2NI The enantiomers of racemic 1—(4—ﬂuorophenyl)—1—(2—(4—(6—(1—methyl—1H—pyrazol—4— yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)—1—(4—ﬂuorophenyl)— 1—(2—(4—(6—(1—methyl—1H— —82— 2014/060746 pyrazol—4—yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (S)—1—(4—ﬂuorophenyl)—1—(2—(4—(6—(1—methyl—1H—pyrazol—4— yl)pyrrolo[2,1—ﬂ[1,2,4]triazin—4—yl)piperazin—1—yl)pyrimidin—5—yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+) C26H27FN10 requires: 498, found: 499 [M + H]+.

Preparation of Common Intermediates Synthesis of 5—(2—phenylpropan—2—yl)—2—(piperazin—1—yl)pyrimidine: U z: N \_/ NJ§N N A|(CH3)3 l —> gN N / PhMe | In a sealed tube, the mixture of tert—butyl 4— (5—benzoylpyrimidin—2—yl) piperazine—l— carboxylate (500 mg, 1.36 mmol) and trimethylaluminum (2 M in toluene, 2.7 mL) in dry toluene (10 mL) was stirred at 100 0°C overnight. LCMS showed the reaction was completed.

The reaction mixture was cooled to RT, quenched with ice—water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, ﬂitered and trated. The residue was purified by Prep—HPLC to get 5—(2—phenylpropan—2—yl)—2— (piperazin—1—yl)pyrimidine (40 mg, 7%) as a yellowish solid. MS (ES+) C17H22N4 requires: 282, found: 283 [M + H]+.

Synthesis of utyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate EISOC N E j N \N ch03 N VI + E j . A oxane, N \N H refl UX’ 1.5h Br IS) Br To a on of 5—bromo—2—chloropyrimidine (50.0 g, 258 mmol) and 1—tert— butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4—dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reﬂux for 1.5 h. The on was cooled to RT, quenched by water (500 mL) and extracted with l ether (1000 mL* 2).

The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate 2 8: 1—4: 1) to give the title compound (70.5 g, 80%) as a white solid. MS (ES+) C13H19BrN402 requires: 342, found: 243 [M + H - 100]+.

Synthesis of tert—butyl 4—(5—acetylpyrimidin—2—yl)piperazine—1—carboxylate [XE0] i) Pd(OAc)2/PPh3 [:0] Q4. V:\\\S "Mdioxane 80 °C )\ \\ iDZNHCITHF ﬂ \ RT, 30 min Br f A mixture of utyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate (5.0 g, 14.6 mmol), palladium diacetate (240 mg, 1.46 mmol), triphenylphosphine (376 mg, 2.92 mmol) and tributyl(1—ethoxyVinyl)stannane (5.3 mL, 16.1 mL) in dioxane (100 mL) was degassed with nitrogen for three times, and the reaction mixture was stirred at 80 0C overnight. The reaction was cooled to RT and diluted with THF (100 mL), followed by the addition of 2 N HCl (100 mL). The mixture was stirred at RT for 30 mins, and LCMS showed the reaction was completed.

The reaction mixture was diluted with ethyl e (200 mL). The organic phase was separated, washed with water (3 x 100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound (3.0 g, 67%). MS (ES+) N4O3 requires: 306, found: 251 [M — 56 + H]+.

Synthesis of 1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanone ||30c N H N (N) Ng TFA NJ§N —84— To a solution of tert—butyl 4—(5—acetylpyrimidin—2—yl)piperazine—1—carboxylate (3 g, 9.8 mmol) in dichloromethane (30 mL) was added triﬂuoroethyl acetate (15 mL), and the mixture was stirred at RT for 30 min. LCMS showed the reaction was completed. The reaction mixture was neutralized with sodium carbonate on and ted with dichloromethane. The organic layer was dried over sodium sulfate, ed and concentrated to afford the title nd as a light yellow solid (2 g, 100%), which was directly used in the next step without further cation. MS (ES+) C10H14N4O requires: 206, found: 207 [M + H]+.

Synthesis of 1—(4—ﬂuorophenyl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol H H ENE E 1 F®Mg3r NiN N N I THF, 0 D C-RT, 3 h \ F To a solution of 1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanone (1.8 g, 8.73 mmol) in dry THF (100 mL) was added (4—ﬂuorophenyl)magnesium bromide (1 M in THF, 87.3 mL) at 0°C under N2 .The mixture was d at RT for 3 h, then quenched with ammonium chloride solution and extracted with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Combi—ﬂash (dicholomethane:methanol 2 10:1) to give the title compound (1.02 g, 38%) as a yellow solid.

Chiral separation of 1—(4—ﬂuorophenyl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol: 2\N Chiral separation N —> The racemate compound (1.02 g) was separated by chiral HPLC to afford enantiomer 1 (E1, 320 mg) and enantiomer 2 (E2, 220 mg). MS (ES+) C16H19FN4O requires: 302, found: 303 [M + H]+. The absolute configuration was assigned randomly.

Chiral separation conditions: Chiral column: OZ—H (4.6*250mm, Sum); Mobile phase: co—solvent EtOH(0. 1% DEA) Synthesis of (S)—2—(4—ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol and (4— ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol: [33$ [:1 6%: [301° [3.]. §—>9 N + —> —> EDCI, DCM, RT NJ§N THF, 78 o N _ C N I/ I I/ / O N | 0 OH ('3 S2 HO F F ["3 r J N [:1 oxane J§N chiral separation NJ\N N /AN HOX©\F $F+| \ / :\: Step 1: Synthesis of 4—ﬂuoro—N—methoxy—N—methylbenzamide: HCIHN EDCI DCM RT 0 N/ To a on of 4—ﬂuorobenzoic acid (200 g, 1.43 mol), N,O—dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0 0C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) CngoFNOZ requires: 183, found 184 [M+H]+; purity: 90% (UV254).

Step 2: Synthesis of tert—butyl 4—(5—(4—ﬂuorobenzoyl)pyrimidin—2—yl)piperazine—1—carboxylate: [foo F I300 N N E I + 1 & THE-78°C NI \N NI /N / O N/ 0\ Kg To a solution of tert—butyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate (50 g, 146.2 mmol) in anhydrous THF (700 mL) was dropwise added n—BuLi (2.5 M in hexane, 70 mL, 175 mmol) at —78 °C under nitrogen. The mixture was stirred at —78 °C for 1 h, followed by the addition of a solution of 4—ﬂuoro—N—methoxy—N—methylbenzamide (30 g, 163.9 mmol) in anhydrous THF (100 mL). After d at —78 °C for another 2 h, the reaction mixture was quenched with ted aqueous NH4Cl (250 mL) and extracted with ethyl acetate (200 mL*3).

The combined c layers were dried over sodium sulfate, filtered and concentrated in vacuo.

The residue was diluted with propan—2—ol (150 mL) and stirred at RT for 30 mins. The solid was collected via filtration, washed with —2—ol (100 mL) and petroleum ether (300 mL), and dried under vacuum to give the title compound (26 g, yield 46%) as a yellow solid. MS (ES+) C20H23FN4O3 requires: 386, found 331 [M—56+H]+; purity: 100% ).

Step 3: Synthesis of tert—butyl 4—(5—(1—(4—ﬂuorophenyl)vinyl)pyrimidin—2—yl)piperazine—1— carboxylate: To a solution of methyltriphenylphosphonium bromide (6.0 g, 16.84 mmol) in THF (40 mL) at — 78 0C was dropwise added n—BuLi (2.4 M, 7.2 mL, 17.19 mmol). After stirred at —78 0C for 1 h, tert—butyl 4—(5—(4—ﬂuorobenzoyl)pyrimidin—2—yl)piperazine—1—carboxylate (1.3 g, 3.37 mmol) was added. The reaction mixture was d at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with aqueous NH4Cl solution and extracted with EA (2 x W0 2015/057873 50 mL). The organic phases were washed with H2O (3x30 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (PE:EA = 10: 1) to get the title compound as a white solid (1.2 g, 93%). MS (ES+) C21H25FN4O2 requires: 384, found: 329 [M—56+1]+.

Step 4: Synthesis of tert—butyl 1—(4—ﬂuorophenyl)—2—hydroxyethyl)pyrimidin—2— yl)piperazine—1—carboxylat: Boc 00c ENN1 [N] NgN BH3'H202 NJ§N F F Tert—butyl 4—(5—(1—(4—ﬂuorophenyl)Vinyl)pyrimidin—2—yl)piperazine—1—carboxylate (1.2 g, 3.12 mmol) was dissolved in THF (30 mL) and then cooled to 0 0C, followed by the addition of BH3.THF (6.24 mL, 6.24 mmol) dropwise. The mixture was stirred at RT for 3 h. To the mixture was added H2O in THF (10%, 8 mL), a solution of NaOH (1.25 g) in 30 mL H20 and H202 (35%, 18 g) sequentially at 0 0C. The mixture was stirred at RT overnight. The mixture was acidified with 1 N HCl and extracted with EA (3x50 mL). The organic phases were washed with aqueous NaHCO3 (50 mL), brine (50 mL), dried over sodium sulfate, ed, concentrated and purified by silica gel chromatography (DCM:CH3OH = 30: 1) to get the title nd as a white solid (0.3 g, 24%). MS (ES+) C21H27FN4O3 requires: 402, found: 403 [M+H]+.

Step 5: Synthesis of 2—(4—ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol: ||30c H H N E J [N] E j N N A NkN HCI-dloxane NJ§N chiral separation N/ —> —> IN I l \ / / HO HO F F To a solution of utyl 4—(5—(1—(4—ﬂuorophenyl)—2—hydroxyethyl)pyrimidin—2—yl)piperazine—1— ylat (450 mg, 1.08 mmol) in dioxane (5 mL) was added HCl/dioxane (5 mL). The mixture was stirred at RT overnight. LCMS showed the reaction was completed. The solution was concentrated and purified by silica gel chromatography (DCM:CH3OH = 10: 1) to get the title compound as a yellow solid (0.2 g, 53%). MS (ES+) C16H19FN4O requires: 302, found: 303 [M+H]+.

The above sample (200 mg, 0.66 mmol) was separated by Chiral—HPLC to get (4— ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol assumed (1St peak, 50 mg, 25%) and phenyl—2—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol assumed (2Ild peak, 50 mg, 25%).

Synthesis of tert—butyl 4—(5—(4—ﬂuorophenoxy)pyrimidin—2—yl)piperazine—1—carboxylate: am EN] [ j OH A j: N / Cu, , IN N / IN pyridine, 120 °C V v o Br 0F A mixture of tert—butyl romopyrimidin—2—yl)piperazine—1—carboxylate (684 mg, 2.0 mmol), 4—ﬂuorophenol (1.1 g, 5.0 mmol), copper (650 mg, 10.0 mmol) and ngCO3 (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0C for 12 h. The mixture was cooled to RT, diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2 20/ 1) to afford the title compound (200 mg, 27%) as a brown solid. MS (ES+) C19H23FN4O3 requires: 374, found: 319 1]+.

