PYRAZOLE DERIVATIVES AS RET KINASE INHIBITORS

Description

Background

[0001] The Rearranged during transfection (RET) kinase is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation, and maintenance of several tissues and cell types. The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.

[0002] RET signaling is mediated by the binding of a group of 35 soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN), and persephin2 (PSPN). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional co-receptor, which can be one of four GDNF family receptor-α (GFRα) family members that are tethered to the cell surface by a glycosylphosphatidylinositol linkage. GFLs and GFRα family members form binary complexes that in turn bind to RET and recruit it into cholesterol-rich membrane subdomains where RET signaling occurs.

[0003] Upon binding of the ligand-co-receptor complex, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt / mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions.

[0004] Disruptions in normal RET activity due to abnormal RET expression stemming from genetic alterations in the RET kinase, including protein-gene fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth, e.g., various cancer types and certain gastrointestinal disorders such as irritable bowel syndrome (IBS). The ability to inhibit abnormal RET activity in patients with cancer or other disorders related to overactive RET signaling would be of great benefit. Additionally, some RET kinase genetic alterations are altering the conformational structure of a RET kinase to such an extent that a given RET kinase inhibitor may be less effective (or ineffective). In such cases, new RET kinase inhibitors that are effective to the modified RET kinase would greatly benefit patients. WO2014 / 141187 discloses substituted pyridones as RET kinase inhibitors. Any references to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).Summary

[0005] Disclosed herein are compounds of formula I: wherein A is C 6 -C 10 aryl or C 5 -C 6 heteroaryl; each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(C 1 -C 4 alkyl)(C 5 -C 6 heteroalkyl), -(C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 heteroalkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 alkyl)(C 3 -C 7 cycloheteroalkyl), -(C 0 -C 4 heteroalkyl)(C 3 -C 7 cycloheteroalkyl), -(C 0 -C 4 alkyl)(C 4 -C 10 bicyclyl), -(C 0 -C 4 alkyl)(C 5 -C 6 aryl), -(C 0 -C 4 alkyl)(C 5 -C 6 heteroaryl), -(C 0 -C 4 alkyl)(C 4 -C 10 heterobicyclyl), C 5 -C 12 spiranyl, C 5 -C 12 heterospiranyl, dimethylphosphoryl, adamantyl, C 1 -C 6 alkoxy, -(C 1 -C 4 alkyl)-SO 2 -(C 1 -C 4 alkyl), difluoromethylsulfanyl, or pentafluorosulfanyl, wherein each R 1 is unsubstituted or when it is capable of being substituted, it is substituted with one or more substituents that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, mono-, di, or trihalomethoxy, mono-, di-, or tri-halomethyl, and C 0 -C 3 alkyl-pyrrolidinyl, where the pyrrolidinyl group is unsubstituted or substituted with one, two or 3 independently selected halogen atoms, and wherein two R 1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4, 5, or 6; X 1 , X 2 , X 3 , and X 4 are each independently N, CH, C-CH 3 , C-CH 2 -OH, C-OCH 3 , C-CH 2 -OCH 3 , or C-halogen; and R 2 is C 1 -C 6 alkyl, -(C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 alkyl)(C 4 -C 7 heterocycloalkyl), -(C 0 -C 4 alkyl)(C 4 -C 10 bicyclic) each optionally substituted with one or more of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl; or a pharmaceutically acceptable salt thereof.

[0006] Further disclosed herein are methods of using the compounds of formula I or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cancer, in particular for the treatment of cancer with abnormal RET expression (e.g., a RET-associated cancer like medullary thyroid cancer or RET fusion lung cancer) are also provided. The methods include administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, to a patient in need.

[0007] Also provided herein are compounds of formula I or pharmaceutically acceptable salts thereof, for use in therapy. Further provided herein, are the compounds of formula I or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for use in the treatment of cancer with abnormal RET expression (e.g., a RET-associated cancer like medullary thyroid cancer or RET fusion lung cancer). The use of compounds of formula I or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for use in the treatment of cancer with abnormal RET expression (e.g., a RET-associated cancer like medullary thyroid cancer or RET fusion lung cancer), is also provided.Description

[0008] Novel RET kinase inhibitor compounds are described herein. These new compounds could address the need for potent, effective treatment of disorders associated with abnormal RET activity, e.g., IBS or cancer, especially cancer stemming from overactive RET signaling (i.e., RET-associated cancers). More specifically, these new compounds could address the need for potent, effective treatment of RET-associated cancers such as lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, or cervical cancer.

[0009] Provided herein are compounds of formula I: wherein A is C 6 -C 10 aryl or C 5 -C 6 heteroaryl; each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(C 1 -C 4 alkyl)(C 5 -C 6 heteroalkyl), -(C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 heteroalkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 alkyl)(C 3 -C 7 cycloheteroalkyl), -(C 0 -C 4 heteroalkyl)(C 3 -C 7 cycloheteroalkyl), -(C 0 -C 4 alkyl)(C 4 -C 10 bicyclyl), -(C 0 -C 4 alkyl)(C 5 -C 6 aryl), -(C 0 -C 4 alkyl)(C 5 -C 6 heteroaryl), -(C 0 -C 4 alkyl)(C 4 -C 10 heterobicyclyl), C 5 -C 12 spiranyl, C 5 -C 12 heterospiranyl, dimethylphosphoryl, adamantyl, C 1 -C 6 alkoxy, -(C 1 -C 4 alkyl)-SO 2 -(C 1 -C 4 alkyl), difluoromethylsulfanyl, or pentafluorosulfanyl, wherein each R 1 is unsubstituted or when it is capable of being substituted, it is substituted with one or more substituents that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, mono-, di, or trihalomethoxy, mono-, di-, or tri-halomethyl, and C 0 -C 3 alkyl-pyrrolidinyl, where the pyrrolidinyl group is unsubstituted or substituted with one, two or 3 independently selected halogen atoms, and wherein two R 1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4, 5, or 6; X 1 , X 2 , X 3 , and X 4 are each independently N, CH, C-CH 3 , C-CH 2 -OH, C-OCH 3 , C-CH 2 -OCH 3 , or C-halogen; and R 2 is C 1 -C 6 alkyl, -(C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 alkyl)(C 4 -C 7 heterocycloalkyl), -(C 0 -C 4 alkyl)(C 4 -C 10 bicyclic) each optionally substituted with one or more of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl; or a pharmaceutically acceptable salt thereof.

[0010] In some aspects, in the compounds and pharmaceutically acceptable salts of formula I, at least one of X 1 , X 2 , X 3 , and X 4 is CH. Sometimes, X 1 , X 2 , X 3 , and X 4 are each CH. Alternatively, at least one of X 1 , X 2 , X 3 , and X 4 is N. In an embodiment, X 1 is N and each of X 2 , X 3 , and X 4 is CH. In another embodiment, X 2 is N and each of X 1 , X 3 , and X 4 is CH. In some compounds, at least one of X 1 and X 2 is C-Cl or C-F. In other compounds, X 1 and X 2 are independently selected from the group consisting of C-Cl and C-F. In still other compounds, X 1 and X 2 are independently selected from the group consisting of C-Cl and C-F, and X 3 and X 4 are both CH. Alternatively, X 1 and X 3 independently selected from the group consisting of C-Cl and C-F. In some compounds, X 2 is C-OCH 3 or C-CH 2 -OH.

[0011] In some compounds and pharmaceutically acceptable salts of formula I, X 2 and X 3 are both N. In other compounds, X 2 and X 3 are both N and X 1 and X 4 are independently selected from CH, C-Cl, C-F, C-OCH 3 and C-CH 2 -OH. In still other compounds, X 2 and X 3 are both N and X 1 and X 4 are both CH. In still other compounds, X 2 and X 3 are both N and X 1 and X 4 are independently CH, C-Cl or C-F. In some compounds, X 1 and X 4 are both N. In other compounds, X 1 and X 4 are both N and X 2 and X 3 are independently selected from CH, C-Cl, C-F, C-OCH 3 and C-CH 2 -OH. In still other compounds, X 1 and X 4 are both N and X 2 and X 3 are both CH. In still other compounds, X 1 and X 4 are both N and X 2 and X 3 are independently CH, C-Cl or C-F.

[0012] In some compounds and pharmaceutically acceptable salts of formula I, X 1 and X 3 are both N and X 2 and X 4 are independently selected from CH, C-Cl, C-F, C-OCH 3 and C-CH 2 -OH. In other compounds, X 1 and X 3 are both N and X 2 and X 4 are both CH. In other compounds, X 1 and X 3 are both N and X 2 and X 4 are independently CH, C-Cl or C-F.

[0013] In the compounds and pharmaceutically acceptable salts of formula I, or pharmaceutically acceptable salts thereof, A-(R 1 ) n is or wherein a wavy line indicates connection to the backbone and the maximum value of n depends on the number of substitutable positions on the A-ring.

[0014] In one aspect, in the compounds and salts of formula I, A-(R 1 ) n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

[0015] In an aspect, in the compounds and pharmaceutically acceptable salts of formula I A-(R 1 ) n is: and the maximum value of n depends on the number of substitutable positions on the A-ring.

[0016] In another aspect, in the compounds and pharmaceutically acceptable salts of formula I A-(R 1 ) n is

[0017] In one embodiment, n is no more than 5. In a further embodiment, n is 1-3 or 1-2. In a further embodiment, when n is three, each R 1 group is independently a halogen, methyl, or a methoxy. In another embodiment, when n is 2, at least one R 1 is a halogen, while the other R 1 is methyl, or a methoxy. In another embodiment, n is 2 and one R 1 is CF 3 . In still another embodiment, n is 2, one R 1 is CF 3 and the other R 1 group is -CH2-piperazinyl, where the piperazinyl is optionally substituted with a C 1 -C 4 alkyl group, such as methyl or ethyl.

[0018] In some aspects, in the compounds and pharmaceutically acceptable salts of formula I A-(R 1 ) n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

[0019] In some aspects, in the compounds and pharmaceutically acceptable salts of formula I A-(R 1 ) n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

[0020] The compounds and pharmaceutically acceptable salts of formula I encompass the compounds and pharmaceutically acceptable salts of formulas Ia, Ib, Ic, and Id: In the compounds and pharmaceutically acceptable salts of formulas Ia, Ib, Ic, and Id, X 1 , X 2 , X 3 , and X 4 of formula I are CH.

[0021] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formula Ie, If, Ig, Ih, Ii, Ij, Ik, Il and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas Ie to Il, correspond to formula I, wherein one of X 1 , X 2 , X 3 , and X 4 is N, while the others are CH.

[0022] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formula Im, In, Io, Ip, Iq, Ir, Is, It, and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas Im, In, Io, Ip, Iq, Ir, Is, and It correspond to compounds of formula I wherein X 2 and X 3 are both N, while X 1 and X 4 are both CH or X 2 and X 3 are both CH, while X 1 and X 4 are both N.

[0023] The compounds of formula I, also encompass the compounds of formula Iu, Iv, Iw, and Ix: The compounds and pharmaceutically acceptable salts of formulas Iu, Iv, Iw, and Ix, correspond to compounds of formula I wherein X 1 and X 3 are both N, while X 2 and X 4 are both CH.

[0024] In the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is -C 1 -C 6 alkyl, -C 1 -C 4 alkyl-tetrahydrofuranyl, -C 1 -C 6 hydroxyalkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 alkyl-O-C 1 -C 2 alkyl, -C 3 -C 6 cycloalkyl, tetrahydrofuranyl, pyranyl, -C 1 -C 4 alkyl - tetrahydropyranyl, -C 1 -C 4 alkyl -C 3 -C 6 cycloalkyl, and azetidinyl, wherein each is unsubstituted or substituted with one or two groups that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl. In an embodiment, the - C 1 -C 6 alkyl is an ethyl group.

[0025] In an aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is tert-butyl, -CH(CH 3 )-cyclopropyl, -2-tetrahydrofuranyl, -3-tetrahydrofuranyl, -3-pyranyl, -4-pyranyl, -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 -(2-tetrahydrofuranyl), -CH 2 -(3-tetrahydrofuranyl), -(CH 2 ) 3 OH, - C(CH 3 ) 2 CH 2 OCH 3 , -CH(CH 3 )CF 3 , -CH 2 CF 3 , -C(CH 3 ) 2 CH 2 OCH 3 , cyclopentyl,

[0026] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0027] In one aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0028] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0029] In yet another aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0030] In still another aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0031] In still another aspect, in the compounds and pharmaceutically acceptable salts of formulas I and Ia to Ix, R 2 is

[0032] In an aspect, the compounds and pharmaceutically acceptable salts of formula I encompass the compounds and pharmaceutically acceptable salts of formulas IIa to IIx, and IIIa to IIIx: The compounds and pharmaceutically acceptable salts of formulas IIa, IIb, IIc, and IId correspond to compounds of formula I whereinX 1 , X 2 , X 3 , and X 4 are CH and R 2 is isopropyl.

[0033] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formula IIe, IIf, IIg, IIh, IIi, IIj, IIk, IIl and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas IIe to IIl, correspond to compounds of formula I, wherein one of X 1 , X 2 , X 3 , and X 4 is N, while the others are CH and R 2 is isopropyl.

[0034] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formulas IIm, IIn, IIo, IIp, IIq, IIr, IIs, IIt, and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas IIm, IIn, IIo, IIp, IIq, IIr, IIs, and IIt correspond to compounds of formula I wherein X 2 and X 3 are both N, while X 1 and X 4 are both CH or X 2 and X 3 are both CH, while X 1 and X 4 are both N and R 2 is isopropyl.

[0035] The compounds of formula I, also encompass the compounds of formula IIu, IIv, IIw, and IIx:

[0036] The compounds and pharmaceutically acceptable salts of formulas IIu, IIv, IIw, and IIx, correspond to compounds of formula I wherein X 1 and X 3 are both N, while X 2 and X 4 are both CH, and R 2 is isopropyl.The compounds and pharmaceutically acceptable salts of formula I encompass the compounds of formula IIIa, IIIb, IIIc, and IIId, and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas IIIa, IIIb, IIIc, and IIId, correspond to compounds of formula I wherein X 1 , X 2 , X 3 , and X 4 are CH, and R 2 is

[0037] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formula IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas IIIe to IIIl correspond to compounds of formula I wherein one of X 1 , X 2 , X 3 , and X 4 is N, while the others are CH, and R 2 is

[0038] The compounds and pharmaceutically acceptable salts of formula I, also encompass the compounds of formula IIIm, IIIn, IIIo, IIIp, IIIq, IIIr, IIIs, IIIt, and pharmaceutically acceptable salts thereof: The compounds and pharmaceutically acceptable salts of formulas IIIm, IIIn, IIIo, IIIp, IIIq, IIIr, IIIs, and IIIt correspond to compounds of formula I wherein X 2 and X 3 are both N, while X 1 and X 4 are both CH or X 2 and X 3 are both CH, while X 1 and X 4 are both N and R 2 is

[0039] The compounds of formula I, also encompass the compounds of formula IIIu, IIIv, IIIw, and IIIx: The compounds and pharmaceutically acceptable salts of formulas IIIu, IIIv, IIIw, and IIIx, correspond to compounds of formula I wherein X 1 and X 3 are both N, while X 2 and X 4 are both CH or X 2 and X 4 are both N, while X 1 and X 3 are both CH, and R 2 is

[0040] In an aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently hydrogen, C 1 -C 6 alkyl, C 4 -C 8 bridged bicycloalkyl, C 5 -C 12 spirane, wherein each R 1 is optionally substituted with one or more of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, or mono-, di-, or tri-halomethyl.

[0041] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently 2-chloro-4-methylphenyl, 2,4-dichloro-3-fluoro-phenyl, 2-methy-4-chloro-phenyl, 2-chloro-4-methoxy-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 2-methoxy-4-chloro-phenyl, 2,2-dimethylpropyl; 2-chloro-4-fluoro-phenyl; 2,4-dichlorophenyl; 1,1-dimethyl-2,2,2-trifluoroethyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; trifluoromethyl; 1,1-dimethyl-2,2-difluoropropyl; 1,1-dimethyl-3,3,3-trifluoropropyl; 1-methylcyclopropyl; (1-methylcyclopropyl)methyl; 3-methylbicyclo[1.1.1]pentan-1-yl; 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl; or (3,3-dimethylcyclobutyl)methyl.

[0042] In a further aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently a C 4 -C 8 bridged bicycloalkyl that is unsubstituted or substituted with 1 or 2 groups independently selected from the group consisting of C 1 -C 4 alkyl, CF 3 , halo, and CN.

[0043] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently a C 4 -C 8 bridged bicycloalkyl that is unsubstituted or substituted with 1 or 2 groups independently selected from the group consisting of methyl, ethyl, CF 3 , halo, and CN.

[0044] In some aspects, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently a bridged C 4 -C 8 bicycloalkyl that is

[0045] In other aspects, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently a C 5 -C 12 spirane that is unsubstituted or substituted with 1 or 2 groups that are independently selected from the group consisting of =O, -OH, C 1 -C 4 alkyl, -CF 3 , and halo each R 1 is independently a C 5 -C 12 heterospirane that is unsubstituted or substituted with 1 or 2 groups that are independently selected from the group consisting of =O, -OH, C 1 -C 4 alkyl, -CF 3 , and halo. Examples of C 5 -C 12 spiranes or C 5 -C 12 heterospiranes include

[0046] In an aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, n is 1 and R 1 is a C 5 -C 12 spirane that is unsubstituted or substituted with 1 or 2 groups that are independently selected from the group consisting of =O, -OH, methyl, ethyl, CF 3 , and halo.

[0047] In yet another aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently halogen, C 1 -C 6 alkyl, - (C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), -(C 0 -C 4 alkyl)(phenyl), -(C 1 -C 4 alkyl)(C 5 -C 6 heteroalkyl), - (C 0 -C 4 heteroalkyl)(C 3 -C 7 cycloheteroalkyl), or -(C 0 -C 4 alkyl)(C 5 -C 6 heteroaryl), wherein each R 1 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, and mono-, di-, or tri-halomethyl.

[0048] In an aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is unsubstituted. In an alternate aspect, each R 1 is substituted with no more than four groups, or no more than three groups or no more than two groups or only with one group.

[0049] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently -CH 2 C(CH 3 ) 3 , -CH(CH 2 CH 3 ) 2 , -CF 2 CH 3 , -CH 2 CH 2 CF 3 , -C(CH 3 ) 2 F, -C(CH 3 ) 2 CF 3 , -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -morpholinyl, -CH 2 -pyrrolidinyl, phenyl, naphthyl, pyran-4-yl, 4-methylphenyl, 4-methoxyphenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 3-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2,4-dimethylphenyl, 4-chlorophenyl, 2-methylphenyl, 3-fluorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-difluoromethoxyphenyl, -C(CH 3 ) 2 SO 2 CH 3 , 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3-chlorophenyl, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, 3-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 2,4,6-trifluoromethylphenyl, 3-tetrahydrofuranyl, -C(CH 3 ) 2 CH 2 CH 3 , -C(CH 3 ) 2 OH, 3,3-dimethylcyclobut-1-yl, 2,3-dichlorobenzyl, 3,3-difluoromethylcyclobutyl, 2,2-dimethylcycloprop-1-yl, 2,2-difluorocyclopropyl, N-methylimidazolyl, 2-methyl-4-chlorophenyl, 2,4-dichloro-3-fluorophenyl, -CH 2 OCH 3 , -CH 2 CF 3 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 3 ,-CH(CH 3 )cyclopropyl, 2,6-difluorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 3-chloropyrid-2-yl, 2-methylpyrid-3-yl, 4-methylpyrid-3-yl, 3,5-dichloropyrid-2-yl, 3,3-difluorocyclopentyl, fluoro, chloro, bromo, 2-methoxy-4-chloro-phenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, benzyl, piperidinyl, 4-methyl-piperidinyl, 4-methoxy-piperidinyl, N-methylpyrazol-3-yl, -C(O)-piperidinyl, -OCHF 2 ,

[0050] In an aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, R 1 is 2,2-dimethylpropyl or

[0051] In a further aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, R 1 is 2,2-dimethylpropyl.

[0052] In a still further aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, R 1 is

[0053] In another aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, each R 1 is independently

[0054] In a different aspect, in the compounds and pharmaceutically acceptable salts of formulas I, Ia to Ix, IIa to IIx and IIIa to IIIx, R 1 is C 1 -C 6 alkyl, which is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, and mono-, di-, and tri-halomethyl.

[0055] In yet another aspect, the compounds and pharmaceutically acceptable salts of formula Iare: or

[0056] In still yet another aspect, the compounds and pharmaceutically acceptable salts of formula I: and Definitions

[0057] The specific chemical naming conventions used herein are intended to be familiar to one of skill in the chemical arts. Some terms are defined specifically for additional clarity.

[0058] As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to six atoms, e.g., "C 1 -C 6 alkyl." In cases where a zero is indicated, e.g., C 0 -C 4 alkyl or C 0 -C 3 alkyl, this component of the substituent group can be absent, thus, if a C 5 heterocycloalkyl substituent is at the R 2 position in formula (I), the C 5 heterocycloalkyl substituent could be described by the -(C 0 -C 4 alkyl)(C 3 -C 7 heterocycloalkyl) substituent as described for R 2 (i.e., the substituent group would be -(C 0 )(C 5 heterocycloalkyl)). Examples include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, and butyl. Similarly, as used herein, the term heteroalkyl means saturated linear or branched-chain monovalent alkyl molecules as defined herein containing one or more heteroatoms that have replaced carbon(s) in the alkyl chain. Typically, there are no more than four heteroatoms or no more than three heteroatoms in the heteroalkyl group.

[0059] As used herein, the term aryl refers to a functional group or substituent derived from an aromatic ring containing six to ten carbon atoms, e.g., C 6 -C 10 aryl, or five to six carbon atoms, e.g., C 5 -C 6 aryl, and no heteroatoms. Examples of aryl groups include phenyl and naphthyl. As used herein, the term heteroaryl refers to a functional group or substituent derived from an aromatic ring containing carbon atoms and one or more heteroatoms (e.g., nitrogen, oxygen, or sulfur) as part of the aromatic ring. Examples include rings having five or six atoms, at least one of which is a heteroatom. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, and thiazolyl.

[0060] As used herein, the term C 3 -C 7 cycloalkyl means a cyclic alkyl molecule containing three to seven carbon atoms. Examples of C 3 -C 7 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl. Similarly, as used herein, the terms heterocycloalkyl and cycloheteroalkyl mean a cycloalkyl molecule as defined herein, containing three to seven total atoms at least one of which is a heteroatom. Heterocycloalkyl or cycloheteroalkyl groups can be fused to other groups, such as phenyl groups. For example, a piperidine fused to a phenyl can form a tetrahydroisoquinoline or a tetrahydroquinoline.

[0061] As used herein, the terms bicyclic, bicyclyl, and bicycloalkyl refer to a group having two or more fused or bridged rings. C 4 -C 10 bicyclic, C 4 -C 10 bicyclyl, and C 4 -C 10 bicycloalkyl contain from four to ten carbon atoms. When the bicyclic group is fused, the two rings share two adjacent atoms. When the bicyclic group is bridged (also referred to as a bridged bicycloalkyl), the two rings share three or more atoms. Bridged bicycloalkyl groups may have four to ten carbon atoms or four to eight carbon atoms. Such groups may be referred to as "C 4 -C 10 bridged bicycloalkyl" or "C 4 -C 8 bridged bicycloalkyl," respectively. Bicyclic molecules can be all aliphatic, all aromatic, or mixed aromatic and aliphatic. The term C 4 -C 10 heterobicyclic refers to C 4 -C 10 bicyclic groups as defined that also include one or more hetero atoms. Examples of bridged bicycloalkyl groups useful with the compounds of formula (I) include, but are not limited to: and

[0062] Examples of C 4 -C 10 heterobicyclic include, but are not limited to:

[0063] As used herein, the terms C 5 -C 12 spiranyl or spirane or spiranes refers to a spirocyclic ring system. C 5 -C 12 spiranyl, C 5 -C 12 spirane and C 5 -C 12 spiranes refer to spirocyclic rings systems having 5 to 12 ring carbons. The spirocyclic ring system contains at least two and up to four rings, at least two of which must be connected via a spiro attachment. C 5 -C 12 spiranes may be unsubstituted or substituted as described herein.

[0064] C 5 -C 12 heterospiranyl refers to a spirocyclic ring system having 5 to 12 ring atoms, at least one of which is a heteroatom, i.e., not a carbon. The heterospiranyl ring system contains two to four rings, at least two of which must be connected via a spiro attachment. C 5 -C 12 heterospiranes may be unsubstituted or substituted as described herein. Examples of substituted and unsubstituted C 5 -C 12 spiranes and C 5 -C 12 heterospiranes include, but are not limited to:

[0065] As used herein, the term halogen or halo means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0066] As used herein, the term oxo means an oxygen that is double-bonded to a carbon atom, which can be represented as =O.

[0067] Compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx can be deuterated or triturated at one or more positions and such deuterated or triturated forms are part of the invention. Deuterium modification involves replacing one or more hydrogen atoms of a drug with deuterium atoms in an attempt to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites. Tritium modification makes the molecule radioactive and allows researchers to determine where the drug is deposited in the body and how it is metabolized.

[0068] The compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx described herein may form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts of the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx are intended to be included. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art (see, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0069] The compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein are generally effective over a wide dosage range. For example, dosages per day fall within the range of about 0.01 mg / kg to about 200 mg / kg. Further, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein can be administered, for example, in an amount of about 0.05 mg / kg to about 150, about 0.1 mg / kg to about 150, about 0.5 mg / kg to about 150 mg / kg, about 1 mg / kg to about 150 mg / kg, about 5 mg / kg to about 150 mg / kg, about 5 mg / kg to about 100 mg / kg, about 20 mg / kg to about 40 mg / kg, about 25 mg / kg to about 35 mg / kg, about 50 mg / kg to about 70 mg / kg, about 55 mg / kg to about 65 mg / kg, about 90 mg / kg to about 110 mg / kg, about 95 mg / kg to about 105 mg / kg, or about 50 mg / kg to about 150 mg / kg.

[0070] Alternatively, compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein can be administered, for example, in an amount of about 0.1 mg / kg to about 15 mg / kg, or about 0.5 mg / kg to about 10 mg / kg, or 1 mg / kg to about 9 mg / kg, or about 2 mg / to about 8 mg / kg or about 3 mg / kg to 7 mg / kg. Additionally, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein can be administered, for example, in an amount of about 1 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4, mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 105 mg / kg, about 110 mg / kg, about 115 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 135 mg / kg, about 140 mg / kg, about 145 mg / kg, about 150 mg / kg, about 155 mg / kg, about 160 mg / kg, about 165 mg / kg, about 170 mg / kg, about 175 mg / kg, about 180 mg / kg, about 185 mg / kg, about 190 mg / kg, about 195 mg / kg, or about 200 mg / kg. Daily administration can be once-daily or in multiple doses, e.g., twice-daily (BID) administration. Dosing can be 160 mg orally twice daily for patients weighing >50kg or 120 mg for patients weighing <50kg. It will be understood that the amount of a compound actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. Possibly CNS involvement / need for increased CNS exposure is also typically considered.

[0071] The compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein can be formulated as pharmaceutical compositions that can be administered by a variety of routes. Such pharmaceutical compositions and processes for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005)). Specifically, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, can be combined with one or more pharmaceutically acceptable carriers, diluents, or excipients. More particularly, the compounds described herein by formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx can be formulated as pharmaceutical compositions. Further, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, can be combined with one or more other therapeutic agents. For example, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, can be a component in a pharmaceutical composition for the treatment of cancer in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents. In concomitant therapies, when patients have multiple driver mutations / alterations detected - such as when an EGFR mutation and a clinically significant RET alteration are detected, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx can be administered in combination with a second therapeutic agent. Examples of combinations include, but are not limited to compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and osimertinib. Other examples of combinations include compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx combined with one or more of platinum based chemotherapeutic acids, and / or non-platinum based chemotherapeutic agents. Pharmaceutical compositions containing the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, can be used in the methods described herein.

[0072] The term "treating" (or "treat" or "treatment") as used herein refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, condition or disorder.

[0073] As used herein, the term "irritiable bowel syndrome" or "IBS" means gastrointestinal disorders including, but not limited to, diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, and inflammatory bowel disease.

[0074] As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers. By "early stage cancer" or "early stage tumor" is meant a cancer that is not advanced or metastatic or is classified as a Stage 0, I, or II cancer. Examples of cancer include, but are not limited to, lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, and cervical cancer.

[0075] The term "RET-associated disease or disorder" as used herein refers to diseases or disorders associated with or having a dysregulation of a RET gene, a RET kinase (also called herein RET kinase protein), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a RET gene, a RET kinase, a RET kinase domain, or the expression or activity or level of any of the same described herein).

[0076] The term "RET-associated cancer" as used herein refers to cancers associated with or having a dysregulation of a RET gene, a RET kinase (also called herein RET kinase protein), or expression or activity, or level of any of the same. Non-limiting examples of a RET-associated cancer are described herein.

[0077] The phrase "dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same" refers to a genetic mutation or alteration. Examples of such genetic mutations causing dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same include, but are not limited to, a RET gene translocation that results in the expression of a fusion protein, a deletion in a RET gene that results in the expression of a RET protein that includes a deletion of at least one amino acid as compared to the wild-type RET protein, a mutation in a RET gene that results in the expression of a RET protein with one or more point mutations, or an alternative spliced version of a RET mRNA that results in a RET protein having a deletion of at least one amino acid in the RET protein as compared to the wild-type RET protein or a RET gene amplification that results in overexpression of a RET protein or an autocrine activity resulting from the overexpression of a RET gene in a cell that results in a pathogenic increase in the activity of a kinase domain of a RET protein (e.g., a constitutively active kinase domain of a RET protein) in a cell. A dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same, can be a mutation in a RET gene that encodes a RET protein that is constitutively active or has increased activity as compared to a protein encoded by a RET gene that does not include the mutation. For example, a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains the 2nd half / portion of RET, and the 1st half of some other gene that is not RET. In some examples, dysregulation of a RET gene, a RET protein, or expression or activity or level of any of the same can be a result of a gene translocation of one RET gene with another non-RET gene.

[0078] Methods for the treatment of RET-associated diseases or disorders, in particular for the treatment of IBS or cancer with abnormal RET expression, using the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein are provided. Examples of cancers with abnormal RET expression include cancers caused by dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same. One such method of treating RET-associated diseases or disorders such as IBS or cancer includes administering a therapeutically effective amount of a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx or pharmaceutically acceptable salts thereof to a patient in need thereof. Another method of treating RET-associated diseases or disorders such as IBS or cancer includes a) detecting a dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the patient; and b) administering a therapeutically effective amount of a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx or a pharmaceutically acceptable salt.

[0079] The dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be the result of one or more chromosome translocations or inversions resulting in a RET gene fusion (i.e., the genetic translocations result in an expressed protein that is a fusion protein containing residues from a non-RET partner protein, and including a minimum of a functional RET kinase domain). Non-limiting examples of RET fusion partners and their associated cancers include ACBD5 (papillary thyroid cancer); AFAP1 (NSCLC); AFAP1L2 (papillary thyroid cancer); AKAP13 (papillary thyroid cancer); BCR (chronic myelomonocytic leukemia); C10orf118 (papillary thyroid cancer); CCDC6 (also called PTC1, D10S170, or H4) (NSCLC, colon cancer, papillary thyroid cancer, adenocarcinomas, lung adenocarcinoma, metastatic colorectal cancer, adenosquamous carcinomas, breast cancer); CCDC88C (NSCLC); CCDC186-RET, CEP55 (diffuse gastric cancer); CGNL1 (pancreatic cancer); CLIP1 (adenocarcinoma); CUX1 (lung adenocarcinoma); DLG5 (non-anaplastic thyroid cancer); DOCK1 (NSCLC); EML4 (papillary thyroid cancer); ERC1 (also called ELKS) (papillary thyroid cancer, breast cancer); ETV6 (salivary cancer); FGFR1OP (CMML, primary myelofibrosis with secondary acute myeloid leukemia); FKBP15 (papillary thyroid cancer); FOXP4 (lung adenocarcinoma); FRMD4A (NSCLC); GOLGA5 (also called PTC5) (papillary thyroid cancer, spitzoid neoplasms); H4L (various); HOOK3 (papillary thyroid cancer); HRH4-RET (thyroid cancer and / or papillary thyroid cancer); HTIF1 (various); KIAA1217 (also called SKT) (papillary thyroid cancer, lung adenocarcinoma, NSCLC); KIAA1468 (also called PTC9 and RFG9) (papillary thyroid cancer, lung adenocarcinoma); KIF13A (NSCLC); KIF5B (NSCLC, ovarian cancer, spitzoid neoplasms, lung adenocarcinoma, adenosquamous carcinomas); KTN1 (also called PTC8) (papillary thyroid cancer); MBD1 (also known as PCM1) (papillary thyroid cancer); MPRIP (NSCLC); MYH10 (infantile myofibromatosis); MYH13 (medullary thyroid cancer); NCOA4 (also called PTC3, ELE1, and RFG) (papillary thyroid cancer, NSCLC, colon cancer, salivary gland cancer, metastatic colorectal cancer, lung adenocarcinoma, adenosquamous carcinomas diffuse sclerosing variant of papillary thyroid cancer, breast cancer, acinic cell cancer, mammary analog secretory cancer); OLFM4 (Small-bowel cancer); PARD3 (NSCLC); PCM1 (papillary thyroid cancer); PIBF1 (bronchiolus lung cell cancer); PICALM (NSCLC); PPFIBP2 (papillary thyroid cancer); PRKAR1A (also called PTC2) (papillary thyroid cancer); PTC1ex9 (a novel CCDC6 rearrangement) (metastatic papillary thyroid cancer); PTC4 (a novel NCO4 / ELE1 rearrangement) (papillary thyroid cancer); RAB61P2 (papillary thyroid cancer); RASAL2 (Sarcoma); RASGEF1A (breast cancer); RBPMS (NSCLC); RFG8 (papillary thyroid cancer); RRBP1 (colon cancer); RUFY1 (colorectal cancer); RUFY2 (NSCLC; papillary thyroid cancer); RUFY3 (papillary thyroid cancer); SLC12A2 (NSCLC); SORBS2 (papillary thyroid cancer); SPECC1L (papillary thyroid cancer; thyroid gland cancer); SQSTM1 (papillary thyroid cancer); TAF3 (pancreatic cancer); TBL1XR1 (papillary thyroid cancer, thyroid gland cancer); TFG (pancreatic cancer); TIF1G (various); TRIM24 (also called PTC6) (papillary thyroid cancer); TRIM27 (also called RFP) (papillary thyroid cancer); AKAP13 (papillary thyroid cancer); TRIM33 (also called PTC7 and RFG7) (NSCLC, papillary thyroid cancer); and UEVLD (papillary thyroid cancer). The fusion protein can be, for example, KIF5B-RET. Fusions that were identified in single tumors included CCDC186-RET, ERC1-RET, KIN1-RET, and RUFY3-RET. Still other RET fusion proteins may not be included in the listing herein or are not yet known; however, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and methods for their use as described herein are expected to be effective inhibitors.

[0080] The dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, can be caused by one or more point mutations, insertions, or deletions in a RET gene (compared to wildtype RET). For reference, the sequence of mature human RET protein (SEQ ID NO: 1) is provided here:

[0081] Non-limiting examples of potentially activating RET kinase protein point mutations, insertions, or deletions as compared to wild-type RET kinase can occur at the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32 (e.g., S32L), 34 (e.g., D34S), 40 (e.g., L40P), 56 (e.g., L56M), 64 (e.g., P64L), 67 (e.g., R67H), 114 (e.g., R114H), 136 (e.g., glutamic acid to stop codon), 145 (e.g., V145G), 180 (e.g., arginine to stop codon), 200, 292 (e.g., V292M), 294, 321 (e.g., G321R), 330 (e.g., R330Q), 338 (e.g., T338I), 360 (e.g., R360W), 373 (e.g., alanine to valine (p.A373V) frameshift), D378-G385delinsE, 393 (e.g., F393L), 423 (e.g., G423R), 432, 446 (e.g., G446R), 505-506 (6-Base Pair In-Frame Germline Deletion in Exon 7), 510 (e.g., A510V), 511 (e.g., E511K), 513 (e.g., G513D), 515 (e.g., C515R, C515S, C515W), 525 (e.g., R525W), 531 (e.g., C531R, or 9 base pair duplication), 532 (e.g., duplication), 533 (e.g., G533C, G533S), 550 (e.g., G550E), 591 (e.g., V591I), 593 (e.g., G593E), 595 (e.g., E595D and E595A), 600 (e.g., R600Q), 602 (e.g., I602V), 603 (e.g., K603Q, K603E), 606 (e.g., Y606C), 609 (e.g., C609Y, C609S, C609G, C609R, C609F, C609W, C609C), 611 (e.g., C611R, C611S, C611G, C611Y, C611F, C611W), 616 (e.g., E616Q), 618 (e.g., C618S, C618Y, C618R, C618T, C618G, C618F, C618W), 620 (e.g., C620S, C620W, C620R, C620G, C620L, C620Y, C620F), 623 (e.g., E623K), 624 (e.g., D624N), 630 (e.g., C630A, C630R, C630S, C630Y, C630F, C630W, C630G), 631 (e.g., D631N, D631Y, D631A, D631G, D631V, D631E), 632 (e.g., E632K, E632G), 632-633 (6-Base Pair In-Frame Germline Deletion in Exon 11), 633 (e.g., 9 base pair duplication), 634 (e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T, or an insertion ELCR, or a 12 base pair duplication, or in combination with A640G, A641A, or A641T) (e.g., causing MTC), 634 / 852 (e.g., C634R / I852M), 635 (e.g., R635G), 636 (e.g., T636P, T636M), 648 (e.g., V648I), 649 (e.g., S649L), 664 (e.g., A664D), 665 (e.g., H665Q), 666 (e.g., K666E, K666M, K666N, K666R), 675 (T675T, silent nucleotide change), 686 (e.g., S686N), 689 (e.g., S689T), 691 (e.g., G691S), 694 (e.g., R694Q), 700 (e.g., M700L), 706 (e.g., V706M, V706A), 713 splice variant (e.g., E713K), 732 (e.g., E732K), 736 (e.g., G736R), 748 (e.g., G748C), 765 (e.g., S765P), 766 (e.g., P766S, P766M6), 768 (e.g., E768Q, E768D), 769 (e.g., L769L), 770 (e.g., R770Q), 771 (e.g., D771N), 777 (e.g., N777S), 778 (e.g., V778I), 781 (e.g., Q781R), 788 (e.g., I788I), 790 (e.g., L790F, L790T), 791 (e.g., Y791F, Y791N), 791 / 852 (e.g., Y791F / I852M), 802, 804 (e.g., V804L, V804M, V804E, V804G, V804S) (e.g., causing MTC), 804 / 918 (e.g., V804M / M918T, V804L / M918T), 805 (e.g., E805K), 804 / 805 (e.g., V804M / E805K), 806 (e.g., Y806F, Y806C, Y806H, Y806Y), 810 (e.g., G810R, G810S, G810A, G810C, G810V), 818 (e.g., E818K), 819 (e.g., S819I), 823 (e.g., G823E), 826 (e.g., Y826M, Y826S), 833 (e.g., R833C), 841 (e.g., P841L, P841P), 843 (e.g., E843D), 844 (e.g., R844W, R844Q, R844L), 848 (e.g., M848T), 852 (e.g., I852M), 865 (e.g., L865V), 870 (e.g., L870F), 873 (e.g., R873W), 876 (e.g., A876V), 881 (e.g., L881V), 882, 883 (e.g., A883F, A883P, A883S, A883T, A883Y), 884 (e.g., E884K), 886 (e.g., R886W), 891 (e.g., S891A), 897 (e.g., R897Q), 898 (e.g., D898V), 900 (e.g., Y900F), 901 (e.g., E901K), 904 (e.g., S904F, S904C), 905 (e.g., Y905F), 907 (e.g., K907E, K907M), 908 (e.g., R908K), 911 (e.g., G911D), 912 (e.g., R912P, R912Q), 918 (e.g., M918T, M918V, M918L, M918R) (e.g., causing MTC), 919 (e.g., A919V), 921 (e.g., E921K), 922 (e.g., S922P, S922Y), 930 (e.g., T930M), 961 (e.g., F961L), 972 (e.g., R972G), 981 (e.g., Y981F), 982 (e.g., R982C), 1009 (e.g., M1009V), 1015 (e.g., Y1015F), 1017 (e.g., D1017N), 1041 (e.g., V1041G), 1064 (e.g., M1064T), 1096 (e.g., Y1096F), In-Frame Deletion in Exons 6 and 11, 3bp In-Frame Deletion in Exon 15, Nucleotide position 2136+2 (e.g., 2136+2T>G), del632-636 ins6, and RET-extracellular cysteine mutation (which is defined as a mutation that included at least one of the following cysteine residues: 609, 611, 618, 620, 630, or 634). Other mutations included D631-liter633delinsE, E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del + D903_S904delinsEP, K666 N, T636-V637insCRT, and D378-G385delinsE. Still other mutations include D631-liter633delinsE, E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del + D903 _S904delinsEP, K666 N, T636-V637insCRT, and D378-G385delinsE. The RET kinase protein point mutations / insertions / deletions can be, for example, M918T, M918V, C634W, V804L, or V804M. Other RET kinase protein point mutations / insertions / deletions may not be included in the listing herein or are not yet known; however, the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and methods for their use as described herein are expected to be effective inhibitors.

[0082] A dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, can also include a splice variation in a RET mRNA which results in an expressed protein that is an alternatively spliced variant of RET having at least one residue deleted (as compared to the wild-type RET kinase) resulting in a constitutive activity of a RET kinase domain.

[0083] A "RET kinase inhibitor" as defined herein refers to compounds that inhibit RET activity using a measurement such as the Biological Assays described below in the examples.

[0084] In some cases, a RET kinase containing a mutation, insertion, or deletion is more resistant to inhibition of its phosphotransferase activity by one or more first RET kinase inhibitor(s), as compared to a wildtype RET kinase or a RET kinase not including the same mutation. Such mutations may not decrease the sensitivity of the cancer cell or tumor having the RET kinase to treatment a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein (e.g., as compared to a cancer cell or a tumor that does not include the particular RET inhibitor resistance mutation). In these cases, a RET inhibitor resistance mutation can result in a RET kinase that has one or more of an increased V max , a decreased K m for ATP, and an increased K D for a first RET kinase inhibitor, when in the presence of a first RET kinase inhibitor, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same first RET kinase inhibitor.

[0085] In other cases, a RET kinase containing a mutation, insertion, or deletion, has increased resistance to a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, as compared to a wildtype RET kinase or a RET kinase not including the same mutation. In such cases, a RET inhibitor resistance mutation can result in a RET kinase that has one or more of an increased V max , a decreased K m , and a decreased K D in the presence of a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein.

[0086] Examples of RET inhibitor resistance mutations can include point mutations, insertions, or deletions in and near the ATP binding site in the tertiary structure of RET kinase, including, but not limited to, the gatekeeper residue, P-loop residues, residues in or near the DFG motif, and ATP cleft solvent front amino acid residues. Additional examples of these types of mutations include changes in residues that may affect enzyme activity and / or drug binding including but are not limited to residues in the activation loop, residues near or interacting with the activation loop, residues contributing to active or inactive enzyme conformations, changes including mutations, deletions, and insertions in the loop proceeding the C-helix and in the C-helix. Specific residues or residue regions that at which mutations are known to create RET inhibitor resistance include but are not limited to the following amino acids (based on the human wildtype RET protein sequence (SEQ ID NO: 1)): 732 (e.g., E732K); 788 (e.g., I788N); 804 (e.g., V804M, V804L, V804E); 804 / 805 (e.g., V804M / E805K); 806 (e.g., Y806C, Y806E, Y806S, Y806H, Y806N); 810 (e.g., G810A, G810C, G810R, G810S, G810V); and 865 (e.g., L865V). Further examples of RET inhibitor resistance mutation positions include, but are not limited to, the following amino acids (based on the human wildtype RET protein sequence (SEQ ID NO: 1)): L730P, G731V, E732K, G733V, E734K, L760M, K761E, E762K, N763D, A764V, S765N, P766A, S767C, E768K, L779M, I788M, M868R, K869E, L870Q, V871M, H872R, R873P, D874Y, L881R, L895M, S896N, R897C, D898Y, V899G, Y900D, E901K, E902K, D903Y, S904C, Y905D, V906M, K907E, R908P, S909C, Q910R, G911C, and R912P. These mutations (which may also include single or multiple amino acid changes, insertions within or flanking the sequences, and deletions within or flanking the sequences) are thought to induce a steric hindrance and / or an active conformational effect that changes inhibitor binding characteristics.