Synthesis of 5—(4—ﬂuorophenylsulfonyl)—2—(piperazin—1—yl)pyrimidine HCl salt: S. [33° [1 [N] N szdba3,Xantphos,DlEA mCPBA,DCM + NAN N x dioxane, 110 °C N / N V V V g) F o o Step 1: Synthesis of tert—butyl 4—(5—(4—ﬂuorophenylthio)pyrimidin—2—yl)piperazine—1— carboxylate: EISOC N SH E j E j N N Pdgdba3,Xantphos, DIEA A 2\ + —> N N dioxane, 110 °C V A stirred solution of tert—butyl 4—(5—bromopyrimidin—2—yl)piperazine—1—carboxylate (1 g, 2.924 mmol), 4—ﬂuorobenzenethiol (561 mg, 4.386 mmol), Pd2(dba)3 (267 mg, 0.292 mmol), Xantphos (169 mg, 0.292 mmol) and DIPEA (754 mg, 5.848 mmol) in dioxane (50 mL) was degassed with en for three times, and then heated at 110 0C for 16 hrs. The reaction mixture was cooled to RT and concentrated under reduced pressure to give a residue, which was ed by ﬂash chromatography (silica gel, 0—20% EtOAc/PE) to afford the title compound as a white solid. (500 mg, yield 44%, purity: 99%). MS (ES+) C19H23FN402S requires: 390, found 391 [M+H]+.

Step 2: Synthesis of tert—butyl 4—(5—(4—ﬂuorophenylsulfonyl)pyrimidin—2—yl)piperazine—1— carboxylate: 80c 80c {.1 [N] NAN mCPBA, DCM 1 N/ N F F A solution of utyl 4—ﬂuorophenylthio)pyrimidin—2—yl)piperazine—1—carboxylate (700 mg, 1.799 mmol) and mCPBA (619 mg, 3.599 mmol) in DCM (20 mL) was stirred at RT for 16 hrs. The reaction mixture was washed sequentially with saturated potassium carbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by ﬂash chromatography a gel, 0—20 % EtOAc/PE) to afford the title compound as a white solid. (600 mg, yield 83%, purity: 100%).

MS (ES+) C19H23FN4O4S es: 422, found 423 [M+H]+.

Step 3: Synthesis of 5—(4—ﬂuorophenylsulfonyl)—2—(piperazin—l—yl)pyrimidine HCl salt: To a solution of tert—butyl 4—(5—(4—ﬂuorophenylsulfonyl)pyrimidin—2—yl)piperazine—l—carboxylate (100 mg, 0.237 mmol) in dioxane was added 4 M HCl/dioxane (6 mL). The mixture was stirred at RT for 3 hrs and concentrated to afford the title compound as a yellow oil, which was used into the next step without further cation. MS (ES+) C14H15FN4OZS requires: 322, found 323 [M+H]+.

Synthesis of (R)—2—(4—ﬂuorophenyl)—2— (2—(piperazin— l —yl)pyrimidin—5—yl)propan— 1—01 and (S)—2— rophenyl)—2—(2—(piperazin— yrimidin—5—yl)propan— 1 —ol: Boo Boo B0C N N N N E E E [N N i N ,1 A /0 P(t-Bun LiN \ —> \ | O Pd2(dba)2 toluene RT 15 hM LDA THF 0 deg, 1 h V F F F E J EN] EN] 1. HCI/1,4—dioxane NAN chiral pre-HPLC 2. aq. NaH003 I NJ\IN NAIN \ \ —Il, HO ' Step 1: Synthesis of tert—butyl 4—(5—(l—(4—ﬂuorophenyl)—2—methoxy—2—oxoethyl)pyrimidin—2— yl)piperazine— l—carboxylate: BOO E E J ,1 j: /o P(t—Bu)3, LiN(Cy)2 N/ + ’ N \ V| O Pd2(dba)2 ,toluene, RT, 15 h F MeO Br 0 To a solution of dicyclohexylamine (3.43 g, 18.94 mmol) in THF (60 mL) at —78 0C was added n—BuLi (2.5 M, 7.9 mL, 18.94 mmol) dropwise. The mixture was stirred at RT for 10 min, followed by the addition of methyl 2—(4—ﬂuorophenyl)acetate (2.69 g, 16.02 mmol) in toluene (60 mL). After stirred at RT for another 10 min, tert—butyl 4—(5—bromopyrimidin—2—yl)piperazine—1— carboxylate (5.0 g, 14.57 mmol), a)3 (667 mg, 0.728 mmol) and P(t—Bu)3 (10%, 1.47 g, 0.728 mmol) were added tially. The reaction mixture was stirred at RT for 15 h, quenched by water (150 mL) and extracted with EA. The combined organic layers were washed with water and brine, dried over , filtered and concentrated. The e was passed a column (silica gel, PE:EA = 6:1) to afford the title compound (0.5 g, 8%) as an orange solid. MS (ES+) C22H27FN4O4 requires: 430, found: 431 [M+H]+.

Step 2: Synthesis of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1—methoxy—1—oxopropan—2—yl)pyrimidin— 2—yl)piperazine—1—carboxylate: U E N2h" N CH3| IN \ —> \ LDA, THF MeO MeO o O F F To a mixture of tert—butyl 4—(5—(1—(4—ﬂuorophenyl)—2—methoxy—2—oxoethyl)pyrimidin—2— yl)piperazine—1—carboxylate (1.0 g, 2.33 mmol) in THF (20 mL) at —78 0C was added LDA (2 M, 2.33 mL, 4.65 mmol) dropwise, After stirred at —78 0C for 30 min, CH3I (0.66 g, 4.65 mmol) was added. After d at RT for another 1 h, the reaction was quenched by water and extracted with EA. The combined organic layers were washed with water and brine, dried over NaZSO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA = 6: 1) to afford the title 2014/060746 nd (0.8 g, 77%) as a yellow solid. MS (ES+) C23H29FN4O4 requires: 444, found: 445 Step 3: Synthesis of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1—hydroxypropan—2—yl)pyrimidin—2— yl)piperazine—1—carboxylate: Boc Boc [N r" / i N IN N/ LiBH4,THF N \ —> \ 0 deg, 1 h MeO HO F F To a mixture of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1—methoxy—1—oxopropan—2—yl)pyrimidin—2— yl)piperazine—l—carboxylate (0.4 g, 0.9 mmol) in THF (10 mL) was added LiBH4 (40 mg, 1.8 mmol). After stirred at RT for 2 h, the reaction was quenched by aq. NH4Cl and extracted with EA. The combined organic layers were washed with water and brine, dried over NagSO4, filtered and trated. The residue was passed a column (silica gel, PE :EA 2 1:1) to afford the title compound (225 mg, 60%) as a yellow solid. MS (ES+) C22H29FN4O3 requires: 416, found: 417 [M+H]+.

Step 4: Synthesis of (R)—2—(4—ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)propan— 1—ol: [N u N / IN 1. HCI/1,4-dioxane chiral LC —> N2\|N —> 2. aq. NaHC03 \ HO HO F F To a mixture of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1—hydroxypropan—2—yl)pyrimidin—2— yl)piperazine—l—carboxylate (450 mg, 1.08 mmol) in DCM (20 mL) was added 4 M HCl/1,4— dioxane (3 mL). After stirred at RT for 15 h, the reaction mixture was concentrated, the residue was d by aq. NaHCO3 (20 mL) and extracted with DCM. The combined organic layers were washed with water and brine, dried (NazSO4), filtered and concentrated. The residue was separated by chiral Prep—HPLC to give (R)—2—(4—ﬂuorophenyl)—2—(2—(piperazin— 1—yl)pyrimidin—5— yl)propan—l—ol (100 mg, 29%) as a white solid. MS (ES+) C17H21FN4O requires: 316, found: 317 [M+H]+. Chiral HPLC, Column: IC 4.6*150mm 5um, Co—Solvent: EtOH:Hexane = 1:1 (0.1%DEA), RT = 4.22 min.

(S)—2—(4—ﬂuorophenyl)—2—(2—(piperazin—1—yl)pyrimidin—5—yl)propan—1—ol (100 mg, 29%) as a white solid. MS (ES+) C17H21FN4O requires: 316, found: 317 [M+H]+. Chiral HPLC, Column: IC 4.6*150mm 5um, Co—Solvent: EtOH:Hexane = 1:1(0.1%DEA), RT = 5.43 min.

Synthesis of 5—(3—(4—ﬂuorophenyl)oxetan—3—yl)—2—(piperazin— 1—yl)pyrimidine Roe 1'300 Elkoc Roe H N N N N N [N] [N] [N] [N] [N] A A N N paraformaldehyde N N LBH, -10 °C N2\N Ph3P, DIAD NAN TFA ' m ' —’ ' W ' mNAIN \ \ \ \ \ -78 °c ~ RT OH OH /o /0 HO o O O O F F F F F Step 1: Synthesis of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—3—hydroxy— oxy— 1—oxopropan—2— yl)pyrimidin—2—yl)piperazine—1—carboxylate: ||300 Roe [N] [N] N2\|N i rmaldehyde N / —> IN \ LHMDS, THF \ -78 00 ~ RT OH /O /O o 0 F F A solution of tert—butyl 4—(5—(1—(4—ﬂuorophenyl)—2—methoxy—2—oxoethyl)pyrimidin—2— yl)piperazine—1—carboxylate (650 mg, 1.5 mmol) in THF (20 mL, dry) was cooled to —78 °C and protected with N2. Another solution of n—BuLi (1.5 M, 3 mL, ~4.5 mmol) in THF was added to the above cooled solution during 5 min. The reaction mixture was d at —78 °C for 1 h, followed by the addition of paraformaldehyde (405 mg, 15.0 mmol) in one potion under —78 0C.

This solution was stirred at RT overnight. The on was quenched by saturated aqueous NH4Cl (50 mL) and water (50 mL), and extracted with EtOAc (50 mL*4). The combined organic layer were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EA (4:1) to obtain the title compound as a yellow thicky oil (300 mg, 44% yield). MS (ES+) C23H29FN4O5 es: 460, found 461 [M+H]+; purity: 93% (UV214).

WO 57873 Step 2: Synthesis of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1,3—dihydroxypropan—2—yl)pyrimidin—2— yl)piperazine—1—carboxylate: §oc $00 EN] [N] N N N2\N LBH, -10 OC N2\N I —> I \ \ OH OH /O HO F F A solution of 4—(5—(2—(4—ﬂuorophenyl)—3—hydroxy—1—methoxy—1—oxopropan—2—yl)pyrimidin—2— yl)piperazine—1—carboxylate (700 mg, 1.5 mmol) in 20 mL of THF was cooled to —10 0C, followed by the addition of LiBH4 (180 mg, 7.5 mmol) slowly. This e was allowed to warm to RT and stirred overnight. The reaction was ed by MeOH (3 mL) and then concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH, 10:1) to obtain the desired product (300 mg, yield 47%) as a yellow foam. MS (ES+) C22H29FN4O4 requires: 432, found 433 [M+H]+; purity: 67% (UV254).

Step 3: Synthesis of tert—butyl 4—(5—(3—(4—ﬂuorophenyl)oxetan—3—yl)pyrimidin—2—yl)piperazine—1— carboxylate: Soc Soc [N] [N] N2\N l Ph3P, DIAD N / I —> IN \ ziram, THF \ F F A mixture of tert—butyl 4—(5—(2—(4—ﬂuorophenyl)—1,3—dihydroxypropan—2—yl)pyrimidin—2— yl)piperazine—1—carboxylate (650 mg, 1.5 mmol), nylphosphine (470 mg, 1.8 mmol), diisopropyl azodicarboxylate (360 mg, 1.8 mmol) and ziram (500 mg, 1.8 mmol) in THF (50 mL) was heated at 40 0C overnight under N2 and concentrated. The residue was d with EtOAc (40 mL), washed with water (50 mL*2) and brine, dried over Na2S04 and concentrated.

The residue was purified by Prep—HPLC to give the desired product (35 mg, yield 6%) as a white solid. MS (ES+) C22H27FN4O3 requires: 414, found 359 [M +H— 56]+; purity: 93% (UV214).