[0087] Compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein may be useful in treating patients that develop cancers with certain RET inhibitor resistance mutations. For example, resistance mutations that result in an increased resistance to a RET inhibitor like a substitution at amino acid position 804 (e.g., V804M, V804L, or V804E), and / or one or more other RET inhibitor resistance mutations like those discussed above may be treated by either dosing in combination or as a follow-up therapy to existing drug treatments. For example, if a patient is treated with a first RET kinase inhibitor and the patient develops a RET inhibitor resistance mutation, the patient could then be subsequently treated with a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof (assuming that the compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein is a suitable inhibitor of the particular RET kinase inhibitor mutation present). As another example, if a patient is known to have a particular RET kinase inhibitor mutation (or multiple mutations), the patient could simultaneously be treated with multiple RET kinase inhibitors including a compound (or compounds) of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof that are effective against the RET kinase inhibitor mutation(s) present). Examples of currently known RET kinase inhibitors include pazopanib, sitravatinib, regorafenib, motesanib, RXDX-105, alectinib, BLU6864, cabozantinib, dovitinib, foretinib, lenvatinib, ponatinib, pralsetinib, selpercatinib, sorafenib, sunitinib, and vandetanib.

[0088] The types of cancers that can be treated using the compounds of formula I, formula Ia, formula Ib, formula Ic, formula Id and pharmaceutically acceptable salts thereof, include hematological cancer or solid tumor cancer. Examples of the types of cancer that can be treated using a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein include lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., Anaplastic thyroid cancer, Hurthle cell thyroid cancer, follicular thyroid cancer, poorly differentiated thyroid cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, and cervical cancer. Specifically, the types of cancer can be lung cancer or thyroid cancer. More specifically, the cancer can be non-small cell lung carcinoma or medullary thyroid cancer. Further examples of the types of cancers that can be treated using the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and the methods as described herein include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, pulmonary carcinosarcoma, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasms, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, unknown primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0089] Examples of the types of hematological cancers that can be treated using the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and the methods as described herein include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF / IPF / PMF). In one embodiment, the hematological cancer (e.g., the hematological cancer that is a RET-associated cancer) is AML or CMML.

[0090] Examples of the types of solid tumor cancers that can be treated using the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx and the methods as described herein include thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., lung adenocarcinoma, small-cell lung carcinoma), pancreatic cancer, pancreatic ductal carcinoma, xanthogranuloma tumor, breast cancer, colon cancer, colorectal cancer, rectal neuroendocrine cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma, and melanoma.

[0091] Also provided herein is a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, for use in the treatment of RET-associated diseases or disorders such as IBS or cancer. Cancers that can be treated using a compound of formula I, Ia, Ib, Ic and / or Id, or pharmaceutically acceptable salts thereof, t are described herein above. The treatment of RET-associated diseases or disorders can also include a step of performing an in vitro assay using a biological sample from a patient, determining the presence of a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and administering a therapeutically effective amount of the compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, to the patient if a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is present. In these uses, the biological sample can be a tumor sample and the tumor sample can be analyzed using methods known to those of skill in the art such as genomic / DNA sequencing. Additionally, in these uses the sample can be obtained from the patient prior to the first administration of the compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein. In these uses of the compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein in a therapy can be based upon a patient being selected for treatment by having at least one dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Also, in these therapeutic uses a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, or pharmaceutically acceptable salts thereof, may be administered to the patient at a dose of about 1 mg / kg to 200 mg / kg (effective dosage sub-ranges are noted herein above).

[0092] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The designations "isomer 1" and "isomer 2" refer to the compounds that elute from chiral chromatography first and second, respectively, under the conditions described herein and if chiral chromatography is initiated early in the synthesis, the same designation is applied to subsequent intermediates and examples. Additionally, the intermediates described in the following schemes may contain a number of nitrogen or oxygen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene 's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007). Certain abbreviations are defined as follows: "ACN" refers to acetonitrile; "ATP" refers to adenosine triphosphate; "bis(pinacolato)diboron" refers to 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane; "Boc" refers to tert-butoxycarbonyl; "Boc 2 O" refers to di-tert-butyl dicarbonate; "BSA" refers to Bovine Serum Albumin; "BTFFH" refers to Fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; "Bu" refers to butyl; "COMU ®< " refers to (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; "DCM" refers to dichloromethane or methylene chloride; "DIPEA" refers to N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine; "DMAP" refers to 4-dimethylaminopyridine; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "DTT" refers to dithiothreitol; "EtOAc" refers to ethyl acetate; "ee" refers to enantiomeric excess; "Et 2 O" refers to diethyl ether; "EtOH" refers to ethanol or ethyl alcohol; "FA" refers to formic acid; "GST" refers to glutathione S-transferase; "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate,; "HEK" refers to human embryonic kidney; "hr" or "hrs" refers to hour or hours; "HOAc" refers to acetic acid; "HTRF" refers to homogeneous time resolved fluorescence; "IgG" refers to immunoglobulin G; "IPA" refers to isopropyl alcohol or isopropanol; "IPAm" refers to Isopropylamine; "iPr 2 O" refers to isopropyl ether; "[Ir(OMe)(1,5-cod)] 2 " refers to di-mu-methanolatodiiridium(Ir-Ir) - cycloocta-1,5-diene or (1,5-cyclooctadiene)(methoxy)iridium(I) dimer or bis(1,5-cyclooctadiene)di-µ-methoxydiiridium(I); "KOAc" refers to potassium acetate; "LDA" refers to lithium diisopropylamide; "MeI" refers to methyl iodide or iodomethane; "MeOH" refers to methanol or methyl alcohol; "MeTHF" refers to 2-methyltetrahydrofuran; "min" refers to minute or minutes; "Mn(dpm) 3 " refers to manganese(3+) tris[(3Z)-2,2,6,6-tetramethyl-5-oxo-3-hepten-3-olate], Mn(TMHD) 3 , Shenvi hydrogenation catalyst, or tris(dipivaloylmethanato)manganese; "NaOAc" refers to sodium acetate; "NaOMe" refers to sodium methoxide; "NMI" refers to 1-methylimidazole or N-methylimidazole; "Parkins catalyst" refers to hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) and is CAS # 173416-05-2; "PBS-T" refers to Phosphate Buffered Saline + Tween ®< 20; "Pd(dppf)Cl 2 )" refers to [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium (II); "Pd(dppf)Cl 2 )·CH 2 Cl 2 " refers to [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium (II), coupled with DCM; "PE" refers to petroleum ether; "PhSiH 3 " refers to phenylsilane; "RT" refers to room temperature; "SFC" refers to supercritical fluid chromatography; "tert-BuOH" refers to tert butyl alcohol; "TBTU" refers to O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate or N,N,N',N'-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate; "TCFH" refers to N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "T3P ®< " refers to propanephosphonic acid anhydride, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, or PPACA; "t (R) " refers to retention time and "WT" refers to wild-type.

[0093] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. As an illustration, compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present invention is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.

[0094] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are generally readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally similar compounds and the procedures described in the Preparations and Examples which follow including any novel procedures. Intermediates and processes useful for the synthesis of the compounds described by formula (I) are intended to be included in this description.

[0095] Scheme 1 depicts the preparation of the compounds of (12). A person of ordinary skill in the art will recognize that borylation of aryl bromide (1) under typical Miyaura reaction conditions may provide boronic ester (2). Treatment of boronic ester (2) with the appropriate bromopyrazole (3) and metal catalyst, under Suzuki coupling conditions, may afford amino pyrazole (9).

[0096] Alternatively, palladium-catalyzed carbonylation of aryl bromide (1) with carbon monoxide and benzyl alcohol may provide benzyl carboxylate (4). Palladium-catalyzed debenzylation of benzyl carboxylate (4) with hydrogen may provide carboxylic acid (5). Preparation of the acyl chloride of acid (5) and subsequent reaction with malononitrile under basic conditions may afford malononitrile (6). Methylation of vinyl alcohol (6) may be achieved with dimethyl sulfate to provide methoxy (7). Reacting the appropriately substituted hydrazine (8) with the dinitrile Michael acceptor (7) can also afford amino pyrazole (9).

[0097] Treatment of boronic ester (2) with the appropriate bromopyrazole (10) and metal catalyst, under Suzuki coupling conditions, may afford amino pyrazole (11). Carboxylic acid (12) may be obtained by saponification of ester (11) with the proper nucleophilic base.

[0098] Alternatively, carboxylic acid (12) may also be obtained from the ester (9) in a two-step one pot reaction of oxidation and saponification using peroxide and base.

[0099] Scheme 2 depicts the preparation of the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein. Saponification of ester (1) may furnish carboxylic acid (14) in essentially the same manner as described for the carboxylic acid (12) in Scheme 1. The skilled artisan will recognize that carboxylic acid (14) and primary amine (13) may be joined by utilizing the appropriate amide coupling reagent under conditions suitable for amide bond formation to provide amide (15). Borylation of aryl bromide (15) under typical Miyaura reaction conditions, followed by treatment of the in-situ boronic ester with bromopyrazole (10) and metal catalyst, under Suzuki coupling conditions, may afford compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx.

[0100] Alternatively, amide coupling of carboxylic acid (12) and primary amine (13) may provide compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx in essentially the same manner described for amide (15) above.

[0101] Scheme 3 depicts additional preparations of the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein. Protection of primary amine (16) with an appropriate protecting group may provide the mono- or bis- protected amino pyrazole (17). Iridium-catalyzed C-H borylation of pyrazole (17), followed by treatment of the in-situ boronic ester with aryl bromide (1) and metal catalyst, under Suzuki coupling conditions, may afford biaryl (18). Saponification of ester (18) may furnish carboxylic acid (19) in essentially the same manner as described for the carboxylic acid (12) in Scheme 1. Amide coupling of carboxylic acid (19) and primary amine (13) may provide amide (20) in essentially the same manner as described for the amide (12) in Scheme 2. The nitrile moiety of amino pyrazole (20) may be converted to carboxamide (21), under a variety of conditions such as metal catalyzed hydration, acidic hydrolysis, and oxidation. Removal of the protecting group from the protected amino pyrazole (21) may provide additional compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein.

[0102] Scheme 4 depicts alternative preparations of the compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein. Reacting the appropriately substituted hydrazine (8) with the dinitrile Michael acceptor (22) can afford amino pyrazole (23) in essentially the same manner as described for the amino pyrazole (9) in Scheme 1. Treatment of aryl bromide (23) with the appropriate alkylzinc halide and metal catalyst, under Negishi coupling conditions may afford tert-butyl ester (24). Acidic deprotection of tert-butyl ester (24) may provide carboxylic acid (25).

[0103] Alternatively, saponification of ester (9) may furnish carboxylic acid (25) in essentially the same manner as described for the carboxylic acid (12) in Scheme 1. Amide coupling of carboxylic acid (25) and primary amine (13) may provide amide (31) in essentially the same manner as described for the amide (12) in Scheme 2.

[0104] Alternatively, amide coupling of carboxylic acid (26) and primary amine (13) may provide amide (27) in essentially the same manner as described for the amide (12) in Scheme 2. Saponification of ester (27) may furnish carboxylic acid (28) in essentially the same manner as described for the carboxylic acid (12) in Scheme 1. Preparation of the acyl chloride of acid (28) and subsequent reaction with malononitrile under basic conditions may afford malononitrile (29). Methylation of vinyl alcohol (29) may be achieved with dimethyl sulfate to provide methoxy (30). Reacting the appropriately substituted hydrazine (8) with the dinitrile Michael acceptor (30) can afford amino pyrazole (31) in essentially the same manner as described for the amino pyrazole (9) in Scheme 1.

[0105] The nitrile moiety of amino pyrazole (31) may be converted to additional compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx as described herein, under a variety of conditions such as metal catalyzed hydration, acidic hydrolysis, and oxidation.

[0106] In an optional step, a pharmaceutically acceptable salt of a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx can be formed by reaction of an appropriate free base of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx with an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions. Additionally, the formation of such salts can occur simultaneously upon deprotection of a nitrogen protecting group. The formation of such salts is well known and appreciated in the art. See, for example, Gould, P.L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977). "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986). One of ordinary skill in the art will appreciate that a compound of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx is readily converted to and may be isolated as a pharmaceutically acceptable salt.Preparations and ExamplesPreparation 1tert-Butyl N-(tert-butoxycarbonyl)-N-(5-iodo-4-methyl-1,3-thiazol-2-yl)carbamate

[0107]

[0108] A mixture of 5-iodo-4-methyl-1,3-thiazol-2-amine (16.0 g, 66.7 mmol), Boc 2 O (32.0 g, 146 mmol) and DMAP (0.81 g, 6.63 mmol) in THF (200 mL) is stirred for 2 hr at RT under N 2 . The mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 12:1 to 5:1 PE:EtOAc to give the title compound (20.0 g, 68%) as a yellow solid. ES / MS (m / z) 441.0 (M+H).Preparation 25-(2,2-Dimethylpropyl)-4-methyl-1,3-thiazol-2-amine

[0109]

[0110] Zinc chloride (5.84 mL, 4.09 mmol, 0.7 M in THF) is added to a solution of bromo(2,2-dimethylpropyl)magnesium (6.50 mL, 3.25 mmol, 0.5 M in THF) at 0 °C and the mixture is stirred for 30 min at 0 °C under N 2 . To this mixture is added tert-butyl N-(tert-butoxycarbonyl)-N-(5-iodo-4-methyl-1,3-thiazol-2-yl)carbamate (1.20 g, 2.73 mmol) and Pd(t-Bu 3 P) 2 (0.28 g, 0.55 mmol) in portions over 1 min at RT. The mixture is stirred for an additional 2 hr at 100 °C under N 2 . The reaction is quenched by the addition of saturated aq. NH 4 Cl (20 mL) at RT. The mixture is extracted with EtOAc (2x50 mL). The combined organic extracts are washed with brine (2x30 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 45% to 52% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (80 mg, 16%) as a yellow solid. ES / MS (m / z) 185.1 (M+H).Preparation 3Methyl 2-[4-bromo-3-(bromomethyl)phenyl]acetate

[0111]

[0112] To a stirred solution of methyl 2-(4-bromo-3-methyl-phenyl)acetate (5.50 g, 22.6 mmol) in CCl 4 (200 mL) at RT under N 2 is added successively 1-bromopyrrolidine-2,5-dione (4.23 g, 23.8 mmol) and 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (1.30 g, 7.92 mmol). The reaction mixture is stirred at 80 °C for 5 hr. The mixture is poured in a solution of NaHCO3 and the aqueous layer is extracted with DCM (2x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The material is purified by silica gel chromatography, eluting with a gradient of 2% to 10% EtOAc in cyclohexane to give the title compound as a colorless oil (1.69 g, 23%). ES / MS (m / z) 342 (M+Na).Preparation 4Methyl 2-[4-bromo-3-(methoxymethyl)phenyl]acetate

[0113]

[0114] To a stirred solution of methyl 2-[4-bromo-3-(bromomethyl)phenyl]acetate (0.60 g, 1.86 mmol) in MeOH (10 mL) at 5 °C under N 2 is added NaOMe (0.41 mL, 2.19 mmol, 30 wt% in MeOH). The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated, H 2 O is added to the residue, and the mixture is extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried over NaSO 4 , filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil (0.42 g, 83%). ES / MS (m / z) 274 (M+H).Preparation 5Methyl 2-(4-bromo-3-chloro-2-fluoro-phenyl)acetate

[0115]

[0116] To 2-(4-bromo-3-chloro-2-fluorophenyl)acetic acid (0.50 g, 1.78 mmol) in MeOH (15 mL) at 0 °C under N 2 is added dropwise thionyl chloride (0.39 mL, 5.33 mmol). The mixture is allowed to warm to RT and stirred for 16 hr. The mixture is concentrated under reduced pressure and dried under vacuum. The material is purified by silica gel chromatography, eluting with a gradient of 25% to 100% DCM in heptane to give the title compound as a colorless oil (0.50 g, 100%).

[0117] The following compound in Table 1 is prepared essentially as described for methyl 2-(4-bromo-3-chloro-2-fluoro-phenyl)acetate, using the appropriate acid, adjusting the reaction time to determine completion of the reaction, and purifying chromatography as appropriate, and substituting EtOH for MeOH to prepare the ethyl ester if desired. Table 1Prep No.Chemical NameStructure6Ethyl 3-methylbicyclo[1.1.1]pentane-1-carboxylate Preparation 7Methyl 2-[4-bromo-3-(tert-butoxymethyl)phenyl]acetate

[0118]

[0119] To a suspension of Ag-trifluoromethanesulfonate (0.44 g, 1.71 mmol) in dry tert-BuOH (10 mL) and dry DCM (20 mL), protected from visible light, is added a solution of methyl 2-[4-bromo-3-(bromomethyl)phenyl]acetate (0.50 g, 1.55 mmol) in dry DCM (5 mL) at RT under N 2 . The reaction mixture is stirred at RT for 16 hr, then poured into saturated aq. NaHCO 3 . The aqueous layer is extracted with DCM (2x). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound as a colorless oil (0.51 g, 95%). 1< H NMR(d 6 -DMSO, 400 MHz) δ (ppm) 7.53 (d, J=8.1 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.12 (dd, J=8.1, 2.3 Hz, 1H), 4.41 (s, 2H), 3.70 (s, 2H), 3.62 (s, 3H), 1.25 (s, 9H).Preparation 82-[(tert-Butoxycarbonyl)[(tert-butoxycarbonyl)amino]amino]-2-methylpropan-1-ol

[0120]

[0121] To a stirred solution of Mn(dpm) 3 (0.42 g, 0.69 mmol) in IPA (150 mL) is added methallyl alcohol (5.00 g, 69.3 mmol), di-tert-butyl azodicarboxylate (24.0 g, 103 mmol), and PhSiH 3 (7.50 g, 69.3 mmol) dropwise at 0 °C under N 2 . The mixture is stirred for 1 hr at 0 °C under N 2 and for 12 hr at RT under N 2 . The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography, eluting with a gradient of 10: 1 to 4: 1 PE:EtOAc to give the title compound (15.0 g, 71 %) as a white solid. 1< H NMR (CDCl 3 , 300 MHz) δ 4.30-4.02 (m, 2H), 3.42-3.19 (m, 1H), 1.59-1.42 (m, 24H).Preparation 92-Hydrazinyl-2-methylpropan-1-ol 2HCl

[0122]

[0123] To a solution of 2-[(tert-butoxycarbonyl)[(tert-butoxycarbonyl)amino]amino]-2-methylpropan-1-ol (15.0 g, 49.3 mmol) in 1,4-dioxane (100 mL), HCl (50 mL, 4 N in 1,4-dioxane) is added and the mixture is stirred for 2 hr at RT. The reaction is concentrated under reduced pressure. The crude product is triturated with Et 2 O (30 mL) to give the title compound (4.4 g, 63%) as a white solid. 1< H NMR (d 6 -DMSO, 300 MHz) δ 6.41 (s, 5H), 3.40 (s, 2H), 1.14 (s, 6H).Preparation 10tert-Butyl N-(1-methylcyclopropyl)-N-nitroso-carbamate

[0124]

[0125] To a stirred solution of tert-butyl N-(1-methylcyclopropyl)carbamate (2.00 g, 11.7 mmol) in DCM (20 mL) is added tert-butyl nitrite (2.40 g, 23.3 mmol) in portions at RT under N 2 and the mixture is stirred for 2 hr at RT under N 2 . The mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with 25:1 to 20:1 PE:EtOAc to give the title compound (1.30 g, 55%) as a brown liquid. 1< H NMR (d 6 -DMSO) δ 1.59 (s, 9H), 1.10 (s, 3H), 0.86-0.84 (m, 2H), 0.70-0.65 (m, 2H).Preparation 11(1-Methylcyclopropyl)hydrazine hydrochloride

[0126]

[0127] To a stirred solution of tert-butyl N-(1-methylcyclopropyl)-N-nitroso-carbamate (1.20 g, 5.99 mmol) in HCl (8 mL, 4 N in 1,4-dioxane) is added Zn (0.78 g, 11.9 mmol) in portions at 0 °C under N 2 and the mixture is stirred for 12 hr at RT under N 2 . The mixture is filtered, the filter cake is washed with H 2 O (3x10 mL), and the filtrate is concentrated under reduced pressure to give the title compound (2.0 g, crude) as an off-white solid which is used directly without further purification. 1< H NMR (d 6 -DMSO) δ 1.30 (s, 3H), 0.77-0.73 (m, 2H), 0.54-0.50 (m, 2H).Preparation 12Methyl spiro[2.2]pentane-2-carboxylate

[0128]

[0129] To a stirred solution of spiro[2.2]pentane-1-carboxylic acid (95%, 1.25 g, 10.6 mmol) in Et 2 O (37.5 mL) and MeOH (7.5 mL) at 0 °C is added 2 M diazomethyl(trimethyl)silane in hexanes (6.9 mL, 13.8 mmol) dropwise. The reaction mixture is stirred at RT overnight. Et 2 O is removed under reduced pressure and the reaction mixture is diluted with pentane (125 mL). The solution is washed with saturated aq. NaHCO 3 (2x), H 2 O (3x), and brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (1.53 g, crude) as a yellow oil which is used directly without further purification.Preparation 132-(Trifluoromethyl)spiro[3.3]heptane-2-carbonyl chloride

[0130]

[0131] 2-(Trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid (1.02 g, 4.90 mmol) is suspended in DCM (40 mL) and DMF (0.10 mL). The slurry is cooled to 0 °C and oxalyl chloride (3.0 mL, 6.00 mmol, 2 M in DCM) is added. The reaction is stirred at 0 °C for 5 min then allowed to warm to RT and stirred for 1 hr. The solvent is removed under reduced pressure to give a yellow residue. The residue is used without further purification.

[0132] The following compounds in Table 2 are prepared essentially as described for 2-(trifluoromethyl)spiro[3.3]heptane-2-carbonyl chloride using the appropriate acid, oxalyl chloride (1-1.5 eq) and solvents (DCM, DMF) ranging from 0-50 mL and adjusting reaction time to determine completion of the reaction. The reaction temperature can range from 0 °C-25 °C. Table 2Prep No.Chemical NameStructure144-(Trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl chloride 152-(1-Methylcyclopropyl)acetyl chloride 164,4,4-Trifluoro-3,3-dimethyl-butanoyl chloride Preparation 17Benzyl 2,2-dimethylcyclobutanecarboxylate

[0133]

[0134] To a stirred solution of 2,2-dimethylcyclobutane-1-carboxylic acid (1.50 g, 11.7 mmol) in DCM (20 mL) at 0 °C under N 2 is added dropwise oxalyl chloride (1.0 mL, 11.7 mmol) followed by DMF (30 µL). The mixture is slowly allowed to warm to RT and stirred for 5 hr. Benzylalcohol (1.4 mL, 13.5 mmol) is added dropwise at 0°C and the reaction mixture is slowly allowed to warm to RT and stirred for 20 hr. The mixture is poured into saturated aq. NaHCO 3 . The aqueous layer is extracted with pentane (2x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 5% to 50% DCM in pentane to give the title compound (2.6 g, 100%) as a colorless oil. ES / MS (m / z) 219 (M+H).Preparation 182-[2-(3,3-Dimethylcyclobutyl)-1,3-dioxolan-2-yl]acetonitrile

[0135]

[0136] To a stirred solution of 3-(3,3-dimethylcyclobutyl)-3-oxo-propanenitrile (0.60 g, 4.00 mmol) in DCM (8 mL) at 25 °C under N 2 is added ethane-1,2-diol (0.67 mL, 12.0 mmol) and chloro(trimethyl)silane (1.5 mL, 12.0 mmol). The reaction mixture is stirred at reflux for 12 hr and cooled to RT. NaHCO 3 (aq) is added. The aqueous layer is extracted with DCM. The combined organic extract is washed with brine, dried over Na 2 SO 4 , filtered, and dried under vacuum. The residue is purified by silica gel chromatography, eluting with a gradient of 10% to 30% EtOAc in cyclohexane to give the title compound (0.56 g, 72%) as a colorless oil. 1< H NMR (d 6 -DMSO, 400 MHz) δ (ppm) 4.09-3.98 (m, 2H), 4.01-3.90 (m, 2H), 2.79 (s, 2H), 2.61 (s, 2H), 1.79-1.57 (m, 6H), 1.41 (s, 2H), 1.12 (s, 3H), 1.01 (s, 3H).Preparation 194-(1-Methylcyclopropyl)-3-oxo-butanenitrile

[0137]

[0138] ACN (0.36 mL, 6.89 mmol) and benzyl 2-(1-methylcyclopropyl)acetate (1.27 g, 6.22 mmol) are combined in THF (15 mL) under N 2 and cooled to -78 °C. LDA (11.0 mL, 22.0 mmol, 2 M in THF) is added dropwise and the reaction is stirred for 10 min at -78 °C. The reaction is allowed to warm to 21 °C over 1 hr. The reaction is acidified to pH 1 with conc. HCl and the mixture is extracted with EtOAc (3x100 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.4 g, crude) as an orange oil. The material is used without further purification.Preparation 203-Oxo-3-[2-(trifluoromethyl)spiro[3.3]heptan-2-yl]propanenitrile

[0139]

[0140] ACN (0.28 mL, 5.36 mmol) and benzyl 2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylate (1.40 g, 4.69 mmol) are combined in THF (15 mL) under N 2 and cooled to -78 °C. LDA (2.82 mL, 5.64 mmol, 2 M in THF) is added dropwise and the reaction is stirred for 10 mins at -78 °C. The reaction is allowed to warm to 21 °C over 1 hr. The reaction is acidified to pH 1 with conc. HCl and the mixture is extracted with EtOAc (3x100 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.05 g, 97%) as an orange oil. This material is used directly without further purification.

[0141] The following compounds in Table 3 are prepared essentially as described for 3-oxo-3-[2-(trifluoromethyl)spiro[3.3]heptan-2-yl]propanenitrile using the appropriate base (LDA or nBuLi in hexanes or THF) from 1.2-4.2 equivalents and adjusting reaction time to determine completion of the reaction. Table 3Prep. No.Chemical nameStructure213-Oxo-4-[1-(trifluoromethyl)cyclopropyl]butanenitrile 223-Oxo-3-(4-(trifluoromethyl)bicyclo[2.2.1]heptan-1-yl)propanenitrile 1< 233-(4-Fluorobicyclo[2.2.2]octan-1-yl)-3-oxopropanenitrile 243-(2,2-Difluorospiro[3.3]heptan-6-yl)-3-oxo-propanenitrile 1< nBuLi used instead of LDA. Preparation 253-[3-Methylbicyclo[1.1.1]pentan-1-yl]-3-oxopropanenitrile

[0142]

[0143] To THF (5 mL) is added n-BuLi (1.71 mL, 4.28 mmol, 2.5 M in THF) at 0 °C under N 2 . To the mixture is added ACN (0.24 mL, 4.59 mmol) in THF (5 mL) dropwise over 5 min at -78 °C under N 2 . The mixture is stirred for 1 hr at -78 °C. To the mixture is added methyl 3-methylbicyclo[1.1.1]pentane-1-carboxylate (0.40 g, 2.85 mmol) in THF (5 mL) dropwise at -78 °C under N 2 . The mixture is stirred for 1 hr at RT. The reaction is quenched by the addition of saturated aq. NH 4 Cl (20 mL) at 0 °C. The mixture is acidified to pH 4 with 1 N aq. HCl and extracted with DCM (3x50 mL). The combined organic extracts are washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (0.36 g, 85%) as a brown liquid. The crude product is used without further purification.Preparation 263-(3-Fluorobicyclo[1.1.1]pentan-1-yl)-3-oxopropanenitrile

[0144]

[0145] To a stirred solution of n-BuLi (2.0 mL, 2.5 M in n-hexanes, 5.00 mmol) in THF (20 mL) is added a solution of ACN (0.28 mL, 5.36 mmol) in THF (4 mL) dropwise at -78 °C under N 2 . The mixture is stirred for 30 min at -78 ° C. To the mixture is added a solution of methyl 3-fluorobicyclo[1.1.1]pentane-1-carboxylate (0.48 g, 3.33 mmol) in THF (4 mL) dropwise over 10 min at -78 ° C. The mixture is allowed to warm to RT and stirred for an additional 3 hr. The reaction is quenched with saturated aq. NH 4 Cl, acidified to pH 4 with 2 N aq. HCl, and extracted with DCM (3x50 mL). The combined organic extracts are washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (0.50 g, crude) as a brown oil. The crude product is used without further purification. 1< H NMR (CDCl 3 , 300 MHz) δ 3.57 (s, 2H), 2.50 (d, 6H).Preparation 273-Oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile

[0146]

[0147] n-BuLi (0.83 mL, 2.08 mmol, 2.5 M in hexanes) is added to THF (10 mL) at 0 °C under N 2 . ACN (0.12 mL, 2.30 mmol) in THF (2 mL) is added dropwise over 2 min at -78 °C under N 2 and the reaction is stirred for 1 hr at -78 °C. Methyl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.27 g, 1.39 mmol) in THF (2 mL) is added dropwise to the reaction mixture at -78 °C and the reaction is stirred at RT for 12 hr. The reaction is quenched by the addition of saturated aq. NH 4 Cl (20 mL), acidified to pH 4 with conc. HCl, and extracted with DCM (3x50 mL). The combined organic extracts are washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (0.29 g, crude). The crude product is used without further purification. 1< H NMR (CDCl 3 , 300 MHz) δ 3.54 (s, 2H), 2.39 (s, 6H).

[0148] The following compounds in Table 4 are prepared essentially as described for 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile, adjusting reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction can be allowed to warm to RT after the carboxylate is added. n-BuLi can be in hexanes or THF. Table 4Prep. No.Chemical nameStructure283-(2-Cyanoacetyl)bicyclo[1.1.1]pentane-1-carbonitrile 293-Oxo-3-[4-(trifluoromethyl)bicyclo[2.2.1]heptan-1-yl]propanenitrile 303-(3-Chloropyridin-2-yl)-3-oxopropanenitrile 313-(2,2-Dimethylcyclopropyl)-3-oxo-propanenitrile 324-(1-Methylcyclobutyl)-3-oxo-butanenitrile 333 -Oxo-3 -spiro[2.2]pentan-2-yl-propanenitrile 344-(2,2-Difluorocyclopropyl)-3-oxo-butanenitrile 353-Oxo-3-spiro[2.3]hexan-2-yl-propanenitrile 363-(2,2-Dimethylcyclobutyl)-3-oxo-propanenitrile 373-(3,3-Difluoro-1-methylcyclobutyl)-3-oxo-propanenitrile 384,4-Difluoro-5,5-dimethyl-3-oxo-hexanenitrile Preparation 395-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

[0149]

[0150] A solution of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (0.50 g, 2.59 mmol), hexane-2,5-dione (0.91 mL, 7.76 mmol) and HOAc (0.015 mL, 0.26 mmol) in toluene (10 mL) is stirred for 2 hr at 100 °C under N 2 . The mixture is concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 30% to 50% ACN in H 2 O (0.1% FA) to give the title compound (0.61 g, 87%) as a yellow solid. ES / MS (m / z) 272.1 (M+H).Preparation 403-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

[0151]

[0152] A solution of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (0.50 g, 1.84 mmol), MeI (0.46 mL, 7.39 mmol) and K 2 CO 3 (0.51 g, 3.69 mmol) in ACN (10 mL) is stirred for 4 hr at 80 °C under N 2 . The mixture is concentrated under reduced pressure. The residue is purified by preparative TLC, eluting with 5:1 PE:EtOAc to give the title compound (95 mg, 18%) as a white solid. ES / MS (m / z) 286.2 (M+H).Preparation 411-Methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-amine

[0153]

[0154] A solution of KOH (53 mg, 0.94 mmol) in EtOH (1 mL) and H 2 O (1 mL) is added to a solution of hydroxylamine HCl (0.13 g, 1.87 mmol) in EtOH (2 mL). 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (90 mg, 0.32 mmol) is added and the mixture is stirred for 4 hr at 100 °C under N 2 . The mixture is concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 10% to 30% ACN in H 2 O (0.1% FA) to give the title compound (45 mg, 68%) as a white solid. ES / MS (m / z) 208.1 (M+H).Preparation 423-[(1-Methylcyclopropyl)methyl]isoxazol-5-amine

[0155]

[0156] 4-(1-Methylcyclopropyl)-3-oxo-butanenitrile (1.40 g, 10.2 mmol) is dissolved in H 2 O (15 mL). NaOH (0.45 g, 11.3 mmol) is added followed by hydroxylamine sulfate (1.84 g, 11.2 mmol). The pH is adjusted to ~10 with 2 M aq. NaOH (5.0 mL, 10.0 mmol). The mixture is heated to 100 °C for 1.5 hr. Conc. HCl (1 mL) is added and the mixture is stirred for 15 min. The mixture is diluted with H 2 O (30 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts are dried over anhydrous NH 2 SO 4 and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 10% to 70% EtOAc in hexanes to give the title compound (0.54 g, 35%). ES / MS (m / z) 153.0 (M+H).Preparation 433-(3-Fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine

[0157]

[0158] To a stirred solution of 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxopropanenitrile (0.50 g, 3.26 mmol) in MeOH (5 mL) is added hydroxylamine HCl (0.68 g, 9.79 mmol) and KOAc (0.96 g, 9.78 mmol) at 0 °C under N 2 . The mixture is stirred for 5 hr at RT under N 2 . The mixture is poured into H 2 O (50 mL) and extracted with DCM (3x50 mL). The combined organic extracts are dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 25% to 45% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (0.22 g, 40%) as a light yellow solid. ES / MS (m / z) 169.1 (M+H).Preparation 443-(Bicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine

[0159]

[0160] To a stirred solution of 3-(bicyclo[1.1.1]pentan-1-yl)-3-oxopropanenitrile (0.87 g, 6.44 mmol) in MeOH (10 mL) is added hydroxylamine HCl (1.34 g, 19.3 mmol) and KOAc (1.89 g, 19.3 mmol) at 0 °C under N 2 . The mixture is stirred for 5 hr at RT under N 2 . The mixture is poured into H 2 O (50 mL) and extracted with DCM (3x50 mL). The combined organic extracts are dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is washed with hexanes (2x5 mL) to give the title compound (0.73 g, 75%) as a light yellow solid. ES / MS (m / z) 151.3 (M+H).Preparation 453-(3-Methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-amine

[0161]

[0162] To a stirred mixture of 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-3-oxopropanenitrile (0.35 g, 2.35 mmol) and hydroxylamine HCl (0.18 g, 2.59 mmol) in H 2 O (8 mL) is added NaOH (0.19 g, 4.75 mmol) in portions at RT under N 2 . The mixture is stirred for 1 hr at 100 °C under N 2 . The mixture is allowed to cool to RT. The precipitated solids are collected by filtration and washed with H 2 O (3x20 mL) to give the title compound (0.30 g, 78%) as a light yellow solid. ES / MS (m / z) 165.1 (M+H).Preparation 463-(3-(Trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine

[0163]

[0164] A mixture of 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile (0.28 g, 1.38 mmol), hydroxylamine HCl (0.11 g, 1.58 mmol) and H 2 O (10 mL) is added NaOH (0.11 g, 2.75 mmol) in portions at RT under N 2 . The mixture is heated to 100 °C for 1 hr. The mixture is allowed to cool to RT and is extracted with DCM (3x50 mL). The combined organic extracts are washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting solid is triturated with Et 2 O (10 mL). The solids are collected by filtration and washed with Et 2 O to give the title compound (0.22 g, 73%). ES / MS (m / z) 219.2 (M+H).

[0165] The following compounds in Table 5 are prepared essentially as described for 3-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine using the appropriate reagents (hydroxylamine sulfate or hydroxylamine HCl) about 1-6 equivalents, bases (NaOH, NaOAc, or KOAc) about 1-6 equivalents in the appropriate solvent (EtOH, MeOH, H 2 O, or 1,4-dioxane), adjusting the reaction time to determine completion of the reaction and using appropriate chromatography conditions or precipitation for purification. The reaction temperature can range from 0 to 100 °C and the reaction mixture can be acidified in work-up if appropriate. The reagents can be added together at 0 °C in portions or all at once. Table 5Prep No.Chemical NameStructureES / MS m / z (M+H)473-Spiro[3.3]heptan-2-ylisoxazol-5-amine 179.1483-[2-(Trifluoromethyl)spiro[3.3]hepta n-2-yl]isoxazol-5-amine 247.1493-[[1-(Trifluoromethyl)cyclopropyl]me thyl]isoxazol-5-amine 207.1503-(4-(Trifluoromethyl)bicyclo[2.2.1]h eptan-1-yl)isoxazol-5-amine 247.1513-(3,3,3-Trifluoro-2,2-dimethylpropyl)isoxazol-5-amine 209.0523-(3,3-Dimethylcyclobutyl)isoxazol-5-amine 167.1533-(4-Fluorobicyclo[2.2.2]octan-1-yl)isoxazol-5-amine 211.2543-(2,2-Difluorospiro[3.3]heptan-6-yl)isoxazol-5-amine 215.1553-(3,3-Difluorocyclobutyl)isoxazol-5-amine 175.1563-Spiro[2.3]hexan-5-ylisoxazole-5-amine 165.1573-(3-Bicyclo[1.1.1]pentanylmethyl)iso xazol-5-amine 165.1583-(3,5-Dichloropyridin-2-yl)-1,2-oxazol-5-amine 230593-(3-Chloropyridin-2-yl)isoxazol-5-amine 195.0603-(4-Methylpyridin-3-yl)-1,2-oxazol-5-amine 176.1 1< 613-(2-Methylpyridin-3-yl)-1,2-oxazol-5-amine 1< 623-(2,2-Dimethylcyclopropyl)isoxazol-5-amine 152633-Spiro[2.2]pentan-2-ylisoxazol-5-amine 151643-[(2,2-Difluorocyclopropyl)methyl]isox azol-5-amine 175653-Spiro[2.3]hexan-2-ylisoxazol-5-amine 165.3665-Spiro[2.3]hexan-2-ylisoxazol-3-amine 165.3673-(2,2-Dimethylcyclobutyl)isoxazol-5-amine 167685-(2,2-Dimethylcyclobutyl)isoxazol-3-amine 167 2< 693-[(1-Methylcyclobutyl)methyl]isoxaz ol-5-amine 166 2< 703-(3,3-Difluoro-1-methylcyclobutyl)isoxazol-5-amine 189 2< 713-(1,1-Difluoro-2,2-dimethylpropyl)isoxazol-5-amine 191723-(5-Amino-1,2-oxazol-3-yl)bicyclo[1.1.1]pentane-1-carbonitrile 176.3733-[4-(Trifluoromethyl)bicyclo[2.2.1]h eptan-1-yl]-1,2-oxazol-5-amine 247.2 1< No base is used and after work-up, the product is used without further purification, 2< After heating for 2 hr at 70-100 °C, c HCl (0.9 equiv) is added and the mixture is heated at 60-100 °C for 30 min-24 hr. The mixture is cooled to 0 °C and the pH adjusted to 9-11 with 30% aq NaOH or NaHCO 3 and worked up as above. Preparation 743-(3,3-dimethylcyclobutyl)-4-fluoro-isoxazol-5-amine

[0166]

[0167] To 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (0.46 g, 1.30 mmol) and 3-(3,3-dimethylcyclobutyl)isoxazol-5-amine (0.20 g, 1.20 mmol) in a sealed vial is added ACN (12 mL). The mixture is irradiated at 100 °C for 20 min under microwave conditions. The reaction is cooled to RT and concentrated under reduced pressure. The crude material is purified by reversed-phase chromatography (C18Aq column), eluting with a gradient of 0% to 100% ACN in H 2 O (0.1% HOAc). The desired fractions are combined and concentrated to remove ACN. To the remaining aqueous solution is added saturated aq. NaHCO 3 until a pH of 9 is reached. The mixture is extracted with DCM (2x10 mL). The organic extracts are combined, dried over anhydrous Na 2 SO 4 , diatomaceous earth is added, and the mixture is concentrated under vacuum. The material is further purified by silica gel chromatography, eluting with a gradient of 5% to 40% EtOAc in cyclohexane to give the title compound (48 mg, 22%). ES / MS (m / z) 185.3 (M+H).

[0168] The following compounds in Table 6 are prepared essentially as described for 3-(3,3-dimethylcyclobutyl)-4-fluoro-isoxazol-5-amine using the appropriate adjusting reaction time to determine completion of the reaction, and purification conditions as appropriate. Table 6Prep. No.Chemical nameStructureES / MS m / z (M+H)753-(2,2-Dimethylpropyl)-4-fluoro-isoxazol-5-amine 173.3764-Fluoro-3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-amine 183 Preparation 775-(2-Methylbutan-2-yl)-1,2-oxazol-3-amine

[0169]

[0170] To a stirred mixture of 4,4-dimethyl-3-oxohexanenitrile (3.00 g, 21.6 mmol) and hydroxylamine sulfate (3.89 g, 23.7 mmol) in MeOH (5 mL) and H 2 O (45 mL) is added NaHCO 3 (4.53 g, 53.9 mmol) in portions at RT under N 2 . The mixture is stirred for 5 hr at 65 °C under N 2 . The mixture is allowed to cool to RT. The mixture is acidified to pH 1 with conc. HCl and stirred for 20 min at reflux under N 2 . The mixture is allowed to cool to RT and the pH adjusted to 8 with NaOH. The mixture is extracted with DCM (3x200 mL). The combined organic extracts are washed with brine (2x200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 40% ACN in H 2 O (0.1% NH 4 HCO 3 ), to give the title compound (1.20 g, 36%) as a light yellow solid. 1< H NMR (CDCl 3 ) δ 5.53 (s, 1H), 1.66 (q, 2H), 1.27 (s, 6H), 0.82 (t, 3H).Preparation 785-(3,3-Dimethylcyclobutyl)isoxazol-3-amine

[0171]

[0172] To a sealed vial is added hydroxylamine HCl (0.79 g, 11.4 mmol) in MeOH (0.5 mL) and 7 M NH 3 in MeOH (2.0 mL, 14.0 mmol). The suspension is stirred at 25 °C for 30 min. A solution of 2-[2-(3,3-dimethylcyclobutyl)-1,3-dioxolan-2-yl]acetonitrile (0.56 g, 2.87 mmol) in MeOH (0.5 mL) and quinolin-8-ol (42 mg, 0.29 mmol) are added and the mixture is stirred at 65 °C for 12 hr and cooled to RT. The mixture is filtered, the filtrate is concentrated under reduced pressure, and re-concentrated from toluene (3x) to give the intermediate 2-[2-(3,3-dimethylcyclobutyl)-1,3-dioxolan-2-yl]-N'-hydroxy-acetamidine as a yellow solid which is used without further purification. In a sealed vial, 2-[2-(3,3-dimethylcyclobutyl)-1,3-dioxolan-2-yl]-N'-hydroxy-acetamidine is dissolved in EtOH (2 mL) and acidified to pH 1 with conc. HCl. The reaction mixture is stirred at 80 °C for 12 hr. The mixture is concentrated under reduced pressure and the residue is diluted with DCM. Saturated aq. NaHCO 3 is added until the solution is basic (pH 11). The organic layer is separated and the aqueous phase is extracted with DCM. The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 0% to 5% MeOH in DCM to give the title compound as a yellow solid (30 mg, 6.3%). ES / MS (m / z) 167 (M+H).Preparation 79Methyl 2-[2-methoxy-4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] acetate

[0173]

[0174] Methyl 2-(4-bromo-2-methoxy-phenyl)acetate (0.15 g, 0.579 mmol), bis(pinacolato)diboron (0.18 g, 0.709 mmol), KOAc (95%, 0.18 g, 1.74 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2) (95%, 22 mg, 0.029 mmol) and 1,4-dioxane (2.7 mL) are added together. The reaction mixture is stirred at 80 °C overnight. The reaction is quenched with H 2 O and DCM is added. The two layers are separated and the aqueous phase is extracted with DCM (3x10 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated under vacuum to give the title compound as a brown oil which is used crude without further purification. ES / MS (m / z) 307.2 (M+H).