Step 4: Synthesis of 5—(3—(4—ﬂuorophenyl)oxetan—3—yl)—2—(piperazin—1—yl)pyrimidine: [E] z: l l \ DCM, 60 °C, 4 h \ 0 o F F A solution of tert—butyl 3—(4—ﬂuorophenyl)oxetan—3—yl)pyrimidin—2—yl)piperazine—1— carboxylate (22 mg, 0.05 mmol) in DCM (1 mL) was d with TFA (0.5 mL) at 60 0C for 3 h and then concentrated under reduced pressure. The residue (30 mg, crude, yellow solid, 100% yield) was directly used into the next step without further purification. MS (ES+) C17H19FN4O requires: 314, found 315 [M+H]+; purity: 87% (UV254). sis of (S)—1—(5—ﬂuoropyridin—2—yl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol and (R)— 1— (5—ﬂuoropyridin—2—yl)—1—(2—(piperazin—1—yl)pyrimidin—5—yl)ethanol: ECbz Cbz N ZI NiN E U N N n-BuLi NJ§N Pd/C, H2 NIJ§N Chiral—HPLC EZJ'+? —’ N / | —> THF -78°Cto RT / IPA, RT, O/N / N N ’ / HO | Ho | \ \ F F Step 1: Synthesis of benzyl 4—(5—(1—(5—ﬂuoropyridin—2—yl)—1—hydroxyethyl)pyrimidin—2— yl)piperazine—1—carboxylate: Cbz 20 c-N E] F E] N N N2\N \ n-BuLi N / NIJ§N \ THF oRT / F To a solution of 2—bromo—5—ﬂuoropyridine (1.3 g, 7.50 mmol) in anhydrous THF (30 mL) was added n—BuLi (2.76 mL, 6.62 mmol) at —78 0C dropwise, and the mixture was stirred at —78 0C for 2 h, followed by the addition of benzyl 4—(5—acetylpyrimidin—2—yl)piperazine—1—carboxylate (1.5 g, 4.41 mmol). The reaction mixture was allowed to warm to RT and d overnight. LCMS showed the reaction was completed. The solution was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 100 mL). The combined c layers were washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep—HPLC to afford the title compound (0.4 g, 20%) as a white solid. MS (ES+) C23H24FN5O3 requires: 437, found: 438 [M + H]+.

Step 2: Synthesis of (S)— l—(5—ﬂuoropyridin—2—yl)— l—(2— (piperazin— l —yl)pyrimidin—5—yl)ethanol and (R)— l —(5—ﬂuoropyridin—2—yl)— l —(2—(piperazin— l—yl)pyrimidin—5—yl)ethanol: Cbz H [N [N] N N NJ§N Pd/C, H2 NJ§N Chiral-HPLC ' ' / |PA,RT,O/N / N N HO /| HQ \ \ F F A suspension of benzyl 4—(5—(l—(5—ﬂuoropyridin—2—yl)—l—hydroxyethyl)pyrimidin—2— yl)piperazine—l—carboxylate (420.0 mg, 0.96 mmol) and Pd/C (200.0 mg) in i—PrOH was exposed to 1 atm H2 atmosphere (H2 balloon) and stirred at RT overnight. LCMS showed the reaction was completed. The reaction mixture was ed through a pad of Celite. The filtrate was concentrated and ed by silica gel tography (DCM:CH3OH 2 10:1) to get the title compound as a white solid (153 mg, 53%). MS (ES+) C15H13FN50 requires: 303, found: 304 [M+H]+.

The racemate compound (290 mg, 0.96 mmol) was separated by Chiral—HPLC to get (S)—l—(5— ﬂuoropyridin—2—yl)—l—(2—(piperazin—l—yl)pyrimidin—5—yl)ethanol (peak 1, 80 mg, 28%) and (R)—l— (5—ﬂuoropyridin—2—yl)—l—(2—(piperazin—l—yl)pyrimidin—5—yl)ethanol (peak 2, 80 mg, 28%).

Synthesis of (S)—tert—butyl 4—(5—( l — (4—ﬂuorophenyl)Vinyl)pyrimidin—2—yl)—3— xymethyl)piperazine— l —carboxylate: 2—(1—(4—Fluorophenyl)Vinyl)—4,4,5,5—tetramethyl—1,3,2—dioxaborolane (138 mg, 0.556 mmol), (S)— tert—butyl 4—(5—bromopyrimidin—2—yl)—3—(hydroxymethyl)piperazine—1—carboxylate (103 mg, 0.276 mmol), 2 M sodium carbonate (0.35 mL, 0.700 mmol), and PdCl2(dppf)—DCM adduct (17.3 mg, 0.021 mmol) were taken up in 1,4—dioxane (2 mL) in a 2—5 mL microwave Vial. The reaction was stirred at 100 °C for 18 hours. Room ature was attained, the reaction mixture was filtered through a plug of Celite eluting with MeOH, and the te was concentrated in vacuo while loading onto Celite. The residue was purified by MPLC (0—100% hexanes) to give (S)—tert—butyl 4—(5—(1—(4—ﬂuorophenyl)Vinyl)pyrimidin—2—yl)—3— (hydroxymethyl)piperazine—1—carboxylate (107 mg, 0.258 mmol, 94 % yield) as an orange gum.

MS (ES+) C22H27FN4O3 requires: 414, found: 415 [M + H]+.

Synthesis of (S)—2,2,2—triﬂuoro— 1—(4—ﬂuorophenyl)— 1 —(2— (piperazin— 1 —yl)pyrimidin—5— yl)ethanamine: Step 1: Synthesis of (R,Z)—2—methyl—N—(2,2,2—triﬂuoro—1—(4—ﬂuorophenyl)ethylidene)propane—2— sulfinamide: (R)—2—Methylpropane—2—sulfinamide (0.64 g, 5.28 mmol), 2,2,2—triﬂuoro—l—(4— ﬂuorophenyl)ethanone (0.53 g, 2.76 mmol) and titanium(IV) isopropoxide (1.5 mL, 512 mmol) were stirred in THF (13 mL) at 70 °C for 18 hours. Room temperature was attained, saturated NaCl and EtOAc were added, and the resulting biphasic suspension was stirred for 5 minutes.

The suspension was filtered through Celite to remove the titanium residues, and the c phase was separated. The aqueous phase was extracted a second time with EtOAc. The combined organic ts were washed with brine, dried over NaZSO4, ed, and concentrated in vacuo while loading onto silica. cation of the e by MPLC (0—20% EtOAc—hexanes) gave (R,Z)—2—methyl—N—(2,2,2—triﬂuoro—l—(4—ﬂuorophenyl)ethylidene)propane—2—sulfinamide (0.23 g, 0.779 mmol, 28.2 % yield) as a yellow oil.

Step 2: Synthesis of tert—butyl 4—(5— ((S)— l —(((R)—tert—butylsulfinyl)amino)—2,2,2—triﬂuoro— l — (4— ﬂuorophenyl)ethyl)pyrimidin—2—yl)piperazine— l—carboxylate: o o T F [N] [N] \/\/LI >L§+N\ NJ§N NJ§N I 0": / F F tert—Butyl 4—(5—bromopyrimidin—2—yl)piperazine—l—carboxylate (0.242 g, 0.705 mmol) was taken up in THF (3.5 mL) and cooled to —78 0C. A solution of IlBuLi, 2.5 M in hexanes (0.31 mL, 0.775 mmol) was added at a fast dropwise rate from a syringe. The resulting e was stirred at —78 °C for 15 minutes. A solution of (R,Z)—2—methyl—N—(2,2,2—triﬂuoro—l—(4— ﬂuorophenyl)ethylidene)propane—2—sulfinamide (0.225 g, 0.762 mmol) in THF (0.5 mL) was added at a fast dropwise rate from a syringe. The reaction mixture was stirred at —78 °C for 5 minutes before warming to room temperature. After 45 minutes, ted NH4Cl was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over NaZSO4, filtered, and concentrated in vacuo. Purification of the e by MPLC (0— 80% EtOAc—hexanes) gave tert—butyl 4—(5—((S)—l—(((R)—tert—butylsulfinyl)amino)—2,2,2—triﬂuoro— l—(4—ﬂuorophenyl)ethyl)pyrimidin—2—yl)piperazine—l—carboxylate (304 mg, 0.543 mmol, 77 % yield) as a pale yellow gum. The absolute stereochemistry was assigned randomly.

MS (ES+) C25H33F4N503S requires: 559, found: 560 [M + H]+.

Step 3: Synthesis of (S)—2,2,2—triﬂuoro— uorophenyl)— l —(2—(piperazin— l—yl)pyrimidin—5— yl)ethanamine: of 22!: [N] l N/ N X —’ \ NI /N\ 3 NH2 F7?; F F F tert-Butyl 4-(5-((S)- l-(((R)-tert—butylsulfinyl)amino)-2,2,2-triﬂuoro- l-(4- ﬂuorophenyl)ethyl)pyrimidin—2—yl)piperazine—l—carboxylate (302 mg, 0.540 mmol) was stirred in 4 M HCl in l,4—dioxane (3 mL)/MeOH (3 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue was partitioned between saturated NaHCO3 and EtOAc. The organic phase was extracted a second time with EtOAc. The combined organic extracts were washed with brine, dried over NazSO4, filtered, and concentrated in vacuo to give (S)—2,2,2— triﬂuoro—l—(4—ﬂuorophenyl)—l—(2—(piperazin—l—yl)pyrimidin—5—yl)ethanamine (190 mg, 0.535 mmol, 99 % yield) with ~88% e.e. r purification by chiral SFC gave 2,2—triﬂuoro—l— (4—ﬂuorophenyl)—l—(2—(piperazin—l—yl)pyrimidin—5—yl)ethanamine (123.7 mg, 0.348 mmol, 71.2 % yield) with ~99% e.e.

MS (ES+) C16H17F4N5 requires: 355, found: 356 [M + H]+.