[0175] The following compound in Table 7 is prepared essentially as described for methyl 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate using the appropriate reagents, adjusting reaction time to determine completion of the reaction and purifying by chromatography as appropriate. The reaction temperature can range from about 80-100 °C, filtered through talcum powder, and purified as appropriate. Table 7Prep No.Chemical NameStructureES / MS m / z (M+H)80Methyl 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] acetate 313 Preparation 81Methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)-3-chlorophenyl]acetate

[0176]

[0177] A solution of methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.00 g, 3.22 mmol), 5-amino-3-bromo-1-isopropylpyrazole-4-carbonitrile (0.73 g, 3.22 mmol), Pd(dppf)Cl 2 (0.47 g, 0.64 mmol), and K 3 PO 4 (2.05 g, 9.66 mmol) in 1,4-dioxane:H 2 O (12 mL, 5:1) is stirred for 2 hr at 120 °C under N 2 and cooled to RT. The solution is filtered through diatomaceous earth and washed with EtOAc (200 mL), filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 10% to 50% ACN in H 2 O, to give the title compound (0.30 g, 28%) as a white solid. ES / MS (m / z) 333.1 (M+H).

[0178] The following compound in Table 8 is prepared essentially as described for methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)-3-chlorophenyl]acetate, adjusting reaction time to determine completion of the reaction and purifying by titration or chromatography as appropriate. The reaction temperature can range from RT to 120 °C. Table 8Prep No.Chemical NameStructureES / MS m / z (M+H)82Ethyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-fluoro-phenyl]acetate 331.1 Preparation 83Methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)-2,3-difluorophenyl]acetate

[0179]

[0180] To a stirred mixture of methyl 2-(4-bromo-2,3-difluorophenyl)acetate (5.00 g, 18.9 mmol) and bis(pinacolato)diboron (5.75 g, 22.6 mmol) in 1,4-dioxane (30 mL) is added KOAc (3.70 g, 37.7 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (1.54 g, 1.88 mmol) at RT. The mixture is stirred for 1 hr at 80 °C under N 2 , filtered, and the filter cake is washed with 1,4-dioxane (5 mL). To the filtrate is added 5-amino-3-bromo-1-isopropylpyrazole-4-carbonitrile (4.75 g, 20.7 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (1.54 g, 1.88 mmol), K 2 CO 3 (5.21 g, 37.7 mmol) and H 2 O (7 mL) at RT. The mixture is stirred for 1 hr at 80 °C. The mixture is allowed to cool to RT and the residue is purified by silica gel chromatography, eluting with 3:1 to 2:1 PE:EtOAc to give the title compound (4.90 g, 78%) as a yellow solid. ES / MS (m / z) 335.1 (M+H).Preparation 84Benzyl 2-fluoro-4-(2-methoxy-2-oxoethyl)benzoate

[0181]

[0182] To a solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (5.45 g, 22.1 mmol), TEA (9.2 mL, 66.0 mmol) and benzyl alcohol (2.5 mL, 24.0 mmol) in toluene (150 mL) is added Pd(dppf)Cl 2 (0.32 g, 0.44 mmol) in a pressure tank. The mixture is purged with N 2 for 1 min and then is pressurized to 30 atm with CO. The mixture is stirred for 24 hr at 115 °C under a CO atmosphere. The mixture is allowed to cool to RT, filtered, and the filter cake is washed with EtOAc (2x50 mL). The filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with a gradient of 10:1 to 3:1 PE:EtOAc to give the title compound (2.63 g, 39%) as a colorless oil. ES / MS (m / z) 320.05 (M+NH 3 +H).Preparation 852-Fluoro-4-(2-methoxy-2-oxoethyl)benzoic acid

[0183]

[0184] To a solution of benzyl 2-fluoro-4-(2-methoxy-2-oxoethyl)benzoate (2.63 g, 8.70 mmol) in MeOH (25 mL) is added Pd / C (10%, 0.90 g, 0.85 mmol) at RT under N 2 . The mixture is stirred for 2 hr at RT under H 2 . The mixture is filtered, the filter cake is washed with MeOH (2x10 mL), and the filtrate is concentrated under reduced pressure to give the title compound (1.51 g, 82%) as a white solid which is used without further purification.Preparation 86Methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]acetate

[0185]

[0186] To a stirred solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (40.0 g, 206 mmol) and a few drops of DMF in DCM (300 mL) is added oxalyl chloride (21.2 mL, 247 mmol) dropwise at 0 °C. The mixture is stirred for 2 hr at RT. The mixture is concentrated under reduced pressure to give the intermediate methyl 2-(4-(chlorocarbonyl)phenyl)acetate. In another vessel, a solution of malononitrile (13.6 g, 206 mmol) in THF (100 mL) is added dropwise to a stirred suspension of NaH (16.5 g, 412 mmol, 60% in mineral oil) in THF (100 mL) at 0-10 °C under N 2 . The mixture is stirred for 20 min at RT. To this mixture is added methyl 2-(4-(chlorocarbonyl)phenyl)acetate in THF (200 mL) dropwise at 0-10 °C. The mixture is stirred for 1 hr at RT. Dimethyl sulfate (23.4 mL, 247 mmol) is added and the mixture is refluxed overnight at 80 °C under N 2 . H 2 O (300 mL) is added and the mixture is extracted with EtOAc (3x200 mL). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 4:1 to 1:1 PE:EtOAc to give the title compound (42.0 g, 80%) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.51-7.40 (m, 4H), 3.96 (s, 3H), 3.75 (s, 3H), 3.74 (s, 2H).Preparation 87Methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]acetate

[0187]

[0188] A solution of methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]acetate (2.50 g, 9.76 mmol) and isopropylhydrazine HCl (1.29 g, 11.7 mmol) and TEA (4.1 mL, 29.4 mmol) in EtOH (40 mL) is stirred for 1 hr at RT under N 2 . The mixture is concentrated under reduced pressure and extracted with EtOAc (3x100 mL). The combined organic extracts are washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by trituration with Et 2 O (50 mL) to give the title compound (2.00 g, 69%) as a yellow solid. ES / MS (m / z) 299.0 (M+H).Preparation 88Methyl 2-[4-(5-amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)-2-methoxy-phenyl]acetate

[0189]

[0190] Methyl 2-[2-methoxy-4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (67%, 0.21 g, 0.460 mmol), 5-amino-3-bromo-1-isopropyl-pyrazole-4-carboxamide (0.14 g, 0.567 mmol), K 2 CO 3 (0.13 g, 0.941 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (19 mg, 0.0231 mmol) are added together in a mixture of 1,4-dioxane (3.7 mL) and H 2 O (0.73 mL). The reaction is heated at 140 °C for 1 hr under microwave irradiation. The reaction mixture is filtered through diatomaceous earth, washed with EtOAc, and evaporated to dryness. The crude material is purified by silica gel chromatography, eluting with a gradient of 0% to 8% MeOH in DCM to give the title compound (0.17 g, quantitative yield). ES / MS (m / z) 347.2 (M+H).

[0191] The following compound in Table 9 is prepared essentially as described for methyl 2-[4-(5-amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)-2-methoxy-phenyl]acetate adjusting the reaction time to determine completion of the reaction and purification as appropriate. Table 9Prep. No.Chemical nameStructureES / MS m / z (M+H)89Methyl 2-[4-(5-amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)-2,6-difluoro-phenyl]acetate 353 Preparation 90tert-Butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate

[0192] Preparation 91tert-Butyl N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate

[0193]

[0194] To a stirred solution of 5-amino-1-isopropyl-pyrazole-4-carbonitrile (4.80 g, 32.0 mmol) in THF (205 mL) is added successively N,N-dimethylpyridin-4-amine (0.38 g, 3.11 mmol), TEA (13 mL, 93.3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (14.7 g, 67.4 mmol). The reaction mixture is stirred at RT overnight. The reaction mixture is quenched with saturated aq. NH 4 Cl (15 mL) and extracted with EtOAc (3x20 mL). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 2% to 30% EtOAc in cyclohexane to give tert-butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate as an off white solid (7.67 g, 68%), ES / MS (m / z) 373 (M+Na) and tert-butyl N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate as an off-white solid (1.12 g, 14%), ES / MS (m / z) 251 (M+H).Preparation 92Methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,3-difluorophenyl]acetate

[0195]

[0196] THF (4.8 mL) is added to tert-butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate (0.79 g, 2.25 mmol), bis(pinacolato)diboron (0.46 g, 1.81 mmol), [Ir(OMe)(1,5-cod)] 2 (31 mg, 0.047 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (26 mg, 0.093 mmol) under N 2 . The mixture is stirred at reflux for 4 hr. The reaction mixture is cooled to RT and concentrated under reduced pressure. The residue is dissolved in a mixture of 4:1 DCM:EtOAc (20 mL) and this solution is passed through a pad of silica gel (2 g). The pad is washed with 3:1 DCM:EtOAc (2x10 mL). The filtrates are combined, concentrated under reduced pressure, and dried under vacuum to give a crude residue. To the residue under N 2 is added Cs 2 CO 3 (2.14 g, 6.57 mmol) and methyl 2-(4-bromo-2,3-difluorophenyl)acetate (0.50 g, 1.89 mmol) in 1,4-dioxane (10 mL). Pd(dppf)Cl 2 )·CH 2 Cl 2 (0.10 g, 0.123 mmol) and 4Å molecular sieves are then added under Ar. The mixture is heated to 90 °C overnight. The mixture is cooled to RT, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate is diluted with H 2 O and the aqueous layer is extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 2% to 80% DCM in EtOAc to give the title compound (0.64 g, 94% purity, 73%) as a beige solid. ES / MS (m / z) 435 (M+H).Preparation 93Methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]phenyl]acetate

[0197]

[0198] To tert-butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate (4.50 g, 12.8 mmol), bis(pinacolato)diboron (2.61 g, 10.3 mmol), [Ir(Ome)(1,5-cod)] 2 (0.18 g, 0.267 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.15 g, 0.535 mmol) under N 2 is added THF (25 mL). The mixture is stirred at reflux for 4 hr. The mixture is cooled to RT and concentrated under reduced pressure. The residue is dissolved in a mixture of 4:1 DCM:EtOAc (20 mL) and the solution is passed through a pad of silica gel and washed with 3:1 DCM:EtOAc (2x10 mL). The filtrates are combined, concentrated under reduced pressure, and dried under vacuum to give a crude residue. To the residue under N 2 is added Cs 2 CO 3 (10.5 g, 32.2 mmol) and methyl (4-bromophenyl)acetate (2.50 g, 10.9 mmol) in 1,4-dioxane (50 mL). Pd(dppf)Cl 2 )·CH 2 Cl 2 (0.53 g, 0.642 mmol) and 4Å molecular sieves are then added under Ar. The mixture is heated to 90 °C for 12 hr, cooled to RT, diluted with EtOAc, and filtered through diatomaceous earth. To the filtrate is added H 2 O and the aqueous layer is extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude brown oil is purified by silica gel chromatography, eluting with a gradient of 2% to 80% DCM in EtOAc to give the title compound as a white solid (3.80 g, 87%). ES / MS (m / z) 399 (M+H).

[0199] The following compounds in Table 10 are prepared essentially as described for methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]phenylacetate using the appropriate reagents, adjusting reaction time to determine completion of the reaction and purifying by chromatography as appropriate. K 2 CO 3 can be substituted for Cs 2 CO 3 . Temperature can range from about 50-90 ° for the second coupling reaction. The mono and bis tert-butoxycarbonyl amino compounds can be isolated and both carried on to give a common product at a later step. Table 10Prep No.Chemical NameStructureES / MS m / z (M+H)94Methyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-3-fluorophenyl] acetate 517.495Ethyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-chloro-3-fluoro-phenyl]acetate 46596Ethyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2-chloro-3-fluoro-phenyl]acetate 56597Methyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-3-chloro-2-fluoro-phenyl]acetate 55198Methyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-3-methylphenyl] acetate 51299Methyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-3-chlorophenyl] acetate 533100Methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-3-chlorophenyl] acetate 433101Ethyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,5-difluorophenyl] acetate 449102Methyl 2-[4-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2,6-difluorophenyl] acetate 557 M+Na Preparation 1032-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]phenyl]acetic acid

[0200]

[0201] To a stirred solution of methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]phenyl]acetate (3.80 g, 9.54 mmol) in MeOH (40 mL) is added 2 M NaOH (14 mL, 28 mmol). The reaction mixture is stirred at 25 °C for 1 hr. The organic layer is concentrated. H 2 O is added and KHSO 4 (3.92 g, 28.8 mmol) in H 2 O is added dropwise. The precipitate formed is filtered, washed with H 2 O, and dried under vacuum to give the title compound (2.88 g, 79%) which is used without further purification. ES / MS (m / z) 385 (M+H).

[0202] The following compounds in Table 11 are prepared essentially as described for2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]phenyl]acetic acid and adjusting reaction time to determine completion of the reaction. 1,4-Dioxane can be substituted for MeOH, NH 4 Cl can be substituted for KHSO 4 and the product can be extracted from H 2 O if appropriate. The mono and bis tert-butoxycarbonyl amino compounds can be isolated and both carried on to give a common product at a later step. Table 11Prep. No.Chemical nameStructureES / MS m / z (M+H)1042-[4-(5-Amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)-2-methoxyphenyl]acetic acid 333.11052-[4-(5-Amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)-2,6-difluorophenyl]acetic acid 3391062-[4-Bromo-3-(methoxymethyl)phenyl]ac etic acid 283 M+Na1072-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-3-fluorophenyl]acetic acid 403.41082-[4-[5-[bis(tert-Butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-3-fluorophenyl]acetic acid 5031092-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-3-methylphenyl]acetic acid 3991102-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-3-chlorophenyl]acetic acid 4181112-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,6-difluorophenyl]acetic acid 421 Preparation 1122-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,3-difluorophenyl]acetic acid

[0203]

[0204] To methyl 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,3-difluoro-phenyl]acetate (0.64 g, 1.47 mmol) in 1,4-dioxane (6.5 mL) and H 2 O (2 mL) is added 1 M LiOH hydrate (4.4 mL, 4.40 mmol). The mixture is stirred at RT overnight. The reaction mixture is concentrated and poured into H 2 O and washed with EtOAc. The aqueous layer is acidified with 1 M aq. KHSO 4 to pH 2-3 then extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound as a beige solid (0.54 g, 94% purity, 82%). ES / MS (m / z) 421 (M+1).Preparation 113Methyl 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoate

[0205]

[0206] To a stirred solution of [4-(methoxycarbonyl)phenyl]acetic acid (20.0 g, 103 mmol) and 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (17.5 g, 113 mmol) and DIPEA (89.5 mL, 514 mmol) in DMF (200 mL) is added T3P ®< (328 g, 515 mmol, 50% in DMF) in portions at 0 °C. The mixture is stirred for 2 hr at 50 °C. To the mixture is added EtOAc (1 L). The mixture is washed with H 2 O (3x300 mL). The organic layer is separated, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 8:1 to 4:1 PE:EtOAc to give the title compound (31.0 g, 91%) as a light yellow solid. ES / MS (m / z) 331.2 (M+H).

[0207] The following compounds in Table 12 are prepared essentially as described for methyl 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoate using the appropriate reagents, adjusting the reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification or used without further purification. The reaction temperature can range from RT to 100 °C. T3P ®< can be added in DCM instead of DMF. Table 12Prep No.Chemical NameStructureES / MS m / z (M+H)114Methyl 4-([[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoate 389.2115Methyl 4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1]he ptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]benzoate 423.1116Methyl 4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]benzoate 341.3 Preparation 1174-([[3-(2,2-Dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoic acid

[0208]

[0209] To a stirred solution of methyl 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoate (31.0 g, 93.8 mmol) in THF (240 mL) and H 2 O (80 mL) is added LiOH (11.2 g, 468 mmol) in portions at RT. The mixture is stirred overnight. The mixture is acidified to pH 5 with 2 N HCl and extracted with EtOAc (3x200 mL). The combined organic extracts are washed with brine (3x50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (28.5 g, 96%) as a white solid. ES / MS (m / z) 317.2 (M+1).

[0210] The following compounds in Table 13 are prepared essentially as described for 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoic acid using the appropriate ester, adjusting the reaction time to determine completion of the reaction, adjusting the pH to 1-5 after completion, and collecting by extraction or precipitation as appropriate. A solvent mixture of 1,4-dioxane / H 2 O or MeOH / H 2 O can be used if needed for solubility and the temperature can range from about RT to 50 °C. 1 M NaOH can be substituted for LiOH and citric acid or KHSO 4 can be substituted for HCl. Table 13Prep. No.Chemical nameStructureES / MS m / z (M+H)1184-([[3-(2-Chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoi c acid 375.11194-[([3-[4-(Trifluoromethyl)bicyclo[2. 2.1]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]benzoi c acid 409.11202-[4-Bromo-3-(tert-butoxymethyl)phenyl]acetic acid 323.1 M+Na1212-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-chloro-3-fluorophenyl]acetic acid 4371222-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-3-chloro-2-fluorophenyl]acetic acid 4371232-[4-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,5-difluorophenyl]acetic acid 4211244-[[(3-[3-Methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]benzoi c acid 327.1

[0211] The following compounds in Table 14 are prepared essentially as described for methyl 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoate using the appropriate reagents, adjusting the reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification or used without further purification. The reaction temperature can range from RT to 100 °C. T3P ®< can be added in DCM or EtOAc instead of DMF. Table 14Prep No.Chemical NameStructureES / MS m / z (M+H)1252-[4-Bromo-3-(methoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide 4071262-[4-Bromo-2-(methoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide 4081272-[4-Bromo-2-(tert-butoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide 4491282-[4-Bromo-3-(tert-butoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide 449.2 Preparation 1292-[4-Bromo-2-(hydroxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide

[0212]

[0213] To TFA (16.6 mL), (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (5.42 g, 25.8 mmol) and triethylsilane (1.0 mL, 6.26 mmol) under N 2 is added 2-[4-bromo-2-(tert-butoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide (0.29 g, 0.645 mmol) in DCM (8.29 mL). The reaction is stirred for 4 hr. The reaction mixture is concentrated under reduced pressure and dried under vacuum. The material is dissolved in THF (9 mL) and H 2 O (4.5 mL). Saturated aq. NaHCO 3 (4 mL) is added and the mixture is stirred at RT for 1 hr. THF is removed under vacuum. The mixture is diluted with DCM (10 mL) and the organic layer is separated, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM to give the title compound (0.20 g, 79%). ES / MS (m / z) 394 (M+H).Preparation 1305-Amino-3-[2-(tert-butoxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide

[0214]

[0215] To bis(pinacolato)diboron (93 mg, 0.366 mmol), 2-[4-bromo-3-(tert-butoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide (0.15 g, 0.334 mmol), KOAc (0.11 g, 1.12 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (28 mg, 0.033 mmol) under N 2 is added dry THF (4 mL). The reaction mixture is degassed with Ar for 15 min and then heated to 50 °C. The reaction is stirred at 50 °C overnight, at 65 °C for a second night and then at 80 °C for 24 hr. The reaction mixture is cooled to RT. 5-Amino-3-bromo-1-isopropyl-pyrazole-4-carboxamide (0.11 g, 0.445 mmol) in THF (1.3 mL) and K 3 PO 4 (0.22 g, 1.04 mmol) in H 2 O (1.3 mL) are added. The reaction mixture is degassed with Ar and XantPhos Pd G3 (17 mg, 0.0167 mmol) is added. The mixture is heated to 50 °C overnight. The mixture is filtered through a pad of talcum powder; H 2 O is added to the filtrate and the mixture is extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM to give the title compound as a brown powder (67 mg, 37%). ES / MS (m / z) 537 (M+H).Preparation 1312-[4-(2,2-Dicyano-1-hydroxyeth-1-en-1-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide

[0216]

[0217] To a stirred solution of 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoic acid (32.0 g, 101 mmol) and DMF (0.16 mL, 2.14 mmol) in DCM (350 mL) is added oxalyl chloride (10.6 mL, 124 mmol) dropwise at 0 °C. The mixture is stirred for 2 hr at RT. The mixture is concentrated under reduced pressure to give crude 4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoyl chloride. To a solution of malononitrile (6.31 g, 95.5 mmol) in THF (100 mL) is added NaH (7.65 g, 191 mmol, 60% in mineral oil) at 0 °C. The mixture is stirred for 15 min. 4-([[3-(2,2-Dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)benzoyl chloride (32.0 g, 95.6 mmol) in THF (150 mL) is added dropwise to the 0 °C solution and the mixture is stirred for 2 hr and allowed to warm to RT. The mixture is diluted with H 2 O (300 mL), acidified to pH 5 with 2 N HCl, and extracted with EtOAc (3x200 mL). The combined organic extracts are washed with brine (3x100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (30.0 g, 82%). The crude product is used directly without further purification. ES / MS (m / z) 365.1 (M+H).

[0218] The following compounds in Table 15 are prepared essentially as described for 2-[4-(2,2-dicyano-1-hydroxyeth-1-en-1-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide under N 2 if desired and adjusting the reaction time to determine completion of the reactions. The malononitrile in THF and NaH can be stirred from 15-30 min at 0 ° to RT. The reaction can be acidified or concentrated to dryness and purified by chromatography as appropriate. Table 15Prep. No.Chemical nameStructureES / MS m / z (M+H)132N-[3-(2-Chloro-4-fluorophenyl)-1,2-oxazol-5-yl]-2-[4-(2,2-dicyano-1-hydroxyeth-1-en-1-yl)phenyl]acetamide 423.11332-[4-(2,2-Dicyano-1-hydroxyeth-1-en-1-yl)phenyl]-N-[3-[4-(trifluoromethyl)bicyclo[2.2. 1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 457134Methyl 2-(4-(2,2-dicyano-1-hydroxyvinyl)-3-fluorophenyl)acetate 1352-[4-(2,2-Dicyano-1-hydroxyeth-1-en-1-yl)phenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide 375.3 Preparation 1362-[4-(2,2-Dicyano-1-methoxyeth-1-en-1-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide

[0219]

[0220] To a stirred solution of 2-[4-(2,2-dicyano-1-hydroxyeth-1-en-1-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide (25.0 g, 68.6 mmol) and TEA (28.7 mL, 206 mmol) in ACN (240 mL) is added dimethyl sulfate (39.0 mL, 411 mmol) dropwise at RT under N 2 . The mixture is stirred for 14 hr at 50 °C under N 2 . The mixture is diluted with EtOAc (500 mL), washed with brine (3x50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 8:1 to 2:1 PE:EtOAc to give the title compound (9.0 g, 35%) as a light yellow solid. ES / MS (m / z) 379.1 (M+H).

[0221] The following compounds in Table 16 are prepared essentially as described for 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide adjusting the reaction time to determine completion of the reaction and purification as appropriate. The temperature can range from about 50 °C to 80 °C. Table 16Prep. No.Chemical nameStructureES / MS m / z (M+H)137N-[3-(2-Chloro-4-fluorophenyl)-1,2-oxazol-5-yl]-2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]acetamide 437.11382-[4-(2,2-Dicyano-1-methoxyeth-1-en-1-yl)phenyl]-N-[3-[4-(trifluoromethyl)bicycl o[2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 471.2139Methyl 2-(4-(2,2-dicyano-1-methoxyvinyl)-3-fluorophenyl)acetate 292.2, M+NH 3 + H1402-[4-(2,2-Dicyano-1-methoxyeth-1-en-1-yl)phenyl]-N-(3-[3-methylbicyclo[1.1.1]pe ntan-1-yl]-1,2-oxazol-5-yl)acetamide 389.1 Preparation 141Methyl 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetate

[0222]

[0223] To a stirred mixture of (1-methylcyclopropyl)hydrazine HCl (crude, 2.00 g, 16.3 mmol) and TEA (1.6 mL, 11.5 mmol) in EtOH (20 mL) is added methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]acetate (0.48 g, 1.87 mmol) in portions at RT under N 2 . The mixture is stirred for 2 hr at 50 °C under N 2 . The mixture is allowed to cool to RT and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 50% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (0.50 g, 86%) as a white solid. ES / MS (m / z) 311.3 (M+H).

[0224] The following compounds in Table 17 are prepared essentially as described for methyl 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetate using the appropriate reagents, adjusting reaction time to determine completion of the reaction and purifying by chromatography as appropriate. The reaction temperature can range from RT to 80 °C, the solvent can be THF if appropriate, and the base can be DIPEA or TEA. Table 17Prep No.Chemical NameStructureES / MS m / z (M+H)142Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3 -yl]phenyl] acetate 367.2143Methyl 2-[4-[5-amino-4-cyano-1-(1-methoxy-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]acetate 343.3144Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)pyrazol-3-yl]phenyl]acetate 353.2145Methyl 2-[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]acetate 339.1146Methyl 2-[4-(5-amino-4-cyano-1-cyclobutylpyrazol-3-yl)phenyl] acetate 311.21472-[4-[5-Amino-4-cyano-1-(1-hydroxypropan-2-yl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide 447.31482-[4-[5-Amino-4-cyano-1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide 461.2149Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3 -yl]phenyl] acetate 367.1150Methyl 2-[4-(5-amino-1-tert-butyl-4-cyanopyrazol-3-yl)phenyl] acetate 313.21512-(4-(5-Amino-4-cyano-1-cyclopentyl-1H-pyrazol-3-yl)phenyl)acetate 325152Methyl 2-(4-(5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetate 375.1 M+Na153Methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl] acetate 299154Methyl 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-3-fluorophenyl)acetate 329.1 Preparation 1552-(4-(5-Amino-4-cyano-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide

[0225]

[0226] 2-Hydrazino-2-methylpropan-1-ol HCl (43 mg, 0.306 mmol), EtOH (1.5 mL), TEA (0.12 mL, 0.861 mmol), and 2-(4-(2,2-dicyano-1-methoxyvinyl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide (0.11 g, 0.291 mmol) are added together and stirred for 18 hr at 45 °C. The mixture is diluted with H 2 O (1 mL) and extracted with EtOAc (3×3 mL). The organic extracts are concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes to give the title compound (39 mg, 30%) as a white solid. ES / MS (m / z) 451.3 (M+H).

[0227] The following compounds in Table 18 are prepared essentially as described for 2-(4-(5-amino-4-cyano-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide using the appropriate hydrazine from 1-3 equivalents, adjusting reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction temperature can range from RT to 45 °C, and THF can be substituted for the solvent based on solubility. Table 18Prep. No.Chemical nameStructureES / MS m / z (M+H)1562-(4-(5-Amino-4-cyano-1-(1-cyclopropylethyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 447.21572-(4-(5-Amino-4-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 449.21582-(4-(5-Amino-4-cyano-1-cyclopentyl-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 447.21592-(4-(5-Amino-4-cyano-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 463.21602-(4-(5-Amino-4-cyano-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 463.21612-(4-(5-Amino-4-cyano-1-((1R,3R)-3-ethoxycyclobutyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 477.21622-(4-(5-Amino-4-cyano-1-(3-hydroxypropyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 437.21632-(4-(5-Amino-4-cyano-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 463.21642-(4-(5-Amino-4-cyano-1-(1-hydroxypropan-2-yl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 437.21652-(4-(5-Amino-1-(tert-butyl)-4-cyano-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 435.21662-[4-(5-Amino-4-cyano-1-cyclopropyl-pyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)isoxazol-5-yl]acetamide 419.21672-(4-(5-Amino-1-(bicyclo[1.1.1]pentan-1-yl)-4-cyano-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 445.21682-(4-(5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 461.11692-[4-[5-Amino-4-cyano-1-(1-hydroxypropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]acetamide 495.11702-[4-[5-Amino-4-cyano-1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]acetamide 509.31712-[4-[5-Amino-4-cyano-1-(1-hydroxypropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-[4-(trifluoromethyl)bicyclo[2.2. 1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 529.11722-[4-[5-Amino-4-cyano-1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-[4-(trifluoromethyl)bicyclo[2.2. 1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 543.4 Preparation 1732-(4-(5-Amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid

[0228]

[0229] To a mixture of methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]acetate (7.40 g, 24.8 mmol), NaOH (5.96 g, 149 mmol), H 2 O (24 mL), DMSO (12 mL) and EtOH (60 mL) is added H 2 O 2 (38.0 mL, 372 mmol, 30% in H 2 O) at RT. The mixture is heated to 40 °C and stirred for 6 hr. The mixture is quenched with saturated aq. Na 2 S 2 O 3 and adjusted to pH 4 with dilute aq. HCl. The mixture is extracted with EtOAc (3x200 mL). The combined organic extracts are concentrated under reduced pressure and the resulting solid is triturated with EtOAc (20 mL). The precipitated solid is collected by filtration, washed with water (3x60 mL), and dried under reduced pressure to give the title compound (4.30 g, 57%) as a yellow solid. ES / MS (m / z) 303.1 (M+H).Preparation 1742-(4-(5-Amino-4-carbamoyl-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid

[0230]

[0231] To a stirred mixture of methyl 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetate (0.50 g, 1.61 mmol) and NaOH (0.32 g, 8.00 mmol) in EtOH / H 2 O / DMSO (5 mL / 2 mL / 1 mL) is added H 2 O 2 (2.43 mL, 23.8 mmol, 30% in H 2 O) dropwise at RT under N 2 . The mixture is stirred overnight at 50°C. The reaction is quenched with saturated aq. Na 2 SO 3 (10 mL) at RT. The residue is adjusted to pH 4 with 1 N aq. HCl and extracted with EtOAc (5x50 mL). The combined organic extracts are washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate is concentrated under reduced pressure. The resulting solid is triturated with EtOAc (10 mL) and the precipitated solids are collected by filtration and washed with EtOAc (3x5 mL) to give the title compound (0.20 g, 40%) as a white solid. ES / MS (m / z) 315.2 (M+H).

[0232] The following compounds in Table 19 are prepared essentially as described for2-(4-(5-amino-4-carbamoyl-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid, adjusting the reaction time to determine completion of the reaction and purifying by titration or chromatography as appropriate. The reaction temperature can range from about RT to 50 °C and about 15-30 equiv of H 2 O 2 can be used. The reagents can also be added together at about 0 °C. Table 19Prep No.Chemical NameStructureES / MS m / z (M+H)175[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)-3-chlorophenyl]acetic acid 337.1176[4-(5-Amino-1-tert-butyl-4-carbamoylpyrazol-3-yl)phenyl]acetic acid 317.11772-(4-(5-Amino-4-carbamoyl-1-cyclopentyl-1H-pyrazol-3-yl)phenyl)acetic acid 3291782-(4-(5-Amino-4-carbamoyl-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetic acid 357.1179[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)-2-fluorophenyl]acetic acid 321.1 Preparation 1802-(4-(5-Amino-4-carbamoyl-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetic acid, Isomer 1

[0233] Preparation 1812-(4-(5-Amino-4-carbamoyl-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetic acid, Isomer 2

[0234] 2-(4-(5-Amino-4-carbamoyl-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetic acid (0.500 g, 1.40 mmol) is separated by Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 µm; mobile phase A: hexanes (0.1% TFA), Mobile Phase B: IPA with a flow rate of 20 mL / min eluting with 25% B in 12.5 min; to give the title compound of Isomer 1 as a light yellow solid t (R) 6.7 min, (0.240 g, 48%), ES / MS (m / z) 357.1 (M+H), [α] D 25< = -15.789 (C=0.304, MeOH) and Isomer 2 as a light yellow solid t (R) 9.5 min (0.210 g, 42%), ES / MS (m / z) 357.1 (M+H), [α] D 25< = 17.197 (C=0.314, MeOH).Preparation 1822-[4-(1-Isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)phenyl]acetic acid

[0235]

[0236] To 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.100 g, 0.331 mmol) in acetone (5 mL) is added TFA (0.005 mL). The mixture is stirred for 2 hr at 50 °C, concentrated under reduced pressure, and dried under vacuum to give the title compound as a yellow solid (0.113 g, 100%) which is used without further purification. ES / MS (m / z) 343.2 (M+H).

[0237] The following compounds in Table 20 are prepared essentially as described for 2-[4-(1-isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)phenyl]acetic acid and adjusting reaction time to determine completion of the reaction. Table 20Prep No.Chemical NameStructureES / MS m / z (M+H)1832-[4-(1-Isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]acetic acid; ½ TFA 373.2 1< 1842-[2,6-Difluoro-4-(1-isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)phenyl]acetic acid 379 1< Ethoxyethane HCl is substituted for TFA and the mixture is stirred at RT for 30 min. Preparation 1852-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid

[0238]

[0239] A solution of methyl 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetate (4.30 g, 13.9 mmol) and LiOH (1.66 g, 69.3 mmol) in THF (40 mL) and H 2 O (10 mL) is stirred for 3 hr at RT under N 2 . The mixture is concentrated under reduced pressure, diluted with H 2 O (10 mL) and acidified to pH 3 with 1 N aq. HCl. The precipitated solids are collected by filtration and washed with H 2 O (3x30 mL) to give the title compound (4.00 g, 97%) as a white solid. ES / MS (m / z) 297.3 (M+H).

[0240] The following compounds in Table 21 are prepared essentially as described for 2-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid using the appropriate ester, adjusting the reaction time to determine completion of the reaction, adjusting the pH to 1-5 after completion, and collecting by extraction or precipitation as appropriate. A solvent mixture of 1,4-dioxane / H 2 O or MeOH / H 2 O can be used if needed for solubility and the temperature can range from about RT to 50 °. 1 M NaOH can be substituted for LiOH and citric acid or KHSO 4 can be substituted for HCl. Table 21Prep. No.Chemical nameStructureES / MS m / z (M+H)186[4-[5-Amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]acetic acid: 353.11872-[4-[5-Amino-4-cyano-1-(2-methoxy-1,1-dimethylethyl)pyrazol-3-yl]phenyl]acetic acid 329.21882-[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methylethyl)pyrazol-3-yl]phenyl]acetic acid 339.2 M+Na189[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]acetic acid 325.1190[4-(5-Amino-4-cyano-1-cyclobutylpyrazol-3-yl)phenyl]acetic acid 297.21914-[5-Amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]acetic acid 353.2192[4-(5-Amino-1-tert-butyl-4-cyanopyrazol-3-yl)phenyl]acetic acid 299.2193[4-(5-Amino-1-tert-butyl-4-cyanopyrazol-3-yl)phenyl]acetic acid 299.21942-(4-(5-Amino-4-cyano-1-cyclopentyl-1H-pyrazol-3-yl)phenyl)acetic acid 3111952-(4-(5-Amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-3-yl)phenyl)acetic acid 339.2196[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)-2-fluorophenyl]acetic acid 303.21972-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-3-fluorophenyl)acetic acid 315.2198[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)-2,3-difluorophenyl]acetic acid 321.1199[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]acetic acid 285.1 Preparation 2002-[(4-Bromo-2,3-difluorophenyl)(methoxy)methylidene]propanedinitrile

[0241]

[0242] NaH (1.67 g, 41.8 mmol, 60% in mineral oil) and malononitrile (1.37 g, 20.7 mmol) are added to THF (50 mL) at 0 °C. The mixture is stirred for 30 min at 0 °C under N 2 . To this mixture is added 4-bromo-2,3-difluorobenzoyl chloride (5.30 g, 20.7 mmol) in THF (10 mL) dropwise at 0 °C. The mixture is stirred for 1 hr at RT. The intermediate mixture of 2-[(4-bromo-2,3-difluoro-phenyl)-hydroxy-methylene]propanedinitrile is used directly without further purification. ES / MS (m / z) ( 79< Br / 81< Br) 282.9 / 284.9 (M-H). Dimethyl sulfate (2.4 mL, 25.3 mmol) is added to the solution of 2-[(4-bromo-2,3-difluoro-phenyl)-hydroxymethylene]propanedinitrile (theoretical 5.90 g, 20.7 mmol) in THF (60 mL). The mixture is stirred overnight at reflux under N 2 . The solution is cooled to RT and concentrated under reduced pressure. The crude product is dissolved in EtOAc (200 mL) and diluted with H 2 O (200 mL) and extracted with EtOAc (3x300 mL). The organic extracts are washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography, eluting with a gradient of 3:1 to 2:1 PE:EtOAc to give the title compound (3.00 g, 48%) as a yellow solid.Preparation 2015-Amino-3-(4-bromo-2,3-difluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

[0243]

[0244] A solution of 2-[(4-bromo-2,3-difluorophenyl)(methoxy)methylidene]propanedinitrile (2.50 g, 8.36 mmol), (1-methylcyclopropyl)hydrazine HCl (3.07 g, 25.0 mmol), and TEA (5.8 mL, 41.6 mmol) in THF (30 mL) is stirred for 1 hr at RT under N 2 . The reaction is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with a gradient of 3:1 to 2:1 PE:EtOAc to give the title compound (2.50 g, 85%) as a light yellow solid. ES / MS (m / z) ( 79< Br / 81< Br) 353.1 / 355.1 (M+H).Preparation 202tert-Butyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]acetate

[0245]

[0246] A solution of 5-amino-3-(4-bromo-2,3-difluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile (1.80 g, 5.10 mmol), tert-butyl 2-(bromozincio)acetate (3.98 g, 15.3 mmol) and Pd(t-Bu 3 P) 2 (0.26 g, 0.509 mmol) in THF (20 mL) is stirred for 1 hr at 80 °C under N 2 and allowed to cool to RT. The solution is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with a gradient of 2:1 to 1:1 PE:EtOAc to give the title compound (0.50 g, 25%) as a yellow solid. ES / MS (m / z) 389.2 (M+H).Preparation 2032-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluoro-phenyl]acetic acid

[0247]

[0248] A solution of tert-butyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]acetate (0.49 g, 1.26 mmol) and TFA (5 mL) in DCM (10 mL) is stirred for 2 hr at RT under N 2 and concentrated under reduced pressure. The mixture is diluted with Et 2 O (20 mL) and concentrated under reduced pressure to give the title compound (0.40 g, 96%) as a yellow solid. ES / MS (m / z) 333.1 (M+H).Preparation 2042-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]-N-(3-[3-fluorobicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide

[0249]

[0250] A solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluoro-phenyl]acetic acid (80 mg, 0.241 mmol), 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine (49 mg, 0.291 mmol), DIPEA (0.25 mL, 1.44 mmol), and T3P ®< (0.46 g, 0.723 mmol, 50% in EtOAc) in DCM (3.00 mL) is stirred for 1 hr at 50 °C under N 2 . The mixture is cooled to RT and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 40% to 60% ACN in H 2 O (0.1% FA) to give the title compound (60 mg, 52%) as a yellow solid. ES / MS (m / z) 483.1 (M+H).Preparation 2052-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide

[0251]

[0252] To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluoro-phenyl]acetic acid (80 mg, 0.241 mmol), 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (47 mg, 0.286 mmol) and DIPEA (0.13 mL, 0.746 mmol) in DCM (3 mL) is added T3P ®< (0.46 g, 0.723 mmol, 50% in EtOAc). The reaction is stirred for 2 hr at 50 °C in a sealed tube. The mixture is cooled to RT and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 40% to 60% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (70 mg, 61%) as a white solid. ES / MS (m / z) 479.1 (M+H).Preparation 2062-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)-N-(3-(2-chloro-4-fluorophenyl)isoxazol-5-yl)acetamide

[0253]

[0254] 2-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid (60 mg, 0.202 mmol) is dissolved in DCM (0.41 mL) and treated with 3-(2-chloro-4-fluorophenyl)isoxazol-5-amine (47 mg, 0.221 mmol), T3P ®< (0.77 g, 1.21 mmol, 50% in EtOAc), and DIPEA (0.21 mL, 1.18 mmol) at 0 °C. The mixture is stirred for about 20 min, evaporated to dryness, and used without further purification. ES / MS (m / z) 491.1 (M+H).Preparation 2072-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(pyridin-2-yl)-1,2-oxazol-5-yl]acetamide

[0255]

[0256] To a stirred mixture of [4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]acetic acid (0.100 g, 0.352 mmol) and 3-(pyridin-2-yl)-1,2-oxazol-5-amine (62 mg, 0.385 mmol) in DCM (3 mL) is added T3P ®< (0.337 g, 0.530 mmol, 50% in EtOAc) and DIPEA (0.31 mL, 1.78 mmol). The mixture is stirred for 2 hr at RT and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 10% to 50% ACN in H 2 O (0.1% FA) to give the title compound (70 mg, 47%) as a light yellow solid. ES / MS (m / z) 428.2 (M+H).