The synthetic protocols that can be used to prepare the nds disclosed herein are indicated below. The NMR and LC MS data obtained for compounds disclosed herein are also shown below. —lOO— WO 57873 Compound Synthetic 1 LC/MS H NMR Number Protocol (M+1) 1 1 360 2 1 386 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 2H), 8.15 (d, J : 5.2 Hz, 1H), 7.34 — 7.13 (m, 5H), 6.32 (d, J : 5.2 Hz, 1H), 5.95 (s, 1H), 3.93 (s, 3H), 3.89 (dd, J : 6.7, 3.6 Hz, 4H), 3.79 (s, 2H), 3.76 (dd, J : 6.4, 3.8 Hz, 4H). 1H—NMR (400 MHz, DMSO-dg + 1d D20) (3 ppm 8.33 (s, 2H), 7.99 (s, 1H), 7.94 (d, 1H, J: 1.6 Hz), 7.86 (s, 1H), 7.81 (s, 1H), .18 (m, 6H), 4.09—4.01 (m, 4H), 3.89- 3.83 (m, 4H), 3.84 (s, 3H), 3.80 (s, 2H). 1H—NMR (500 MHz, CDC13) (3 ppm 8.24 (s, 2H), 7.91 (s, 1H), 7.71, 7.70 (s, s, 2H), 7.58 (s, 1H), 7.32—7.29 (m, 2H), 7.247.17 (m, 5H), 6.82 (br. s., 1H), 4.94 (br. s., 1H), 4.61 (br. s., 1H), 4.52—4.49 (m, 2H), 3.96 (s, 3H), 3.87— 3.85 (br., 1H), 3.82 (s, 2H), 3.71-3.64 (br, 2H), 1.29 (d, 3H, J: 7.0 Hz). 1H—NMR (400 MHz, DMSO-dé) (3 ppm 8.35 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J: 1.2 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.31—7.29 (m, 4H), 7.22-7.18 (m, 2H), 4.09-4.06 (m, 5H), 3.96—3.88 (m, 4H), 3.85 (s, 3H), 1.58 (d, 3H, J: 7.6 HZ). 1H—NMR (400 MHz, DMSO-dé) (3 ppm 8.35 (s, 2H), 8.03 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.32—7.29 (m, 4H), 7.22—7.17 (m, 2H), 4.09—4.04 (m, 5H), 3.91—3.86 (m, 7H), 1.58 (d, 3H, J: 7.2 Hz). —101— 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 11 1 7.39 - 7.25 (m, 4H), 7.24 - 7.15 (m, 2H), 6.77 (d, J = 8.8 467 Hz, 1H), 5.79 (d, J = 4.1 Hz, 1H), 5.63 (d, J = 4.0 Hz, 1H), 4.13 - 4.05 (m, 4H), 3.84 (s, 4H), 3.71 - 3.64 (m, 4H). 12A 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.83 (br. s., 4 1H), 8.40 (s, 2H), 8.10-7.86 (m, 4H), 7.44 (d, 2H, J = 7.6 467 Hz), 7.36-7.15 (m, 4H), 4.10-4.07 (m, 4H), 3.91- 3.88 (m, 4H), 1.74 (s, 3H). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 13 8.01 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 4 7.43-7.37 (m, 2H), 7.30 (t, 2H, J = 8.0 Hz), 7.23-7.16 (m, 467 2H), 5.01 (s, 1H), 4.11-4.03 (m, 4H), 3.92-3.85 (m, 4H), 3.84 (s, 3H), 2.32 (s, 2H). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (s, 2H), 8.03 (d, J = 0.8 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.87 (s, 14 1 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.34 - 7.19 (m, 3H), 7.19 - 470 7.06 (m, 2H), 4.14 - 4.05 (m, 4H), 3.90 (dd, J = 6.7, 4.0 Hz, 4H), 3.85 (s, 3H), 3.80 (s, 2H). 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.38 (s, 2H), 8.04 (s, 1H), 8.00 (d, 1H, J = 1.0 Hz), 7.89 (s, 1H), 7.83 1 (s, 1H), 7.24 (d, 1H, J = 1.0 Hz), 7.21-7.18 (m, 2H), 7.06- 472 7.03 (m, 2H), .12 (m, 4H), 3.94-3.92 (m, 4H), 3.86 (s, 3H). 1H-NMR (400 MHz, DMSO-d 6) δ ppm 8.45 (d, 1H, J = 1.6 Hz), 8.34 (s, 2H), 8.06 (d, 2H, J = 8.4 Hz), 7.93 (s, 16 1 1H), 7.86 (d, 2H, J = 8.4 Hz), 7.62 (d, 1H, J = 1.6 Hz), 473 7.32-7.18 (m, 5H), 4.14 (t, 4H, J = 5.2 Hz), 3.92 (t, 4H, J = 5.2 Hz), 3.81 (s, 2H). 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.57 (s, 17 1 2H), 8.10 (s, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.88 (s, 2H), 480 7.33 - 7.21 (m, 3H), 7.19 - 7.12 (m, 1H), 7.05 (td, J = 7.9, 1.6 Hz, 1H), 4.24 - 4.08 (m, 4H), 4.08 - 3.93 (m, 4H). 1H NMR (400 MHz, DMSO-d 6) δ 8.33 (s, 2H), 8.16 (d, J = 1.7 Hz, 1H), 7.88 (s, 1H), 7.79 – 7.70 (m, 2H), 7.36 (d, 18 1 J = 1.8 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.26 – 7.15 (m, 3H), 7.00 – 6.92 (m, 2H), 4.11 (dd, J = 6.6, 4.1 Hz, 4H), 3.93 – 3.85 (m, 4H), 3.80 (s, 2H), 3.77 (s, 3H). 1H-NMR (500 MHz, CDCl 3) δ ppm 8.24 (s, 2H), 7.96 (br. s., 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.32-7.17 (m, 5H), 19 1 6.84 (br. s., 1H), 4.97 (br. s., 1H), 4.65 (br. s., 1H), 4.54 480 (br. s., 2H), 3.87 (s, 3H), 3.86-3.82 (m, 5H), 2.41 (s, 3H), 1.32 (d, 3H, J = 3.5 Hz). 1H—NMR (400 MHz, DMSO-ds) (3 ppm 8.28 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J: 1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.35—7.25 (m, 4H), 7.24-7.16 (m, 2H), 4.11—4.09 (m, 4H), 3.92-3.89 (m, 4H), 3.85 (s, 3H), 1.64 (s, 6H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 8.39 (s, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.28 (t, 2H, J : 8.0 Hz), 7.22—7.15 (m, 2H), 4.11—4.05 (m, 4H), .86 (m, 4H), 3.84 (s, 3H), 2.38 (s, 2H), 1.73 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 8.40 (s, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.28 (t, 2H, J : 8.0 Hz), 7.22—7.15 (m, 2H), 4.11—4.05 (m, 4H), 3.92—3.86 (m, 4H), 3.84 (s, 3H), 2.39 (s, 2H), 1.73 (s, 3H). 1H-NMR (400 MHz, DMSO-d6) 5 ppm 8.36 (s, 2H), 8.04 (s, 1H), 8.00 (d, 1H, J : 1.6 Hz), 7.89 (s, 1H), 7.83 (s, 1H), 7.42—7.39 (m, 2H), 7.25—7.20 (m, 3H), 5.50 (s, 1H), 5.41 (s, 1H), .12 (m, 4H), 4.00—3.97 (m, 4H), 3.86 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 8.40 (s, 2H), 8.03 (s, 1H), 7.97 (d, 1H, J: 1.6 Hz), 7.87 (s, 1H), 7.81 (s, 1H), .44 (m, 2H), 7.33—7.29 (m, 2H), 7.22—7.19 (m, 2H), 5.81 (s, 1H), 4.10—4.07 (m, 4H), 3.92-3.87 (m, 4H), 3.85 (s, 3H), 1.83 (s, 3H).

H-NMR (400 MHz, DMSO-dg) (3 ppm 8.40 (s, 2H), 8.03 (s, 1H), 7.97 (d, 1H, J: 2.0 Hz), 7.87 (s, 1H), 7.81 (s, 1H), 7.46—7.43 (m, 2H), 7.33—7.29 (m, 2H), 7.22—7.21 (m, 2H), 5.81 (s, 1H), 4.10—4.07 (m, 4H), 3.92-3.89 (m, 4H), 3.85 (s, 3H), 1.82 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 12.85 (s, 1H), 8.41 (s, 2H), 8.11 (s, 1H), 8.01 (d, 1H, J: 1.6 Hz), 7.89- 7.87 (m, 2H), 7.48-7.45 (m, 2H), 7.25 (d, 1H, J: 1.6 Hz), 7.13—7.09 (m, 2H), .08 (m, 4H), 3.92-3.89 (m, 4H), 2.45 (br. s., 2H), 1.73 (s, 3H). 1H-NMR (400 MHZ, CDC13) 8 ppm 8.35 (s, 2H), 7.90 (s, 1H), 7.70-7.69 (m, 2H), 7.56 (s, 1H), .35 (m, 2H), 7.05-7.00 (m, 2H), 6.77 (d, 1H, J = 2.0 HZ), 5.13 (s, 1H), 4.15-4.12 (m, 4H), 4.02-3.99 (m, 4H), 3.99 (s, 3H). 1H-NMR (400 MHZ, CDC13) 8 ppm 8.35 (s, 2H), 7.90 (s, 1H), 7.70-7.69 (m, 2H), 7.57 (s, 1H), 7.38-7.35 (m, 2H), 7.05-7.00 (m, 2H), 6.77 (d, 1H, J = 2.0 HZ), 5.13 (s, 1H), 4.15-4.12 (m, 4H), 4.02-3.99 (m, 4H), 3.95 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 12.81 (br. s., 1H), 8.39 (s, 2H), 8.10-8.00 (br, 1H), 8.00 (d, 1H, J = 1.2 HZ), 7.95-7.85 (br, 1H), 7.86 (s, 1H), 7.47-7.44 (dd, 2H, J = 8.8, 5.6 HZ), 7.24 (d, 1H, J = 1.2 HZ), 7.12 (t, 2H, J = 8.8 HZ), 5.90 (s, 1H), 4.09-4.07 (m, 4H), 3.91-3.88 (m, 4H), 1.81 (s, 3H). —103— 1H—NMR (400 MHz, DMSO-dg) 5 ppm 12.81 (br. s., 1H), 8.39 (s, 2H), 8.09 (br. s., 1H), 8.00 (d, 1H, J: 1.2 Hz), 3 7.87-7.86 (m, 2H), 7.47—7.44 (m, 2H), 7.24 (d, 1H, J: 486 1.2 Hz), 7.12 (t, 2H, J: 8.8 Hz), 5.90 (s, 1H), 4.09—4.07 (m, 4H), 3.91—3.88 (m, 4H), 1.81 (s, 3H). lH-NMR (500 MHz, DMSO-d6) 5 ppm 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), .41 (m, 2H), 7.22 (s, 1H), 7.18-7.14 (m, 2H), 6.01 (d, 1H, J : 3.5 Hz), 5.68 (d, 1H, J : 3.0 Hz), 4.09 (br. s., 4H), 3.91 (br. s., 4H), 3.85 (s, 3H). lH-NMR (500 MHz, DMSO-d6) 5 ppm 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.44—7.41 (m, 2H), 7.22 (s, 1H), .14 (m, 2H), 6.01 (s, 1H), 5.68 (s, 1H), 4.09 (br. s., 4H), 3.91 (br. s., 4H), 3.85 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) 5 ppm 8.37 (d, 1H, J : 1.2 Hz), 8.34 (s, 2H), 7.98 (s, 1H), 7.96-7.89 (m, 5H), 7.56 (s, 1H), 7.30—7.20 (m, 6H), 4.14 (t, 4H, J: 6.0 Hz), 3.87 (t, 4H, J: 5.2 Hz), 3.81 (s, 2H). lH-NMR (400 MHz, 6) 5 ppm 8.40 (s, 2H), 8.26 (d, 1H, J : 2.0 Hz), 7.90-7.86 (m, 3H), 7.46-7.41 (m,3H),7.31-7.18(m,5H),4.13-4.10(m,4H),3.91- 3.89 (m, 4H), 3.31—3.29 (br, 2H), 1.73 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.40 (s, 2H), 8.08 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.42 (d, 2H, J : 8.0 Hz), 7.31—7.27 (m, 2H), 7.22-7.18 (m, 2H), 4.12 (q, 2H, J : 7.2 Hz), 4.09—4.07 (m, 4H), 3.92— 3.88 (m, 4H), 2.70-2.60 (m, 2H), 1.74 (s, 3H), 1.39 (t, 3H, J : 7.6 Hz). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.41 (s, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.45—7.39 (m, 2H), 7.31 (t, 2H, J : 8.0 Hz), 7.23—7.17 (m, 2H), 4.11 (s, 1H), .04 (m, 4H), 3.92—3.86 (m, 4H), 3.84 (s, 3H), 2.11 (s, 6H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.41 (s, 2H), 8.02 (s, 1H), 7.97-7.96 (m, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.45—7.39 (m, 2H), 7.31 (t, 2H, J : 8.0 Hz), 7.23— 7.17 (m, 2H), 4.11 (s, 1H), 4.10—4.04 (m, 4H), 3.92—3.86 (m, 4H), 3.84 (s, 3H), 2.12 (s, 6H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.40 (s, 2H), 8.27 (d, 1H, J : 1.6 Hz), 7.90 (s, 1H), 7.84-7.82 (m, 2H), 7.48-7.44 (m, 3H), 7.41—7.37 (m, 2H), 7.27—7.23 (m, 1H), 7.14-7.10(m, 2H), 5.89 (s, 1H),4.14-4.11 (m, 4H), 3.92— 3.90 (m, 4H), 1.81 (s, 3H). 1H—NMR (400 MHz, CDC13) 5 ppm 8.23 (s, 2H), 7.90 (s, 1H), 7.70 (s, 2H), 7.57 (s, 1H), 7.21 (dd, 2H, J: 8.0, 4.0 Hz), 7.01-6.96 (m, 2H), 6.78 (s, 1H), 4.17-4.14(m, 4H), 4.02—3.99 (m, 4H), 3.95 (s, 3H), 1.67 (s, 6H). —104— 1H-NMR (400 MHZ, CDC13) 6 ppm 8.22 (s, 2H), 7.89 (s, 1H), 7.69, 7.68 (s, s, 2H), 7.56 (s, 1H), 7.18-7.15 (m, 2H), 7.01-6.97 (m, 2H), 6.77 (d, 1H, J: 1.6 Hz), 4.15- 4.13 (m, 4H), 4.01-3.98 (m, 4H), 3.95 (s, 3H), 3.64 (t, 1H, J: 8.0 Hz), 2.05-1.98 (m, 2H), 0.92 (t, 3H, J: 8.0 HZ).

H-NMR (400 MHZ, CDCl3-d6) 6 ppm 8.22 (s, 2H), 7.89 (s, 1H), 7.69, 7.68 (s, s, 2H), 7.56 (s, 1H), 7.18-7.15 (m, 2H), 7.01-6.97 (m, 2H), 6.77 (d, 1H, J: 1.6 Hz), 4.15- 4.13 (m, 4H), 4.01-3.98 (m, 4H), 3.95 (s, 3H), 3.64 (t, 1H, J: 7.6 Hz), 2.04-1.99 (m, 2H), 0.92 (t, 3H, J: 7.6 HZ). 1H—NMR (400 MHz, DMSO-d6) 5 ppm 8.39 (s, 2H), 8.02 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.47—7.43 (m, 2H), 7.21 (s, 1H), 7.12—7.07 (m, 2H), 4.11—4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H), 1.72 (s, 3H). 1H—NMR (400 MHz, 6) 5 ppm 8.39 (s, 2H), 8.02 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), .43 (m, 2H), 7.21 (s, 1H), 7.12—7.07 (m, 2H), 4.11—4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H), 1.72 (s, 3H). 1H—NMR (400 MHz, CDC13) 5 ppm 8.23 (s, 2H), 8.12 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.24—7.20 (m, 2H), 7.01— 7.96 (m, 2H), 6.48 (s, 1H), 4.50 (br. s., 4H), 4.02—4.00 (m, 4H), 3.99 (s, 3H), 1.67 (s, 6H). 1H—NMR (400 MHz, CDC13) 5 ppm 8.38 (s, 2H), 7.91 (s, 1H), 7.70 (s, 2H), 7.57 (s, 1H), 7.41 (dd, 2H, J: 8.0, 4.0 Hz), 7.05—7.01 (m, 2H), 6.79 (s, 1H),4.17-4.15 (m, 4H), 4.05—4.02 (m, 4H), 3.95 (s, 3H), 1.94 (s, 3H). 1H—NMR (400 MHz, CDC13) 5 ppm 8.38 (s, 2H), 7.89 (s, 1H), 7.69 (s, 2H), 7.57 (s, 1H), 7.41 (dd, 2H, J: 8.0, 4.0 Hz), 7.05—7.01 (m, 2H), 6.77 (d, 1H, J: 1.2 Hz), 4.17— 4.15 (m, 4H), 4.05—4.02 (m, 4H), 3.95 (s, 3H), 1.94 (s, 3H). 1H-NMR (400 MHz, CDC13) 5 ppm 8.37 (s, 2H), 7.88 (s, 1H), 7.67 (s, 2H), 7.65-7.63 (m, 1H), 7.55 (s, 1H), 7.32—7.29 (m, 1H),7.21-7.17 (m, 1H), 7.03-6.98 (m, 1H), 6.76 (s, 1H), .11 (m, 4H), 4.01—3.99 (m, 4H), 3.93 (s, 3H), 2.90 (d, 1H, J : 4.0 Hz), 1.96 (s, 3H). 1H-NMR (400 MHz, CDC13) 5 ppm 8.37 (s, 2H), 7.88 (s, 1H), 7.69 (s, 2H), 7.64 (t, 1H, J : 7.2 Hz), 7.56 (s, 1H), 7.31-7.28 (m, 1H), 7.19 (d, 1H, J : 7.6 Hz), 7.01 (dd, 1H, J : 11.6, 8.4 Hz), 6.77 (s, 1H),4.15-4.13 (m, 4H), 4.03—4.00 (m, 4H), 3.94 (s, 3H), 2.74 (d, 1H, J : 4.4 Hz), 1.97 (s, 3H). 1H-NMR (400 MHz, DMSO-d6) 5 ppm 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J : 1.6 Hz), 7.87 (s, 1H), 7.82 3 (s, 1H), .32 (m, 2H), 7.23 (d, 1H, J : 1.6 Hz), 7.15— 500 7.10 (m, 2H), 4.93 (t, 1H, J : 4.8 Hz), 4.12-4.06 (m, 4H), 4.02—3.97 (m, 1H), 3.94-3.86 (m, 6H), 3.85 (s, 3H). —105— 1H-NMR (400 MHZ, 6) 8 ppm 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J = 1.6 HZ), 7.87 (s, 1H), 7.82 3 (s, 1H), 7.35-7.32 (m, 2H), 7.23 (d, 1H, J = 1.6 HZ), 7.15- 500 7.10 (m, 2H), 4.93 (t, 1H, J = 4.8 HZ), 4.12-4.06 (m, 4H), 4.02-3.97 (m, 1H), 3.94-3.86 (m, 6H), 3.85 (s, 3H). 1H-NMR (400 MHZ, CDC13) 8 ppm 8.37 (br. s., 2H), 7.90 (br. s., 2H), 7.39 (br. s., 2H), 7.03 (br. s., 3H), 6.23 (s, 1H), 4.18-4.14 (m, 4H), 4.04-4.01 (m, 4H), 2.49 (s, 1H), 2.33 (s, 3H), 1.92 (s, 3H). lH-NMR (400 MHz, CDC13) 5 ppm 8.37 (s, 2H), 7.92, 7.91 (s, s, 2H), 8.42-7.38 (m, 2H), 7.05—7.00 (m, 3H), 6.23 (s, 1H), 4.18-4.14 (m, 4H), 4.04—4.01 (m, 4H), 2.36 (s, 1H), 2.34 (s, 3H), 1.93 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.48 (d, 1H, J = 4.8 Hz), 8.41 (d, 1H, J = 3.2 Hz), 8.38 (s, 2H), 8.03 (s, 1H), 7.99 (d, 1H, J :16 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.79-7.76 (m, 1H), 7.23 (d, 1H, J = 1.6 Hz), 6.25 (s, 1H), 4.11-4.08 (m, 4H), 3.94—3.91 (m, 4H), 3.85 (s, 3H), 1.88 (s, 3H). lH-NMR (400 MHz, 6) 5 ppm 8.48 (d, 1H, J = 4.8 Hz), 8.41 (d, 1H, J = 3.2 Hz), 8.38 (s, 2H), 8.03 (s, 1H), 7.99 (d, 1H, J :16 Hz), 7.87 (s, 1H), 7.82 (d, 1H, J = 0.8 Hz), 7.79-7.76 (m, 1H), 7.23 (d, 1H, J = 2.0 Hz), 6.25 (s, 11-4.08(m,4H),3.93-3.91 (m, 4H), 3.85 (s, 3H), 1.87 (s, 3H).

H-NMR (500 MHz, CDC13) 5 ppm 8.47 (s, 2H), 7.92 (s, 1H), 7.72, 7.70 (s, s, 2H), 7.57 (s, 1H),7.20-7.17(m, 1H), 7.11—7.02 (m, 3H), 6.83 (br. s., 1H), 4.97—4.95 (m, 1H), 4.62-4.47 (m, 3H), 3.97—3.95 (m, 4H), 3.76—3.72 (m, 2H), 1.33 (d, 3H, J: 6.5 Hz). 1H NMR (400 MHz, DMSO-d6) 5 8.10 (s, 1H), 8.03 (s, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 1.7 Hz, 1H), 7.20 — 7.10 (m, 4H), 4.15 — 4.04 (m, 4H), 3.98 — 3.88 (m, 4H), 3.86 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 12.84 (s, 1H), 8.38 (s, 2H), 8.05-8.01 (m, 3H), 7.88 (s, 1H), 7.83-7.77 (m, 1H), 7.26 (s, 1H), 7.14—7.09 (m, 2H), 6.05 (s, 1H), 4.12—4.09 (m, 4H), 3.93—3.91 (m, 4H), 1.84 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 12.80 (br s, 1H), 8.34 (s, 2H), 8.02 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.83-7.77 (m, 1H), 7.26 (d, 1H, J = 1.2 Hz), 7.14— 7.08 (m, 2H), 6.05 (br s, 1H), 4.12—4.09 (m, 4H), 3.94— 3.91 (m, 4H), 1.84 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.39 (s, 2H), 8.21 (s, 1H), 7.88 (s, 1H), 7.71 (d, 2H, J = 7.6 Hz), 7.47— 3 7.42 (m, 3H), 7.19 (d, 2H, J = 7.6 Hz), 7.13—7.09 (m, 510 2H), 5.89 (br. s., 1H), 4.11 (br. s., 4H), 3.90 (s, 4H), 2.30 (s, 3H), 1.81 (s, 3H). —106— 1H-NMR (400 MHZ, DMSO-d6) 5 ppm 8.94 (d, 1H, J = 2.4 Hz), 8.41 (s, 2H), 8.34 (d, 1H, J :16 Hz), 8.12-8.10 (m, 1H), 7.91 (s, 1H), 7.54 (d, 1H, J = 1.2 HZ),7.48-7.45 (m, 2H), 7.30—7.27 (m, 15-7.11 (m, 2H), 5.90 (s, 1H),4.13-4.11 (m, 4H), 3.93—3.90 (m, 4H), 2.47 (s, 3H), 1.82 (s, 3H). 1H-NMR (400 MHZ, CDC13) 5 ppm 8.26 (s, 2H), 7.90 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.18-7.05 (m, 4H), 6.77 (d, 1H, J :16 Hz), 5.25 (d, 2H, J = 6.0 Hz), 5.10 (d, 2H, J = 6.0 Hz), 4.17—4.14 (m, 4H), 4.05—4.01 (m, 4H), 3.95 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.40 (s, 2H), 8.26 (s, 1H), 7.90- 7.86 (m, 3H), 7.47-7.44 (m, 3H), 7.26- 7.21 (m, 2H), 7.12-7.08 (m, 2H), 4.13-4.09 (m, 4H), 3.92-3.89 (m, 4H), 2.56-2.54 (br, 2H), 1.72 (s, 3H). 1H-NMR (400 MHZ, 6) 8 ppm 8.40 (s, 2H), 8.08 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.45 (dd, 2H, J = 6.0, 8.8 HZ), 7.22 (s, 1H), 7.12-7.08 (m, 2H), 4.12 (q, 2H, J = 7.2 HZ), 4.10 - 4.07 (m, 4H), 3.91-3.88 (m, 4H), 2.54-2.50 (br, 2H), 1.72 (s, 3H), 1.40 (t, 3H, J = 7.2 HZ).