[0257] The following compounds in Table 22 are prepared essentially as described for 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(pyridin-2-yl)-1,2-oxazol-5-yl]acetamide using the appropriate amine and carboxylic acid with a coupling reagent, about 1-6 equivalents, base, about 1-4 equiv, and solvent, about 0.3-6 mL, adjusting the reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction temperature can range from -20 °C to 50 °C, T3P ®< can be added in 50% EtOAc, 50% DMF, or 50% MeTHF. TCFH can be added in portions and the reaction can be done under N 2 and in a sealed tube. *Coupling reagents: 1 T3P ®< , 2 TCFH, 3 BTFFH, 4 COMU ®< , 5 TBTU, 6 TFFH, 7 HATU 8 EDCI / HOBT Bases: a NMI, b pyridine, c DIPEA Solvents: I EtOAc, II ACN, III DMF, IV DCM, V MeTHF Table 22 Prep. No.Chemical nameStructureES / MS m / z (M+H)*2082-(4-(5-Amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl)-N-(3-(3,3,3-trifluoro-2,2-dimethylpropyl)isoxazol -5-yl)acetamide 474.91, b, I2092-(4-(5-Amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl)-N-(3-(4-fluorobicyclo[2.2.2]octa n-1-yl)isoxazol-5-yl)acetamide 477.21, b, I2102-(4-(5-Amino-4-cyano-1-cyclobutyl-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 433.21, c, III2112-(4-(5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 461.11, c, III2122-(4-(5-Amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl)-N-(3-benzylisoxazol-5-yl)acetamide 441.11, c, III2132-(4-(5-Amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl)-N-(3-(bicyclo[1.1.1]pentan-1-ylmethyl)isoxazol-5-yl)acetamide 431.21, b, I & III2142-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)-N-(3-neopentylisoxazol-5-yl)acetamide 433.21, c, III2152-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[5-(2-methylbutan-2-yl)-1,2-oxazol-3-yl]acetamide 421.21, c, IV2162-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(3,5-dichloropyridin-2-yl)-1,2-oxazol-5-yl]acetamide 496.11, c, IV2172-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[5-(2,2-dimethylpropyl)-1,2-thiazol-3-yl]acetamide 437.12, a, II2192-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[5-(2,2-dimethylpropyl)-1,3-thiazol-2-yl]acetamide 437.11, c, IV2192-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[5-(2,2-dimethylpropyl)-4-methyl-1,3-thiazol-2-yl]acetamide 451.12, a, II2202-[4-[5-Amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide 489.31, c, IV2212-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]phenyl]-N-[3-(3,3-dimethylcyclobutyl)-1,2-oxazol-5-yl]acetamide 445.41, c, IV2222-(4-(5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)-N-(5-neopentylisoxazol-3-yl)acetamide 433.21, c, IV2232-[4-[5-Amino-4-cyano-1-(1-methoxy-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide 487.2 M+Na1, c, IV2242-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]acetamide 497.31, c, IV2252-[4-[5-Amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]acetamide 539.21, c, IV2262-(4-(5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenyl)-N-(3-(3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl)isoxazol-5-yl)acetamide 525.21, c, IV2272-[4-(5-amino-4-cyano-1-cyclobutylpyrazol-3-yl)phenyl]-N-[3-[3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]acetamide 497.21, c, IV2282-[4-[5-Amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pen tan-1-yl]-1,2-oxazol-5-yl)acetamide 499.21, c, IV2292-[4-(5-Amino-1-tert-butyl-4-cyanopyrazol-3-yl)phenyl]-N-(3-[3-methylbicyclo[1.1.1]pen tan-1-yl]-1,2-oxazol-5-yl)acetamide 445.31, c, IV2302-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]phenyl]-N-[3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 525.21, c, IV2312-[4-[5-Amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]-N-[3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 581.11, c, IV2322-[4-(5-Amino-1-tert-butyl-4-cyanopyrazol-3-yl)phenyl]-N-[3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 527.31, c, IV2332-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-3-fluorophenyl)-N-(3-(3-methylbicyclo[1.1.1]pen tan-1-yl)isoxazol-5-yl)acetamide 461.11, c, IV2342-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-3-fluorophenyl)-N-(3-(3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl)isoxazol-5-yl)acetamide 515.11, c, IV2352-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]-2,3-difluorophenyl]-N-[3-[3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]acetamide 533.21, c, IV2362-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]-2,3-difluorophenyl]-N-[3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 561.11, c, IV2372-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-3-fluorophenyl)-N-(3-(4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl)isoxazol-5-yl)acetamide 543.11, c, IV2382-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)-2,3-difluorophenyl]-N-[3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]acetamide 549.31, c, IV2392-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)-2,3-difluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pen tan-1-yl]-1,2-oxazol-5-yl)acetamide 467.21, c, IV2402-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyra zol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pen tan-1-yl]-1,2-oxazol-5-yl)acetamide 443.21, c, IV2412-(4-(5-Amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl)-N-(3-(1,1-difluoroethyl)isoxazol-5-yl)acetamide 415.21, c, IV2422-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]acetamide 421.11, c, IV243tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylcyclopropyl)iso xazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5181, b, V244tert-Butyl N-[4-cyano-2-isopropyl-5-[4-[2-oxo-2-[(3-spiro[2.2]pentan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]p yrazol-3-yl]carbamate 5171, b, V245tert-Butyl N-[4-cyano-5-[4-[2-[[3-[(2,2-difluorocyclopropyl)met hyl]isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5411, b, V246tert-Butyl N-[4-cyano-5-[4-[2-[[3-(3,3-difluorocyclopentyl)iso xazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5551, b, V247tert-Butyl N-[4-cyano-2-isopropyl-5-[4-[2-oxo-2-[(3-spiro[2.3]hexan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]p yrazol-3-yl]carbamate 531.51, b, V248tert-Butyl N-[4-cyano-2-isopropyl-5-[4-[2-oxo-2-[(5-spiro[2.3]hexan-2-ylisoxazol-3-yl)amino]ethyl]phenyl]p yrazol-3-yl]carbamate 5311, b, V249tert-Butyl N-[4-cyano-5-[4-[2-[[5-(2,2-dimethylcyclobutyl)isox azol-3-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5331, b, V250tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylcyclobutyl)isox azol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 533.51, b, V2512-[4-(1-Isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-N-[5-[1-(trifluoromethyl)cyclopr opyl]isoxazol-3-yl]acetamide 517.41, c, III2522-[4-(1-Isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-phenyl]-N-[5-(1-methylcyclopentyl)isox azol-3-yl]acetamide 5201, c, III2532-[2,6-Difluoro-4-(1-isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-N-[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]acetamide 5551, c, III254N-[3-(2,4-Dichlorophenyl)isoxazo 1-5-yl]-2-[4-(1-isopropyl-6,6-dimethyl-4-oxo-5,7-dihydropyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]acetamide 5831,c, III255tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-2-fluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5391, b, V256tert-Butyl N-[5-[3-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-2-fluoro-phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 573.41, b, V257tert-Butyl N-[5-[2-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-3-fluoro-phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 573.41, b, V258tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-2-methylphenyl]-2-isopropyl-pyrazol-3-yl]carbamate 535.51, c, III259tert-Butyl N-[4-cyano-5-[4-[2-[[3-(cyclobutylmethyl)isoxa zol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 519.41, c, III260tert-Butyl N-[5-[2-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 555.41, c, III261tert-Butyl N-[4-cyano-2-isopropyl-5-[4-[2-[[3-[(1-methylcyclobutyl)methy l]isoxazol-5-yl]amino]-2-oxoethyl]phenyl]pyrazol-3-yl]carbamate 533.51, b, V262tert-Butyl N-[4-cyano-5-[4-[2-[[3-(3,3-difluoro-1-methylcyclobutyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5551, b, V263tert-Butyl N-[4-cyano-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)isox azol-5-yl]amino]-2-oxoethyl]-2-fluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 551.51, b, V264tert-Butyl N-[5-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isox azol-5-yl]amino]-2-oxoethyl]phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 567.41, b, V265tert-Butyl N-[5-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isox azol-5-yl]amino]-2-oxoethyl]-3-fluoro-phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 585.41, b, V266tert-Butyl N-[4-cyano-5-[4-[2-[[3-(1,1-difluoro-2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 557.41, b, V267tert-Butyl N-[4-cyano-5-[2-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)i soxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 549.51, b, V268tert-Butyl N-[4-cyano-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)isox azol-5-yl]amino]-2-oxoethyl]-2,3-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 569.41, b, V269tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-2,5-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5571, b, V270tert-Butyl N-[4-cyano-5-[4-[2-[[5-(3,3-dimethylcyclobutyl)isox azol-3-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5331, b, V271tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol -5-yl]amino]-2-oxoethyl]-3,5-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5571, b, V272tert-Butyl N-[5-[2-chloro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)i soxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 5651, b, V273tert-Butyl N-[5-[2-chloro-3-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)i soxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-4-cyano-2-isopropyl-pyrazol-3-yl]carbamate 5831, b, V274tert-Butyl N-[4-cyano-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 551.41, b, V275tert-Butyl N-[4-cyano-5-[3,5-difluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)i soxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5671, b, V276tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5391, b, V277tert-Butyl N-[4-cyano-5-[4-[2-[[4-fluoro-3-(3-methyl-1-bicyclo[1.1.1]pentanyl)i soxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 5491, b, V Preparation 278tert-Butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate

[0258]

[0259] 3-(2,2-Dimethylpropyl)-1,2-oxazol-5-amine (58 mg, 0.376 mmol), 2-[4-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2,3-difluoro-phenyl]acetic acid (0.100 g, 0.238 mmol) and DIPEA (98 µL, 0.563 mmol) are added together in DMF (0.69 mL) under N 2 . T3P ®< (0.454 g, 0.713 mmol, 50% in MeTHF) is added and the reaction is stirred at RT overnight. The mixture is quenched with saturated aq. NH 4 Cl and the aqueous layer is extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 10% to 50% EtOAc in cyclohexane to give the title compound (45 mg, 95% purity, 32%) as a white solid. ES / MS (m / z) 557 (M+H).Preparation 279tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxoethyl]-2,3-difluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate

[0260]

[0261] To tert-butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate (75 mg, 0.135 mmol) and Parkins catalyst (5.8 mg, 0.0135 mmol) under N 2 is added a mixture of tert-BuOH (1.8 mL) and H 2 O (0.9 mL). The mixture is heated to 65 °C for 16 hr. The reaction mixture is cooled to RT and diluted with EtOAc. The organic layer is washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 1% to 10% DCM in MeOH to give the title compound (48 mg, 62%) as a white solid. ES / MS (m / z) 597 (M+Na).Preparation 280tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylcyclopropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate

[0262]

[0263] To a stirred solution of tert-butyl N-[4-cyano-5-[4-[2-[[3-(2,2-dimethylcyclopropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate (0.365 g, 0.704 mmol) in tert-BuOH (10 mL) and H 2 O (5 mL) under N 2 is added Parkins catalyst (15 mg, 0.0352 mmol). The reaction mixture is stirred at 60 °C for 4 hr. The reaction mixture is quenched with saturated aq. NH 4 Cl. The aqueous layer is extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The material is purified by silica gel chromatography, eluting with a gradient of 30% to 80% EtOAc in cyclohexane to give the title compound (0.363 g, 96%) as a white solid. ES / MS (m / z) 559.4 (M+Na).

[0264] The following compounds in Table 23 are prepared essentially as described for tert-butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylcyclopropyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate adjusting reaction time to determine completion of the reaction, using t-BuOH or 4:1 EtOH:H 2 O as solvent, and using appropriate chromatography conditions for purification. Temperature can range from about 60-70 °C. Table 23Prep. No.Chemical nameStructureES / MS m / z (M+H)281tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[4-[2-oxo-2-[(3-spiro[2.2]pentan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]pyrazol-3-yl]carbamate 535282tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-[(2,2-difluorocyclopropyl)methyl]isoxazol -5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 581 M+Na283tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(3,3-difluorocyclopentyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 595.4 M+Na284tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[4-[2-oxo-2-[(3-spiro[2.3]hexan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]pyrazol-3-yl]carbamate 549.4285tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[4-[2-oxo-2-[(5-spiro[2.3]hexan-2-ylisoxazol-3-yl)amino]ethyl]phenyl]pyrazol-3-yl]carbamate 549286tert-Butyl N-[4-carbamoyl-5-[4-[2-[[5-(2,2-dimethylcyclobutyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 551287tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 551.4288tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 557.5289tert-Butyl N-[4-carbamoyl-5-[3-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 613.4 M+Na290tert-Butyl N-[4-carbamoyl-5-[2-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-fluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 613.4 M+Na291tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-methylphenyl]-2-isopropyl-pyrazol-3-yl]carbamate 575.4 M+Na292tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(cyclobutylmethyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 559.4 M+Na293tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[4-[2-[[3-[(1-methylcyclobutyl)methyl]isoxazol-5-yl]amino]-2-oxoethyl]phenyl]pyrazol-3-yl]carbamate 573, M+Na294tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 591.4 M+Na295tert-Butyl N-[4-carbamoyl-5-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 607.4 M+Na296tert-Butyl N-[4-carbamoyl-5-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-fluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 625.4 M+Na297tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(1,1-difluoro-2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 575.4298tert-Butyl N-[4-carbamoyl-5-[2-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 589.4 M+Na299tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 609.4, M+Na300tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,5-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 575301tert-Butyl N-[4-carbamoyl-5-[4-[2-[[5-(3,3-dimethylcyclobutyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 551302tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3,5-difluorophenyl]-2-isopropyl-pyrazol-3-yl]carbamate 597 M+Na303tert-Butyl N-[4-carbamoyl-5-[2-chloro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 605 M+Na304tert-Butyl N-[4-carbamoyl-5-[2-chloro-3-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 623 M+Na305tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(3,3-dimethylcyclobutyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 569.5306tert-Butyl N-[4-carbamoyl-5-[3,5-difluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 607 M+Na307tert-Butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 557308tert-Butyl N-[4-carbamoyl-5-[4-[2-[[4-fluoro-3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 589 M+Na309tert-Butyl (4-carbamoyl-3-(2,3 -difluoro-4-(2-((3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazol-5-yl)carbamate 589.4310tert-Butyl (4-carbamoyl-3-(2,3 -difluoro-4-(2-oxo-2-((3-(3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1-isopropyl-1H-pyrazol-5-yl)carbamate 639.4311tert-Butyl N-[4-carbamoyl-5-[3-chloro-4-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 649.1312tert-Butyl 3-(5-amino-4-carbamoyl-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate 552.3313tert-Butyl N-tert-butoxycarbonyl-N-[4-carbamoyl-5-[4-[2-[[3-[2,4-dichloro-5-[(dimethylamino)methyl]phen yl]isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-2-isopropyl-pyrazol-3-yl]carbamate 771.7 Preparation 3143-(2,4-Dichloro-3-fluoro-phenyl)-3-oxo-propanenitrile

[0265]

[0266] To a stirred solution of LDA (1.35 mL, 2.69 mmol) in THF (4 mL) is added ACN (0.13 mL, 2.47 mmol) dropwise at -78°C under N 2 . The reaction is stirred 1 hr at -78 °C then a solution of methyl 2,4-dichloro-3-fluorobenzoate in THF is added dropwise. Once the addition is complete the reaction is stirred at RT for 2 hr. The reaction is quenched with saturated aq. NH 4 Cl. The pH is adjusted to pH 5 with HCl (1N) then extracted with EtOAc. The organic layer is washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to afford the title compound (0.83 g). This crude material is used without further purification in the preparation of 3-(2,4-dichloro-3-fluoro-phenyl)isoxazol-5-amine.Preparation 3153-(2,4-Dichloro-3-fluoro-phenyl)isoxazol-5-amine

[0267]

[0268] A solution of 3-(2,4-dichloro-3-fluoro-phenyl)-3-oxo-propanenitrile (0.27 g, 1.15 mmol) in EtOH (3.7 mL) and H 2 O (3.7 mL) is treated with hydroxyamine HCl (0.40 g, 5.74 mmol) and KOAc (0.68 g, 6.89 mmol). The mixture is stirred at 60 °C for 1 hr. The reaction is extracted with EtOAc and the organic layer is concentrated in vacuo. The residue is purified by normal phase silica gel chromatography, eluting with 0% to 100% EtOAc in hexanes followed by 0% to 20% MeOH in EtOAc to afford the title compound (0.18 g, 65%). ES / MS (m / z) 247.0 (M+H).Preparation 3162-[5-(5-amino-4-cyano-1-ethyl-pyrazol-3-yl)-2-pyridyl]acetate

[0269]

[0270] A mixture of 5-amino-3-bromo-1-ethyl-pyrazole-4-carbonitrile (233.58 mg, 1.09 mmol), K 2 CO 3 (299.78 mg, 2.17mmol) , Pd(dppf)Cl 2 (79.48 mg, 0.11 mmol), and methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (301 mg, 1.09 mmol) in a reaction vial with 1,4-dioxane (9.05 mL) and H 2 O (1.81mL) is sparged with nitrogen and heated to 80°C for 90 min. The reaction is partitioned between DCM and H 2 O and extracted through a phase separator with DCM (3x). Organic are combined and concentrated in vacuo. The residue is purified by silica chromatography eluting with 0% to 100% EtOAc in hexanes to give the title compound (172 mg, 55.5%). ES / MS (m / z) 286.1 (M+H).Preparation 317Methyl 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]acetate

[0271]

[0272] Methyl 2-(6-chloropyridin-3-yl)acetate (2.00 g, 10.78 mmol), hexabutyldistannane (9.38 g, 16.16 mmol), and Pd(PPh 3 ) 4 (7.47 g, 6.46 mmol) are combined in 1,4-dioxane (40 mL) under N 2 and the reaction is stirred for three days at 65 °C.

[0273] 5-amino-3-bromo-1-isopropylpyrazole-4-carbonitrile (0.75 g, 3.30 mmol) is added to a portion (25%) of the above reaction mixture under N 2 and the reaction is stirred for 12 hr at 75 °C. The solvent is removed under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 2:1 to 1:1 PE:EtOAc to afford crude product. The product is further purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 20% to 50% ACN in H 2 O (0.1% FA) to give the title compound (0.12 g, 15%) as a yellow solid. ES / MS (m / z) 300.2 (M+H).Preparation 318Methyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetate

[0274]

[0275] Methyl 2-(5-bromopyridin-2-yl)acetate (1.00 g, 4.35 mmol), bis(pinacolato)diboron (1.33 g, 5.22 mmol), KOAc (0.85 g, 8.70 mmol), Pd(dppf)Cl 2 (0.32 g, 0.43 mmol) and 1,4-dioxane (30 mL) are added together. The reaction mixture is stirred under N 2 at 100 °C for 2 hr. The reaction is filtered, and the filtrate is concentrated under vacuum to give an intermediate residue.

[0276] The residue, 5-amino-3-bromo-1-isopropylpyrazole-4-carbonitrile (0.99 g, 4.33 mmol), potassium carbonate (1.19 g, 8.60 mmol), Pd(dppf)Cl 2 (0.32 g, 0.43 mmol), 1,4-dioxane (30 mL), and H 2 O (7 mL) are added together. The reaction mixture is stirred under N 2 at 100 °C for 2 hr. The reaction is diluted with H 2 O (50 mL) is extracted with EtOAc (3x100 mL). The combined organic extracts are washed with brine (2x100 mL), dried over Na 2 SO 4 , filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography, eluting with a gradient of 6:1 to 2:1 PE:EtOAc to give the title compound (0.65 g, 50%) as a yellow solid. ES / MS (m / z) 300.1 (M+H).

[0277] The following compounds in Table 24 are prepared essentially as described for methyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetate and adjusting reaction time to determine completion of the reaction. Table 24Prep No.Chemical NameStructureES / MS m / z (M+H)319Ethyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrimidin-2-yl]acetate 315.2320Methyl 2-[5-(5-amino-4-cyano-1-ethyl-pyrazol-3-yl)-2-pyridyl]acetate 286.1 Preparation 3212-[6-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]acetic acid

[0278]

[0279] To methyl 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]acetate (0.10 g, 0.33 mmol) in methanol (2 mL) and H 2 O (2 mL) is added LiOH (0.024 g, 1.00 mmol). The mixture is stirred at 60 °C for 2 hr. The reaction mixture is acidified with 1 M aq. HCl to pH 5 then extracted with EtOAc (2x30 mL). The combined organic extracts are washed with brine (2x20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 5% to 60% ACN in H 2 O (0.1% FA) to give the title compound (0.080 g, 80%) as a yellow solid. ES / MS (m / z) 286.4 (M+H).

[0280] The following compounds in Table 25 are prepared essentially as described for 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]acetic acid and adjusting reaction time to determine completion of the reaction. Table 25Prep No.Chemical NameStructureES / MS m / z (M+H)3222-[5-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetic acid 286.13232-[5-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrimidin-2-yl]acetic acid 287.1 Preparation 324Lithium 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetate

[0281]

[0282] To methyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetate (2.40 g, 8.00 mmol) in THF (20 mL) and H 2 O (4 mL) is added LiOH (0.17 g, 7.20 mmol). The mixture is stirred at RT for 2 hr. The reaction mixture is diluted with H 2 O (20 mL) then washed with EtOAc (3x50 mL). The aqueous layer is concentrated under reduced pressure to give the title compound (1.50 g, 65%) as a yellow solid. ES / MS (m / z) 286.1 (M+H).

[0283] The following compounds in Table 26 are prepared essentially as described for lithium 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-2-pyridyl]acetate and adjusting reaction time to determine completion of the reaction. Table 26Prep No.Chemical NameStructureES / MS m / z (M+H)325Lithium 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrimidin-2-yl]acetate 287.1326Lithium 2-[5-(5-amino-4-cyano-1-ethyl-pyrazol-3-yl)-2-pyridyl]acetate 272.0 Preparation 3275-Amino-3-(5-chloropyrazin-2-yl)-1-isopropyl-pyrazole-4-carbonitrile

[0284]

[0285] To a stirred solution of 5-chloropyrazine-2-carbaldehyde (0.30 g, 2.11 mmol) and isopropylhydrazinehydrochloride (0.26 g, 2.32 mmol) in DMF (4 mL) is added DIPEA (0.30 g, 2.32 mmol) in portions at RT under N 2 . The mixture is stirred for 1 hr at 80 °C then is cooled to RT. To the mixture is added a solution of N-bromosuccinimide (0.41 g, 2.32 mmol) in DMF (4 mL) in portions over 5 min. The mixture is stirred for 2 hr at RT.

[0286] At the same time, to a stirred solution of malonitrile (0.15 g, 2.32 mmol) in EtOH (2 mL) is added sodium ethoxide (0.39 g, 5.80 mmol) at 0 °C under N 2 . The mixture is stirred for 30 min at RT.

[0287] To the second mixture at 0 °C under N 2 is added the first mixture dropwise over 30 min. The reaction is stirred for 2 hr at 80 °C. The mixture is diluted with EtOAc and washed with H 2 O. The organic layer is concentrated under vacuum. The residue is purified by silica gel chromatography, eluting with a gradient of 3:1 to 2:1 PE:EtOAc to give the title compound (0.26 g, 47%) as a white solid. 1< H NMR(d 6 -DMSO, 300 MHz) δ (ppm) 8.88 (d, 1H), 8.82 (d, 1H), 6.80 (s, 2H), 4.56 (m, 1H), 1.37 (d, 6H).

[0288] The following compounds in Table 27 are prepared essentially as described for 5-amino-3-(5-chloropyrazin-2-yl)-1-isopropyl-pyrazole-4-carbonitrile and adjusting reaction time to determine completion of the reaction. Table 27Prep No.Chemical NameStructureES / MS m / z (M+H)3285-Amino-3-(5-bromopyrimidin-2-yl)-1-isopropyl-pyrazole-4-carbonitrile 307.1309.1 Preparation 329tert-Butyl N-[5-(5-bromopyrimidin-2-yl)-4-cyano-2-isopropyl-pyrazol-3-yl]-N-tert-butoxycarbonyl-carbamate

[0289]

[0290] A mixture of 5-amino-3-(5-bromopyrimidin-2-yl)-1-isopropyl-pyrazole-4-carbonitrile (0.35 g, 1.14 mmol), di-tert-butyl dicarbonate (0.50 g, 2.28 mmol), and DMAP (0.029 g, 0.23 mmol) in THF (10 mL) is stirred for 4 hr at RT. The mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 10:1 to 1:1 PE:EtOAc to give the title compound (0.40 g, 69%) as a yellow solid. ES / MS (m / z) 507.0,509.1 (M+H).Preparation 330tert-Butyl 2-[2-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]pyrimidin-5-yl]acetate

[0291]

[0292] A solution of tert-butyl N-[5-(5-bromopyrimidin-2-yl)-4-cyano-2-isopropyl-pyrazol-3-yl]-N-tert-butoxycarbonyl-carbamate (0.39 g, 0.77 mmol), tert-butyl 2-(bromozincio)acetate (0.40 g, 1.54 mmol) and Pd(t-Bu 3 P) 2 (0.079 g, 0.15 mmol) in THF (20 mL) is stirred for 4 hr at 80 °C under N 2 and allowed to cool to RT. The solution is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with EtOAc to afford crude product. The product is further purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 50% ACN in H 2 O (0.1% FA) to give the title compound (0.24 g, 71%) as a yellow solid. ES / MS (m / z) 443.2 (M+H).