H-NMR (400 MHZ, CDC13) 6 ppm 8.38 (s, 2H), 7.92 (s, 1H), 7.83 (d, 1H, J: 1.6 HZ), 7.59-7.55 (m, 2H), 7.43- 7.39 (m, 2H), 7.13-7.09 (m, 2H), 7.05-7.01 (m, 2H), 6.91 (d, 1H, J: 1.6 HZ), 4.18-4.16 (m, 4H), 4.04-4.02 (m, 4H), 2.21 (s, 1H), 1.94 (s, 3H). 1H-NMR (400 MHZ, CDCl3-d5) 6 ppm 8.38 (s, 2H), 7.92 (s, 1H), 7.83 (d, 1H, J: 1.6 HZ), 7.59-7.55 (m, 2H), 7.43-7.39 (m, 2H), 7.13-7.09 (m, 2H), 7.05-7.01 (m, 2H), 6.91 (d, 1H, J: 1.6 HZ), 4.18-4.16 (m, 4H), .02 (m, 4H), 2.21 (s, 1H), 1.94 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.41 (s, 2H), 8.35 (d, 1H, J = 1.6 HZ), 7.92 (s, 1H), .69 (m, 2H), 7.54 (d, 1H, J = 1.2 HZ), 7.49-7.42 (m, 3H), 7.15- 7.06 (m, 3H), 5.89 (s, 1H), 4.14 (t, 4H, J = 6.0 HZ), 3.92 (t, 4H, J = 5.2 HZ), 1.82 (s, 3H). 1H-NMR (400 MHZ, CDC13) 6 ppm 8.29 (s, 2H), 7.90 (s, 1H), 7.69 (d, 2H, J: 1.6 HZ), 7.56 (s, 1H), 7.35-7.31 (m, 2H), 7.04-6.99 (m, 2H), 6.77 (d, 1H, J: 1.6 HZ), 4.16- 4.14 (m, 4H), 4.03-4.01 (m, 4H), 3.95 (s, 3H), 3.16 (s, 3H), 1.82 (s, 3H). 1H-NMR (400 MHZ, DMSO-dg) 6 ppm 8.31 (s, 2H), 8.03 (s, 1H), 7.97 (d, 1H, J: 1.6 HZ), 7.87 (s, 1H), 7.81 (s, 1H), 7.41-7.38 (m, 2H), 7.22 (d, 1H, J: 1.6 HZ), 7.18- 7.13 (m, 2H), 4.11-4.09 (m, 4H), 3.94-3.91 (m, 4H), 3.85 (s, 3H), 3.09 (s, 3H), 1.81 (s, 3H).

H-NMR (400 MHZ, CDC13) 6 ppm 8.36 (s, 2H), 7.89 (s, 1H), 7.69 (s, 2H), 7.56 (s, 1H), 7.40-7.37 (m, 2H), 7.05- 3 6.99 (m, 2H), 6.77 (d, 1H,J=1.2 HZ), 4.16-4.13 (m, 514 4H), 4.03-4.00 (m, 4H), 3.95 (s, 3H), 2.26 (q, 2H, J: 8.0 HZ), 2.07 (br. s., 1H), 0.91 (t, 3H, J: 8.0 HZ). 1H-NMR (400 MHZ, CDC13) 6 ppm 8.36 (s, s, 2H), 7.89 (s, 1H), 7.69 (s, 2H), 7.56 (s, 1H), 7.40-7.37 (m, 2H), 70 3 7.05-7.00 (m, 2H), 6.77 (d, 1H, J: 1.6 HZ), 4.16-4.13 514 (m, 4H), .00 (m, 4H), 3.95 (s, 3H), 2.26 (q, 2H, J: 8.0 HZ), 2.07 (br. s., 1H), 0.91 (t, 3H, J: 8.0 HZ). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.40 (s, 2H), 7.94 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H, J = 1.2 HZ), 7.46 (dd, 2H, J = 5.6, 8.8 HZ), 7.15-7.09 (m, 2H), .87 (br, 1H), 4.11-4.08 (m, 4H), 3.92-3.89 (m, 4H), 3.78 (s, 3H), 2.32 (s, 3H), 1.82 (s, 3H). 1H-NMR (400 MHZ, 6) 8 ppm 8.40 (s, 2H), 7.94 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H, J = 1.6 HZ), 7.48- 7.45 (m, 2H), 7.15-7.09 (m, 3H), 5.89 (s, 1H), 4.11-4.08 (m, 4H), 3.92-3.89 (m, 4H), 3.78 (s, 3H), 2.32 (s, 3H), 1.82 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.32 (s, 2H), 8.00 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.35-7.29 (m, 2H), 7.20 (s, 1H), 7.11 (t, 2H, J = 8.0 HZ), 4.92 (t, 1H, J = 4.0 HZ), 4.69-4.56 (m, 2H), 4.39-4.26 (m, 2H), 4.07 (q, 1H, J = 8.0 HZ), 3.84 (s, 3H), 3.83-3.78 (m, 1H), .58 (m, 2H), 3.55-3.40 (m, 2H), 1.55 (d, 3H, J = 8.0 HZ). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.32 (s, 2H), 8.00 (s, 1H), 7.96-7.95 (m, 1H), 7.85 (s, 1H), 7.78-7.77 (m, 1H), 7.34-7.29 (m, 2H), 7.21-7.20 (m, 1H), 7.14-7.08 (m, 2H), 4.92 (t, 1H, J = 4.0 HZ), 4.67-4.55 (m, 2H), 4.38-4.26 (m, 2H), 4.07 (q, 1H, J = 8.0 HZ), 3.84 (s, 3H), 3.83-3.78 (m, 1H), 3.77-3.58 (m, 2H), 3.55-3.42 (m, 2H), 1.55 (d, 3H, J = 8.0 HZ). 1H NMR (400 MHZ, 6) 8 ppm 8.40 (s, 2H), 8.09 (s, 1H), 7.98 (d, 1H, J = 1.6 HZ), 7.87 (s, 1H), 7.82 (s, 1H), 7.48-7.45 (m, 2H), 7.23 (d, 1H, J = 2.0 HZ), 7.15- 7.12 (m, 2H), 5.89 (s, 1 H), 4.15-4.08 (m, 6H), 3.92 (t, 4H, J = 6.4 HZ), 1.82 (s, 3H), 1.42 (t, 3H, J = 7.2 HZ). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.39 (s, 2H), 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.49-7.44 (m, 2H), 7.22-7.19 (m, 1H), 7.15-7.09 (m, 2H), 5.85 (s, 1H), 4.85-4.77 (m, 1H), 4.64-4.56 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.37 (m, 1H), 3.85 (s, 3H), 3.78- 3.71 (m, 1H), 3.64-3.49 (m, 2H), 1.81 (s, 3H), 1.15 (d, 3H, J = 8.0 HZ). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.39 (s, 2H), 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.49-7.44 (m, 2H), 7.22-7.19 (m, 1H), 7.15-7.09 (m, 2H), 5.85 (s, 1H), 4.85-4.77 (m, 1H), 4.64-4.56 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.37 (m, 1H), 3.85 (s, 3H), 3.78- 3.71 (m, 1H), 3.64-3.49 (m, 2H), 1.81 (s, 3H), 1.15 (d, 3H, J = 8.0 HZ). —108— lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.24 (s, 2H), 8.04 (s, 1H), 7.98 (d, 1H, J : 1.2 Hz), 7.87 (s, 1H), 7.82 3 (s, 1H), 7.30—7.23 (m, 3H), 7.11—7.09 (m, 2H), 5.08-5.05 514 (m, 1H), 4.11-4.08 (m, 4H), 3.92—3.87 (m, 4H), 3.85 (s, 3H), 3.78—3.74 (m, 2H), 1.58 (s, 3H). lH-NMR (400 MHz, 6) 5 ppm 8.24 (s, 2H), 8.04 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.30—7.23 (m, 3H), 7.13—7.09 (m, 2H), 5.08-5.05 (br. s., 1H), 4.10 (br. s., 4H), 3.90 (br. s., 4H), 3.85 (s, 3H), 3.78—3.74 (m, 2H), 1.58 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.22 (s, 2H), 8.04 (s, 1H), 7.99 (d, 1H, J : 1.2 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.65 (dd, 1H, J : 8.4, 6.0 Hz), 7.23 (d, 1H, J : 1.2 Hz), 7.03 (td, 1H, J : 8.4, 2.8 Hz), 6.96 (dd, 1H, J : .0, 2.8 Hz), 5.81 (s, 1H), 4.11-4.08 (m, 4H), 3.92—3.89 (m, 4H), 3.85 (s, 3H), 2.07 (s, 3H), 1.81 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.40 (s, 2H), 8.01 (s, 1H), 7.90 (s, 1H),7.52-7.40(m,2H),7.23-7.19 (m, 2H), 7.15-7.10(m, 2H), 6.78 (s, 1H), 5.89 (s, 1H), 4.10 (br. s., 4H), 3.91 (br. s., 4H), 2.45 (s, 3H), 1.82 (s, 3H). lH-NMR (400 MHz, DMSO-d6) 5 ppm 8.40 (s, 2H), 8.02 (s, 1H, J : 1.6 Hz), 7.90 (s, 1H), .45 (m, 2H), 7.23—7.19(m,2H),7.15—7.10(m,2H), 6.80-6.76 (m, 1H), .89 (s, 1H), .05 (m, 4H), 3.95—3.86 (m, 4H), 2.45 (s, 3H), 1.82 (s, 3H). 1H—NMR (400 MHz, DMSO-dé) 5 ppm 8.41 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H,J=1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.46 (d, 1H, J: 8.8 Hz), 7.36 (d, 1H, J: 8.4 Hz), 7.22 (d, 1H, J: 1.6 Hz), 5.93 (s, 1H), 4.10-4.08 (m, 4H), 3.92—3.90 (m, 4H), 3.85 (s, 3H), 1.82 (s, 3H).

H-NMR (400 MHz, DMSO-ds) 5 ppm 8.41 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J: 1.2 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.46 (d, 1H, J: 8.8 Hz), 7.36 (d, 1H, J: 8.4 Hz), 7.22 (d, 1H, J: 1.6 Hz), 5.93 (s, 1H), 4.10-4.08 (m, 4H), 3.92—3.90 (m, 4H), 3.85 (s, 3H), 1.82 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) 5 ppm 8.32 (s, 2H), 8.04 (s, 1H), 7.99 (d, 1H, J: 1.2 Hz), 7.87 (s, 1H), 7.82-7.77 (m, 2H), 7.23 (d, 1H, J: 1.2 Hz), 7.14-7.08 (m, 2H), 4.10—4.07 (m, 4H), 3.92—3.88 (m, 4H), 3.85 (s, 3H), 1.73 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) 5 ppm 8.32 (s, 2H), 8.04 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.82-7.77 (m, 2H), 7.23 (s, 1H), 7.14-7.08 (m, 2H), 4.10—4.07 (m, 4H), 3.92— 3.88 (m, 4H), 3.85 (s, 3H), 1.73 (s, 3H). lH-NMR (400 MHz, 6) 5 ppm 8.39 (s, 2H), 8.10 (d, 1H, J :1.2 Hz), 7.96 (s, 1H), 7.91 (s, 1H), 7.47— 7.44 (m, 2H), 7.29 (d, 1H, J : 1.2 Hz), 7.12 (t, 2H, J : 8.8 Hz), 5.89 (s, 1H), 4.10-4.08 (m, 4H), 3.91—3.89 (m, 4H), 2.65 (s, 3H), 1.81 (s, 3H). —109— WO 57873 1H-NMR (400 MHz, DMSO-d6) 8 ppm 8.38 (s, 1H), 8.37 (s, 1H), 8.10 (d, 1H, J : 1.2 Hz), 7.96 (d, 1H, J :1.6 3 Hz), 7.91 (d, 1H, J : 2.0 Hz), 7.46—7.43 (m, 2H), 7.28 (s, 517 1H), 7.12 (t, 2H, J : 8.8 Hz), 5.92 (br. s., 1H), 4.09 (br. s., 4H), 3.89 (br. s., 4H), 2.65 (s, 3H), 1.80 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.40 (s, 1H), 8.39 (s, 2H), 8.07 (s, 1H), 7.98 (s, 1H), 7.48-7.44 (m, 2H), 7.15-7.10 (m, 2H), 7.00 (s, 1H), 5.90 (s, 1H), 3.91 (s, 3H), 3.87 (s, 8H), 1.82 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.40 (s, 1H), 8.39 (s, 2H), 8.07 (s, 1H), 7.98 (s, 1H), 7.48-7.45 (m, 2H), 7.15-7.10 (m, 2H), 7.00 (s, 1H), 5.90 (s, 1H), 3.91 (s, 3H), 3.87 (s, 8H), 1.82 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.37 (s, 2H), 8.04 (s, 1H), 7.99 (d, 1H, J : 1.6 Hz), 7.87 (s, 1H), 7.82 (d, 1H, J : 1.2 Hz), 7.41—7.33 (m, 1H), 7.23 (d, 1H, J : 1.6 HZ), 7.05-6.98 (m, 2H), 6.10 (s, 1H), 4.12-4.09 (m, 4H), 3.93—3.91 (m, 4H), 3.85 (s, 3H), 1.90 (s, 3H). 1H-NMR (400 MHZ, DMSO-d6) 8 ppm 8.37 (s, 2H), 8.04 (s, 1H), 7.99 (d, 1H, J : 1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.41—7.34 (m, 1H), 7.23 (d, 1H, J :1.6 Hz), 7.05— 6.98 (m, 2H), 6.10 (s, 1H), 4.12—4.09 (m, 4H), 3.93—3.90 (m, 4H), 3.85 (s, 3H), 1.90 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J: 1.6 Hz), 7.87 (s, 1H), 7.83—7.77 (m, 2H), 7.23 (d, 1H, J: 1.2 Hz), 7.14-7.08 (m, 2H), 6.04 (s, 1H), 4.11-4.08 (m, 4H), .90 (m, 4H), 3.85 (s, 3H), 1.84 (s, 3H).

H-NMR (400 MHZ, DMSO-dg) 8 ppm 8.37 (s, 2H), 8.02 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.47 (dd, 2H, J: 8.4, 5.6 Hz), 7.22-7.16 (m, 3H), 6.40 (s, 1H), 4.86 (td, 2H, J: 45.2, 10.0 Hz), 4.09 (br. s., 4H), 3.92 (br. s., 4H), 3.84 (s, 3H). 1H—NMR (400 MHz, DMSO-dg) (3 ppm 8.38 (s, 2H), 8.02 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.48 Oar. s., 2H), 7.22-7.16 (m, 3H), 6.39 (s, 1H), 4.86 (td, 2H, J: 45.6, 10.0 Hz), 4.09 (br. s., 4H), 3.92 (br. s., 4H), 3.84 (s, 3H). 1H NMR (400 MHz, DMSO-ds) 5 8.57 (s, 2H), 8.02 (s, 1H), 7.98 (d, J: 1.5 Hz, 1H), 7.88 (s, 1H), 7.79 (d, J: 0.8 Hz, 1H), 7.33 — 7.20 (m, 3H), 7.20 — 7.11 (m, 1H), 7.10 — 7.01 (m, 1H), 5.02 (t, J: 5.2 HZ, 1H), 4.67 (d, J: 11.0 HZ, 2H), 4.40 (d, J: 10.2 HZ, 2H), 3.95 — 3.71 (m, 6H), 3.65 — 3.48 (m, 3H). 1H—NMR (400 MHz, DMSO—d6) 5 ppm 5 8.34 (s, 2H), 8.03 (s, 1H), 7.98 (d, 1H, J : 1.2 Hz), 7.87 (s, 1H), 7.83—7.77 (m, 2H), 7.23 (d, 1H, J : 1.2 Hz), 7.14—7.09 , 6.04 (s, 1H), 4.11—4.08 (m, 4H), 3.93—3.90 (m, 4H), 3.85 (s, 3H), 1.84 (s, 3H). —110— 98 1 519 1H-NMR (400 MHz, CDC13) (3 ppm 8.39 (s, 2H), 7.90 (s, 1H), 7.70 (s, 2H), 7.56 (s, 1H), .43 (m, 2H), 7.05- 103 3 7.00 (m, 2H), 6.78 (d, 1H, J: 1.2 Hz), .14 (m, 526 4H), 4.05-4.02 (m, 4H), 3.95 (s, 3H), 1.93 (br. s., 1H), 0.66-0.62 (m, 2H), 0.49-0.45 (m, 2H). 1H-NMR (400 MHz, CDC13) (3 ppm 8.39 (s, 2H), 7.91 (s, 1H), 7.70 (s, 2H), 7.57 (s, 1H), 7.46-7.43 (m, 2H), 7.05- 7.01 (m, 2H), 6.79 (s, 1H), 4.18-4.15 (m, 4H), 4.05-4.02 (m, 4H), 3.95 (s, 3H), 1.90 (br. s., 1H), 0.67-0.63 (m, 2H), 0.48-0.44 (m, 2H).

H-NMR (400 MHz, DMSO-dg) (3 ppm 8.56 (s, 2H), 8.04 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.27-7.24 (m, 3H), 7.17-7.14 (m, 1H), 7.06-7.02 (m, 1H), 4.97 (d, 1H, J : 4.4 Hz), 4.15-4.13 (m, 4H), 4.00 (br. s., 7H), 1.05 (d, 3H, J: 5.6 Hz). 1H-NMR (400 MHz, DMSO-dg) (3 ppm 8.40 (s, 2H), 8.02 (s, 1H), 7.97 (d, 1H, J: 1.6 Hz), 7.86 (s, 1H), 7.81 (s, 1H), 7.54-7.50 (m, 2H), 7.22-7.17 (m, 3H), 6.75 (t, 1H, J : 55.2 Hz), 4.10-4.05 (m, 4H), 3.93-3.90 (m, 4H), 3.84 (s, 3H), 2.70 (s, 2H).

H-NMR (400 MHz, DMSO-dg) (3 ppm 8.39 (s, 2H), 8.02 (s, 1H), 7.99 (d, 1H, J: 1.2 Hz), 7.86 (s, 1H), 7.81 (s, 1H), 7.52 (dd, 2H, J: 5.6, 8.8 Hz), 7.22-7.17 (m, 3H), 6.74 (t, 1H, J: 55.2 Hz), 4.10-4.07 (m, 4H), 3.90-3.90 (m, 4H), 3.84 (s, 3H), 2.69 (s, 2H). 1H-NMR (400 MHz, DMSO-dg) (3 ppm 8.35 (s, 2H), 8.02 (s, 1H), 7.97 (d, 1H, J: 1.6 Hz), 7.86 (s, 1H), 7.81 (s, 1H), 7.50 (dd, 2H, J: 5.2, 8.8 Hz), 7.25-7.20 (m, 3H), 6.78 (s, 1H), 6.70 (t, 1H, J: 54.4 Hz), 4.10-4.08 (m, 4H), 3.94-3.93 (m, 4H), 3.84 (s, 3H). 1H-NMR (400 MHz, g) (3 ppm 8.35 (s, 2H), 8.02 (s, 1H), 7.99 (d, 1H, J: 1.2 Hz), 7.86 (s, 1H), 7.81 (s, 1H), 7.49 (dd, 2H, J : 5.6, 8.8 Hz), 7.25-7.20 (m, 3H), 6.78 (s, 1H), 6.70 (t, 1H, J: 54.8 Hz), 4.21-4.05 (m, 4H), 4.00-3.91 (m, 4H), 3.84 (s, 3H).

H-NMR (400 MHz, DMSO-dg) a 8.34 (s, 2H), 8.04 (s, 1H), 8.00 (d, 1H, J: 1.2 Hz), 7.87-7.86 (m, 2H), 7.34- 7.15 (m, 6H), 4.22-4.04 (m, 6H), 3.91-3.80 (m, 8H), 3.512-3.46 (m, 1H), 2.99-2.52 (m, 3H), 2.55-2.33 (m, 1H). 1H-NMR (400 MHz, DMSO-dé) (3 ppm 8.57 (s, 2H), 8.04 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.29-7.14 (m, 4H), 7.07-7.03 (m, 1H), 4.17-4.14 (m, 4H), 4.11-4.10 (m, 2H), .00 (m, 4H), 3.73-3.71 (m, 2H), 3.42-3.37 (m, 1H), .59 (m, 3H), 2.40-2.33 (m, 2H). —111— 2014/060746 1H NMR (400 MHZ, 6) 5 8.38 (s, 2H), 7.85 (d, J = 2.1 Hz, 2H), 7.52 — 7.37 (m, 2H), 7.19 — 7.03 (m, 3H), 124 2 6.22 (s, 1H), 5.87 (s, 1H), 4.12 — 4.02 (m, 4H), 3.98 (br.s, 2H), 3.94 — 3.81 (m, 4H), 3.52 (t, J = 5.8 Hz, 2H), 2.44 (br.s, 2H), 1.80 (s, 3H).

Biochemical Activity of nds In order to assess the activity of chemical compounds t the relevant kinase of st, the Caliper LifeSciences ophoretic mobility shift technology platform is used.

Fluorescently labeled substrate peptide is incubated in the presence of kinase and ATP so that a reﬂective proportion of the peptide is phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non—phosphorylated (substrate) peptides are passed through the microﬂuidic system of the Caliper EZ Reader 2, under an applied potential ence. The presence of the phosphate group on the product peptide provides a difference in mass and charge between those of the ate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass a LEDS within the instrument, these pools are detected and resolved as te peaks. The ratio between these peaks therefore reﬂects the activity of the chemical matter at that concentration in that well, under those conditions.

KIT D816V assay at Km: In each well of a 384—well plate, 0.04 ng/ul (0.5 nM) of D816V KIT (Carna Bioscience 08—156) was incubated in a total of 12.5 111 of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM e (5-FAM- GEEPLYWSFPAKKK—NH2) and 15 uM ATP at 25 C for 90 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The reaction was stopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plate was then read on a Caliper EZReader 2 (protocol settings: —1.9 psi, upstream voltage —700, downstream voltage — 3000, post sample sip 35s). Data was normalized to 0% and 100% inhibition controls and the IC50 or EC50 calculated using a 4—parameter fit using GraphPad Prism.

PDGFRA D842V assay at Km: In each well of a 384—well plate, 0.7 ng/ul (8 nM) of PDGFRA D842V (ProQinase 0761—0000—1) was incubated in a total of 12.5 111 of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM CSKtide (5-FAM- KKKKEEIYFFF—NH2) and 15 uM ATP at 25 C for 90 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The reaction was —112— WO 57873 stopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plate was then read on a Caliper EZReader 2 (protocol settings: —1.9 psi, upstream voltage —500, downstream voltage — 3000, post sample sip 38s). Data was normalized to 0% and 100% inhibition controls and the IC50 or EC50 calculated using a 4—parameter fit using GraphPad Prism.

Cellular Activity HMC1.2 autophosphorylation assay: 10,000 HMC1.2 cells were incubated in 22 ul culture media (phenol—red free IMDM, no serum) in each well of a 384—well plate and serum starved overnight in a tissue culture incubator (5% C02, 37°C). A 10—point dose concentration series of compound (25 uM—95.4 pM) were then added to the cells in a volume of 3.1 ul to each well (0.25% DMSO final concentration). After 90 minutes, 6 ul of 5X AlphaLISA Lysis Buffer (Perkin Elmer) supplemented with a protease and phosphatase inhibitor cocktail (Cell Signaling logies) was added to each well and shaken at 450 rpm for 15 minutes at 4°C. 10 ul of phospho—Y719 c—KIT and total c—KIT antibodies (15nM final concentration, Cell Signaling Technologies) and 50ug/ml AlphaLISA rabbit acceptor beads (Perkin Elmer) were added to each well and shaken at 300 rpm at room temperature for 2 hours. 10 ul of 100 ug/ml streptavidin donor beads n Elmer) were added to each well, blocked from light with um adhesive and shaken at 300 rpm at room temperature for 2 hours. Fluorescence signal was obtained on Envision (Perkin Elmer) by AlphaScreen 384 well HTS protocol. Data was normalized to 0% and 100% inhibition ls and the IC50 was calculated using Four ter Logistic IC50 curve fitting.

The Table below shows the ty of compounds in a Mast cell leukemia cell line, HMC 1.2. This cell line contains KIT mutated at positions V560G and D816V resulting in constitutive activation of the kinase. The following compounds were tested in an assay to measure direct inhibition of KIT D816V kinase activity by ng KIT autophosphorylation at tyrosine 719 on the KIT protein.

In the Table below, for biochemical D816V and D842V activity, the following designations are used: < 1.00 nM = A; 101—100 nM = B; 1001—1000 nM = C; >100 nM = D; and ND = not determined. For cellular ty in the HMC1.2 cell line, the following ations are used: A means < 50 nM; B means 250 and <100 nM; C means 2100 and <1000 nM; D means 21000 and less than 10000 nM; E means 210000 nM; and ND = not determined. —113— nd INH-KITINH KIT INH PDFGRA Number PHOSD816V D842V HMC1.2 1 D 2 D E 3 C D 4 D E C D 6 D E 7 A A B 8 B C 9 B B A A A A 11 B C 12A A A 13 B C 14 A B A C C 16 B C 17 B C 18 C C E 19 B C B B A 21 B A B 22 A A A 23 C C 24 B C A A 26 A A A 27 B A 28 B A 29 B B B A A A 31 B A 32 B A 33 B C 34 A A B A A A 36 B C 37 C D 38 B B B 39 B A A 40 B C 41 B B B 42 C D 43 B A 44 A A A "wuw"mamamﬁwyawmmmwMﬁwmwwmnnnunmwmmmmm&m%%mwwmmm%m AAABABC AA AAAAAA CBCAAACB CDCCAA BACB B CBB B BAAA CACBACCCCACABAABABAAA ABCCCABAABADDABBA B AA DCAAAACADDBAAA —115— 2014/060746 95 A B 96 A A A 97 A 98 A A C 99 C D 100 A A A 101 B 102 B 103 B C 104 B C 105 B A 106 -_ A 107 D D 108 D D 109 C C 110 B A 111 A 112 B C 113 A A 114 A A 115 A 116 A 117 A B A 118 B C 119 C C 120 B 121 A 122 B B A 123 B B B 124 B A Efficacy in an in vivo model Compound 46 and Dasatinib were evaluated in a P815 mastocytoma xenograft model.

P815 tumor cells (ATCC, Manassas, VA, cat # ATCC® TIE—64) were ined in vitro as a suspension and monolayer culture in RPM11640 medium supplemented with 10% fetal calf serum at 37°C in an atmosphere of 5% C02 in air. The tumor cells were sub—cultured twice weekly by trypsin—EDTA treatment. The cells growing in an ntial growth phase were harvested and counted for tumor inoculation.

Female BALB/c nude mice were used for the study. Each mouse was inoculated subcutaneously in the right ﬂank with the P815 tumor cells (1 X 106) in 0.1 m1 of PBS for tumor development. The treatments were started on day 6 after tumor inoculation when the average —116— tumor size reached approximately 89 mm3. The testing article and vehicle were administrated to the mice according to the regimen shown below.

IIDose Dosing Volume Dosing * ——em 10 o me - QM QDXlO QDXlO Note: * QD 2 once per day, BID 2 twice per day.

Tumor sizes were measured every other day in two dimensions using a caliper, and the volume was expressed in mm3 using the formula: V = 0.5 a X b2 where a and b were the long and short diameters of the tumor, respectively. The tumor size was then used for calculations of both T—C and T/C values. T—C was calculated with T as the median time (in days) required for the treatment group tumors to reach a predetermined size (e.g., 1000 mm3), and C as the median time (in days) for the control group tumors to reach the same size. The T/C value (in t) is an indication of antitumor effectiveness; T and C are the mean volumes of the treated and control groups, tively, on a given day.

TGI was calculated for each group using the formula: TGI (%) = —T0)/ )] x100; Ti is the average tumor volume of a treatment group on a given day, T0 is the average tumor volume of the treatment group on the day of treatment start, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the day of treatment start. Tumor weight was measured at the endpoint.

A statistical analysis of difference in tumor volume and tumor weight among the groups was conducted on the data obtained at the best therapeutic time point after the final dose (the 8th day after the start of ent). A one—way ANOVA was med to compare tumor volume -ll7- 2014/060746 and tumor weight among groups. All data were analyzed using Prism 5.0. p < 0.05 was considered to be statistically significant.

Results. The tumor growth curves of different treatment groups are shown in Figure 1.

Data points represent group mean tumor volume, error bars represent standard error of the mean (SEM). As shown in Figure 1, Compound 46 was effective in inhibiting tumor growth.

Increasing the dose of Compound 46 enhanced the tumor inhibition efficiency.

The results of the body weight changes in the tumor bearing mice are shown in Figure 2.

Data points represent group mean body weight change. Error bars represent standard error of the mean (SEM). As shown in Figure 2, body weight change was limited to less than 5%, even at the higher doses of Compound 46. In contrast, animals treated with vehicle or Dasatinib lost more than 5% body weight.

Thus, Compound 46, as a single agent, produced an able antitumor activity against the P815 mouse mastocytoma cancer xenograft model in this study. In on, the compound was well ted by the tumor—bearing s, as demonstrated by lack of weight loss.

Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and dually indicated to be incorporated by reference.

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than e experimentation, many equivalents to the specific ments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. —llS—

Claims

What we claim is:

1. A compound of Formula II: or a pharmaceutically acceptable salt thereof, n: Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl; Z is selected from C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; wherein each of C1-C6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0-5 occurrences of RC; L is selected from a bond, -(C(R2)(R2))m-, -(C2-C6 alkynylene)-, -(C2-C6 lene)-, -(C1-C6 haloalkylene)-, -(C1-C6 heteroalkylene)-, -(C1-C6 yalkylene)-, -C(O)-, -O-, -S-, -S(O), -S(O)2-, -, -O-(C1-C6 alkylene)-, -(C1-C6 ne)-O-, -C(O)-, -C(O)- N(R2)-, -(C1-C6 alkylene)-N(R2)-, -N(R2)-(C1-C6 alkylene)-, -N(R2)-C(O)-(C1-C6 alkylene)-, -C(O)-N(R2)-(C1-C6 alkylene)-, -S(O)2-, - S(O)2-N(R2)-, -N(R2)-S(O)2-(C1-C6 alkylene)-, and –S(O)2-N(R2)-(C1-C6 alkylene)-; each RA and RB is independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 heterocyclyl, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, monocyclic or ic aralkyl, -N(R2)(R2), cyano, and -OR2; each RC is independently selected from C1-C6 alkyl, C1-C6 l, halo, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, clic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, clic or bicyclic heterocyclylalkyl, nitro, cyano, -C(O)R2, - OC(O)R2, -C(O)OR2, -SR2, -S(O)2R2, -S(O)2-N(R2)(R2), -(C1-C6 alkylene)-S(O)2-N(R2)(R2), -N(R2)(R2), -C(O)-N(R2)(R2), -N(R2)(R2)-C(O)R2, -(C1-C6 alkylene)-N(R2)-C(O)R2, -NR2S(O)2R2, -P(O)(R2)(R2), and –OR2; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, y, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or 2 RC together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of Ra; each R2 is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 thioalkyl, , C1-C6 alkyl, C1-C6 , C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, cycloalkyl and heterocyclyl is ndently substituted with 0-5 occurrences of Rb, or 2 R2 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl ring; each Ra and Rb is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C6 alkoxyl, -C(O)R’, ’, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 yalkyl, -NR’R’, and lkyl, wherein cycloalkyl is substituted with 0-5 occurrences of R’; each R’ is hydrogen, hydroxyl, or C1-C6 alkyl; each R” is hydrogen, C1-C6 alkyl, -C(O)-C1-C6 alkyl, -C(O)-NR’R’; or -C(S)-NR’R’; m, p, and q are each independently 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, n the compound is a compound of Formula III: III.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L is -(C(R2)(R2))m-.

4. The nd of claim 1 or claim 3, or a pharmaceutically acceptable salt thereof, n Ring A is monocyclic or bicyclic aryl.

5. The compound of any one of claims 1 to 4, or a ceutically acceptable salt thereof, wherein Z is monocyclic or bicyclic aryl.

6. The compound of claim 5, wherein Z is phenyl.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is monocyclic or bicyclic aryl.

8. The compound of any one of claims 1 to 4 and 7, or a pharmaceutically acceptable salt thereof, wherein Z is monocyclic heteroaryl.

9. The compound of any one of claims 1 to 4, 7 and 8, wherein Z is selected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl.

10. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is monocyclic or bicyclic heterocyclyl.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein RA is fluoro and q is 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, n the compound is

13. A pharmaceutical composition comprising a pharmaceutically acceptable r and a compound of any of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating mastocytosis in a patient .

15. The use according to claim 14, wherein the mastocytosis is selected from cutaneous ytosis (CM) and systemic mastocytosis (SM).

16. The use ing to claim 15, wherein the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), SM with associated hematologic non-mast cell lineage disease NMD), and mast cell leukemia (MCL).

17. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating gastrointestinal stromal tumor in a patient .

18. The use ing to claim 17, wherein the patient has a D842V mutation in PDGFRα.

19. The use according to claim 17 or claim 18, wherein the patient is refractory to treatment with imatinib, sunitinib, and/or regorafenib.

20. Use of a nd ing to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the cture of a ment for treating acute myeloid leukemia in a patient .

21. The use according to any one of claims 14 to 20, wherein the patient has a mutation in Exon 17 in KIT.

22. The use according to claim 21, wherein the patient has a D816 mutation in KIT.

23. The use according to claim 22, wherein the D816 on is D816V. Blueprint Medicines Corporation By the patent attorneys for the applicant SPRUSON & FERGUSON