[0293] The following compounds in Table 28 are prepared essentially as described for tert-butyl 2-[2-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]pyrimidin-5-yl]acetate and adjusting reaction time to determine completion of the reaction. Table 28Prep No.Chemical NameStructureES / MS m / z (M+H)331tert-Butyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrazin-2-yl]acetate 343.3 Preparation 3322-[5-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrazin-2-yl]acetic acid

[0294]

[0295] To tert-butyl 2-[5-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrazin-2-yl]acetate (0.26 g, 0.76 mmol) is added TFA (10 mL). The mixture is stirred for 30 min at RT and concentrated under reduced pressure to give the title compound as a yellow solid (0.20 g, 91%) which is used without further purification.Preparation 3332-[2-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)pyrimidin-5-yl]acetic acid

[0296]

[0297] To tert-butyl 2-[2-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]pyrimidin-5-yl]acetate (0.22 g, 0.50 mmol) is added 4M HCl in 1,4-dioxane (10 mL). The mixture is stirred for 1 hr at RT and concentrated under reduced pressure. The reaction is adjusted to pH 6 with saturated aqueous NaHCO 3 , then extracted with EtOAc (3x50 mL). The combined organic extracts are concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 40% ACN in H 2 O (0.1% FA) to give the title compound (0.075 g, 53%) as a yellow solid. ES / MS (m / z) 287.1 (M+H).Example 15-Amino-1-isopropyl-3-(4-(2-((3-((1-methylcyclopropyl)methyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide

[0298]

[0299] 3-[(1-Methylcyclopropyl)methyl]isoxazol-5-amine (62 mg, 0.407 mmol) and 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.10 g, 0.331 mmol) are combined in EtOAc (0.38 mL), pyridine (0.64 mL) and ACN (0.64 mL). The mixture is stirred for 5 min and a cloudy suspension is observed. The mixture is cooled to -20 °C and T3P ®< (0.58 mL, 0.99 mmol, 50% in DMF) is added dropwise. The solution is stirred at -20 °C for 45 min. The mixture is diluted with H 2 O (50 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 10% to 100% EtOAc in hexanes to give the title compound (28 mg, 19%). ES / MS (m / z) 437.2 (M+H).Example 25-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide

[0300]

[0301] 5-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)isoxazol-3-amine (0.394 g, 2.03 mmol)) and 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.500 g, 1.65 mmol) are combined in ACN (20 mL), EtOAc (16 mL) and pyridine (2 mL). The mixture is stirred for 2 min until a clear and colorless solution results. The solution is cooled to -20 °C and T3P ®< (1.89 mL, 3.23 mmol, 50% in DMF) is added dropwise. The solution is stirred at - 20 °C for 30 min. The reaction is diluted with H 2 O (8 mL) and extracted with EtOAc (2x10 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes followed by 0% to 10% MeOH (with 0.1% NH 4 OH) in EtOAc to give the title compound (0.363 g, 46%). ES / MS (m / z) 478.8 (M+H).Example 35-Amino-1-isopropyl-3-(4-(2-((3-(1-methylcyclopentyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide

[0302]

[0303] To a mixture of 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (20 mg, 0.066 mmol), 3-(1-methylcyclopentyl)isoxazol-5-amine (11 mg, 0.066 mmol) and [[(E)-(1-cyano-2-ethoxy-2-oxo-ethylidene)amino]oxy-morpholino-methylene]-dimethyl-ammonium hexafluorophosphate (34 mg, 0.079 mmol) in DMF (3 mL) is added DIPEA (0.034 mL, 0.195 mmol) and the mixture is stirred at RT for 6 hr. The mixture is diluted with H 2 O (20 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts are washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes to give the title compound (3.4 mg, 11%). ES / MS (m / z) 451.2 (M+H).Example 45-Amino-3-(4-(2-((3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0304]

[0305] 2-(4-(5-Amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.100 g, 0.331 mmol), 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine (61 mg, 0.363 mmol), T3P ®< (0.28 mL, 0.470 mmol, 50% in EtOAc) and DIPEA (0.17 mL, 0.976 mmol) are added together in DCM (5 mL) in a sealed tube and stirred for 10 hr at RT under N 2 . The mixture is concentrated under reduced pressure and the residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 20% to 50% ACN in H 2 O (0.1% NH 4 HCO 3 ), to give the title compound (67 mg, 45%) as a white solid. ES / MS (m / z) 453.1 (M+H).Example 55-Amino-3-(4-[[(3-[bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl)-1-isopropylpyrazole-4-carboxamide

[0306]

[0307] 2-(4-(5-Amino-4-carbamoyl-1-isopropy1H-pyrazol-3-yl)phenyl)acetic acid (0.100 g, 0.331 mmol), 3-[bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (60 mg, 0.400 mmol) and DIPEA (0.17 mL, 0.976 mmol) are added together in DCM (10 mL). T3P ®< (0.30 mL, 0.504 mmol, 50% in EtOAc) is added and the mixture is stirred for 2 hr at RT under N 2 . The solution is concentrated under reduced pressure and re-dissolved in ACN (5 mL). The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 20% to 60% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (24 mg, 17%) as white solid. ES / MS (m / z) 435.3 (M+H).Example 65-Amino-1-(1-methylcyclopropyl)-3-[4-([[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phenyl]pyrazole-4-carboxamide

[0308]

[0309] To a stirred mixture of 2-(4-(5-Amino-4-carbamoyl-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)acetic acid (70 mg, 0.223 mmol) and NMI (55 mg, 0.670 mmol) in ACN (5 mL) is added 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-amine (65 mg, 0.335 mmol) and TCFH (94 mg, 0.335 mmol) in portions at RT under N 2 . The mixture is stirred for 2 hr at 50 °C under N 2 . The mixture is cooled to RT and concentrated under reduced pressure to a residue. The residue is purified by preparative TLC, eluting with 100% EtOAc and further purified by reversed-phase chromatography (C18 column), eluting with a gradient of 40% to 50% ACN in H 2 O to give the title compound (20 mg, 18%) as a white solid. ES / MS (m / z) 491.2 (M+H).Example 75-Amino-1-isopropyl-3-[4-([[3-(1-methylcyclopropyl)-1,2-oxazol-5-yl]carbamoyl] methyl)phenyl]pyrazole-4-carboxamide

[0310]

[0311] To a stirred mixture of 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.300 g, 0.992 mmol) and 3-(1-methylcyclopropyl)-1,2-oxazol-5-amine (0.151 g, 1.09 mmol) in DCM (10 mL) is added DIPEA (0.26 mL, 1.49 mmol) and T3P ®< (0.71 mL, 1.19 mmol, 50% in EtOAc) in portions at RT under N 2 . The mixture is stirred for 3 hr at RT under N 2 and concentrated to dryness. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 40% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (69 mg, 16%) as a white solid. ES / MS (m / z) 423.3 (M+H).Example 85-Amino-3-[4-([[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3yl]carbamoyl]methyl)phenyl]-1-(propan-2-yl)-1H-pyrazole-4-carboxamide

[0312]

[0313] A solution of 1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-amine (35 mg, 0.169 mmol), 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (56 mg, 0.185 mmol), HATU (96 mg, 0.252 mmol) and DIPEA (0.088 mL, 0.505 mmol) in DMF (2 mL) is stirred for 2 hr at RT under N 2 . The mixture is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 50% to 70% ACN in H 2 O (0.1% FA) to give the title compound (28 mg, 34%) as a white solid. ES / MS (m / z) 492.3 (M+H).Example 95-Amino-1-isopropyl-3-[4-([[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl]pyrazole-4-carboxamide

[0314]

[0315] A solution of 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.150 g, 0.496 mmol), 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-amine (0.106 g, 0.546 mmol), DIPEA (0.35 mL, 2.01 mmol) and T3P ®< (0.59 mL, 0.991 mmol, 50% in EtOAc) in DCM (5 mL) is stirred for 2 hr at RT under N 2 . The mixture is concentrated and the residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 30% to 50% ACN in H 2 O (0.1% FA). The product is further purified by reversed-phase preparative HPLC (Phenomenex Gemini C6-Phenyl column), eluting with a gradient of 37% to 45% ACN in H 2 O (0.05% FA) to give the title compound (81 mg, 34%) as a white solid. ES / MS (m / z) 479.3 (M+H).Example 105-Amino-3-(4-(2-((5-(tert-butyl)isothiazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0316]

[0317] 5-tert-Butylisothiazol-3-amine (47 mg, 0.301 mmol)) and 2-[4-(5-amino-4-carbamoyl-1-isopropyl-pyrazol-3-yl)phenyl]acetic acid (60 mg, 0.198 mmol) are combined in ACN (1.05 mL), EtOAc (0.65 mL) and pyridine (0.31 mL). The mixture is stirred for 2 min until a clear and colorless solution results. The solution is cooled to -20 °C and T3P ®< (0.26 mL, 0.437 mmol, 50% in EtOAc) is added dropwise. The solution is stirred at -20 °C for 30 mins. The reaction is diluted with H 2 O (8 mL) and extracted with DCM (2x10 mL). The combined organic extracts are dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes followed by 0% to 20% MeOH (with 1% NH 4 OH) in EtOAc to give the title compound (21 mg, 24%) as a pale yellow solid. ES / MS (m / z) 441.2 (M+H).Example 115-Amino-1-isopropyl-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl)pyrazole-4-carboxamide

[0318]

[0319] To a stirred mixture of 2-(4-(5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (0.300 g, 0.992 mmol) and 3-[3-methylbicyclo[1.1.1]pentan-1-yl]- 1,2-oxazol-5-amine (0.163 g, 0.993 mmol) in DCM (20 mL) is added DIPEA (0.52 mL, 2.99 mmol) and T3P ®< (0.89 mL, 1.50 mmol, 50% in EtOAc) at RT. The mixture is stirred for 1 hr at 50 °C under N 2 in a sealed tube. The mixture is concentrated under reduced pressure and purified by reversed-phase chromatography (C18 column), eluting with a gradient of 30% to 40% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (90 mg, 20%) as a white solid. ES / MS (m / z) 449.2 (M+H).Example 125-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(2-(trifluoromethyl)phenyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide

[0320]

[0321] 2-(4-(5-Amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (75 mg, 0.248 mmol) and 3-[2-(trifluoromethyl)phenyl]isoxazol-5-amine (53 mg, 0.232 mmol) in EtOAc (0.14 mL) and ACN (0.14 mL) is treated with pyridine (0.14 mL) and T3P ®< (0.28 mL, 0.470 mmol, 50% in EtOAc). The mixture is stirred at 0 °C for 20 min under N 2 , then partitioned between H 2 O and EtOAc. The organic layer is concentrated and purified by reversed-phase preparative HPLC, eluting with a gradient of 5% to 95% ACN in H 2 O (0.2% TFA) to give the title compound (4.1 mg, 3.4%). ES / MS (m / z) 513.1 (M+H).

[0322] The following compounds in Table 29 are prepared essentially as described for 5-amino-1-isopropyl-3-(4-(2-oxo-2-((3-(2-(trifluoromethyl)phenyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide using the appropriate amine and carboxylic acid with a coupling reagent, about 1-6 equivalents, base, about 1-4 equiv and solvent, about 0.3-20 mL, adjusting the reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction temperature can range from -20 °C to 50 °C, T3P ®< can be added in 50% EtOAc, 50% DMF and TCFH can be added in portions. *Coupling reagents: 1 T3P ®< , 2 TCFH, 3 BTFFH, 4 COMU ®< , 5 TBTU, 6 TFFH, 7 HATU, 8 EDCI / HOBT Bases: a NMI, b pyridine, c DIPEA Solvents: I EtOAc, II ACN, III DMF, IV DCM, V THF Table 29 Ex. No.Chemical nameStructureES / MS m / z (M+H)*135-Amino-1-isopropyl-3-(4-(2-((5-(1-methylcyclohexyl)isoxaz ol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 4653, a, II145-Amino-3-(4-(2-((3-(2-chlorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 479.21, b, II155-Amino-3-(4-(2-((3-(2-fluoropropan-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 429.12, a, III165-Amino-1-isopropyl-3-(4-(2-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 558.32, a, III175-Amino-3-(4-(2-((3-cyclohexylisoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 469.24, c, III185-Amino-3-(4-(2-((3-cyclohexylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 450.82, a, III195-Amino-1-isopropyl-3-(4-(2-oxo-2-((2-(trifluoromethyl)pyridin-4-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 447.23, a, I& II205-Amino-1-isopropyl-3-(4-(2-oxo-2-((4-(trifluoromethyl)pyridin-2-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 447.23, a, I& II215-Amino-3-(4-(2-((3,5-bis(trifluoromethyl)phen yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 513.72, a, III225-Amino-1-isopropyl-3-(4-(2-((4-isopropyl-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 488.26, a, I & II235-Amino-3-(4-(2-((4-(dimethylphosphoryl)phe nyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 454.25, c, IV245-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(spiro[3.3]heptan-2-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 463.22, a, I & II255-Amino-3-(4-(2-((5-(4-chloro-2-fluorophenyl)-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 514.22, a, I& II265-Amino-1-isopropyl-3-(4-(2-oxo-2-((4-(pentafluoro- λ 6-sulfanyl)phenyl)amino)et hyl)phenyl)-1H-pyrazole-4-carboxamide 504.25, c, IV275-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(spiro[2.3]hexan-5-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 449.22, a, I& II285-Amino-1-isopropyl-3-(4-(2-((3-(2-methylcyclopropyl)isoxa zol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 423.82, a, III295-Amino-1-isopropyl-3-(4-(2-((3-(2-methoxyphenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 475.21, b, I& II305-Amino-3-(4-(2-((3-(2-chloro-4-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 497.12, a, III315-Amino-3-(4-(2-((5-(bicyclo[2.2.1]heptan-2-yl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.22, a, III325-Amino-1-isopropyl-3-(4-(2-oxo-2-((4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)a mino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 529.22, a, I& II335-Amino-1-isopropyl-3-(4-(2-((5-neopentylisoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 439.33, a, I& II345-Amino-1-isopropyl-3-(4-(2-((4-(4-methoxypiperidin-1-yl)-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 559.26, a, I& II355-Amino-3-(4-(2-((5-(cyclopentylmethyl)isoxa zol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 451.26, a, III365-Amino-3-(4-(2-((3-(2,3-dihydro-1H-inden-5-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 485.22, a, III375-Amino-1-isopropyl-3-(4-(2-((3-(1-methylcyclohexyl)isoxaz ol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 465.22, a, III385-Amino-3-(4-(2-((3-(bicyclo[2.2.1]heptan-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 462.82, a, III395-Amino-3-(4-(2-((5-(bicyclo[2.2.1]heptan-2-yl)-1H-pyrazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 462.21, b, I& II405-Amino-1-isopropyl-3-(4-(2-((5-methyl-4-phenylthiazol-2-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 474.82, a, III415-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-(tetrahydro-2H-pyran-4-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 452.82, a, III425-Amino-1-isopropyl-3-(4-(2-((5-neopentyl-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 455.82, a, III435-Amino-1-isopropyl-3-(4-(2-oxo-2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 488.25, c, IV445-Amino-1-isopropyl-3-(4-(2-oxo-2-((1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 474.25, c, IV455-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(p-tolyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 459.21, b, I& II465-Amino-3-(4-(2-((2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 418.25, c, IV475-Amino-1-isopropyl-3-(4-(2-((3-(4-methoxyphenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 474.21, b, I& II485-Amino-3-(4-(2-((4-cyclopropyl-3-methylphenyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 432.25, c, IV495-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(2-(trifluoromethyl)spiro[3. 3]heptan-2-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 531.22, a, I& II505-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(pentafluoro-λ 6< -sulfaneyl)phenyl)amino)e thyl)phenyl)-1H-pyrazole-4-carboxamide 503.25, c, IV515-Amino-3-(4-(2-((3-(2-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.21, b, I& II525-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-(3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 530.22, a, I& II535-Amino-1-isopropyl-3-(4-(2-((3-isopropyl-4-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 488.25, c, IV545-Amino-3-(4-(2-((3-(2,2-difluorocyclopropyl)phen yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 453.25, c, IV555-Amino-3-(4-(2-((5-cyclopropylisoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 409.21, b, I& II565-Amino-3-(4-(2-((3-(2,4-dimethylphenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 473.21, b, I& II575-Amino-3-(4-(2-((3-(4-chlorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 479.11, b, I& II585-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(o-tolyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 459.21, b, I & II595-Amino-3-(4-(2-((3-(3-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.21, b, I& II605-Amino-3-(4-(2-((3-(bicyclo[2.2.1]heptan-2-ylmethyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 477.21, b, I& II615-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-phenylisoxazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 445.11, b, I& II625-Amino-3-(4-(2-((3-(4-(difluoromethoxy)phenyl )isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 511.11, b, I& II635-Amino-1-isopropyl-3-(4-(2-((3-(2-(methylsulfonyl)propan-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 489.21, b, I& II645-Amino-3-(4-(2-((3-(4-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.11, b, I& II655-Amino-3-(4-(2-((5-cycloheptyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 464.11, b, I& II665-Amino-3-(4-(2-((5-(2,4-difluorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 481.11, b, I& II675-Amino-3-(4-(2-((5-(3-chlorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 479.14, c, III685-Amino-3-(4-(2-((5-cyclobutylisoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 423.21, b, I & II695-Amino-3-(4-(2-((5-(3-fluorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.11, b, I & II705-Amino-1-isopropyl-3-(3 -methyl-4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 493.21, b, I & II715-Amino-3-(4-(2-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 438.21, b, I& II725-Amino-3-(4-(2-((5-(2-fluorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.11, b, I& II735-Amino-1-isopropyl-3-(4-(2-((3-(3-methoxyphenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 475.11, b, I& II745-Amino-3-(4-(2-((3-(3-bromophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 525.11, b, I& II755-Amino-1-isopropyl-3-(4-(2-((3-(2-methyltetrahydrofuran-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 453.21, b, I& II765-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(2,4,6-trifluorophenyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 499.11, b, I& II775-Amino-3-(4-(2-((3-(bicyclo[3.1.0]hexan-3-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 449.21, b, I& II785-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(tetrahydrofuran-3-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 438.81, b, I& II795-Amino-3-(4-(2-((3-cyclobutylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 423.11, b, I& II805-Amino-3-(4-(2-((3-cyclopropylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 408.51, b, I& II815-Amino-3-(4-(2-((3-cyclopropylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1- 396.81, b, I& IIisopropyl-1H-pyrazole-4-carboxamide825-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-((1-(trifluoromethyl)cyclopro pyl)methyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 491.21, b, I& II835-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(tert-pentyl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 438.81, b, I& II845-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(4-(trifluoromethyl)bicyclo[ 2.2.1]heptan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 531.21, c, III855-Amino-3-(3-chloro-4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 513.11, b, I& II865-Amino-3-(4-(2-((3-(cyclopropylmethyl)isoxa zol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 423.11, b, I & II875-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-phenylisoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 445.21, b, I& II885-Amino-3-(4-(2-((3-(3,3-dimethylcyclobutyl)isoxa zol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 451.22, a, III895-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(3-(trifluoromethyl)phenyl)i soxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 513.21, b, I& II905-Amino-3-(4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 425.21, b, I& II915-Amino-3-(4-(2-((3-((difluoromethyl)thio)phe nyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 459.25, c, IV925-Amino-3-(4-(2-((5-(2,4-dichlorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 514.22, a, I& II935-Amino-3-(4-(2-((3-(2,4-dichlorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 512.22, a, I& II945-Amino-3-(4-(2-((5-(2,3-dichlorobenzyl)thiazol-2-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 543.22, a, I & II955-Amino-3-(4-(2-((3-(tert-butyl)isothiazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 441.21, b, I& II965-Amino-3-(4-(2-((3,4-diethylphenyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 434.25, c, IV975-Amino-1-isopropyl-3-(4-(2-((4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 545.25, c, IV985-Amino-3-(4-(2-((3-(tert-butyl)phenyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 434.25, c, IV995-Amino-3-(4-(2-((3-ethyl-4-methylphenyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 420.25, c, IV1005-Amino-3-(4-(2-((3-(6,6-difluorospiro[3.3]heptan-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 499.22, a, I& II1015-Amino-3-(4-(2-((4-ethyl-3-methylphenyl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 420.25, c, IV1025-Amino-3-(4-(2-((3-(3,3-difluorocyclobutyl)isoxaz ol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 459.22, a, I& II1035-Amino-3-(4-(2-((5-(2,4-dichlorophenyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 514.22, a, II & III1045-Amino-1-isopropyl-3-(4-(2-((3-(1-methylcyclopropyl)pheny l)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 432.23, a, III1055-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-(2,2,2-trifluoroethyl)-1,3,4-thiadiazol-2-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 468.12, a, II1065-Amino-1-isopropyl-3-(4-(2-((3-methyl-5-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 460.22, a, III1075-Amino-3-(4-(2-((3-(cyclohexylmethyl)isoxa zol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 465.22, a, II1085-Amino-3-(4-(2-((3-(3-chlorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 479.11, b, I1095-Amino-1-isopropyl-3-(4-(2-((4-methyl-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 460.72, a, III1105-Amino-3-(4-(2-((5-(1,1-difluoroethyl)isoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 433.13, a, III1115-Amino-1-isopropyl-3-(4-(2-((5-(1-methylcyclopentyl)isoxaz ol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 451.24, c, III1125-Amino-1-isopropyl-3-(4-(2-oxo-2-((5-(trifluoromethyl)pyridin-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 447.33, a, III1135-Amino-3-(4-(2-((3-fluoro-5-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 464.72, a, III1145-Amino-1-isopropyl-3-(4-(2-((5-isopropylisoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 410.82, a, I& II1155-Amino-3-(4-(2-((3-(1-cyclopropylethyl)isoxazo l-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 437.22, a, II1165-Amino-3-(4-(2-((3-cyclopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 437.16, a, II1175-Amino-3-(4-(2-((4-fluoro-3-(trifluoromethyl)phenyl)a mino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 463.72, a, III1185-Amino-3-(4-(2-((3-(2,6-difluorophenyl) isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 481.12, a, I& II1195-Amino-3-(4-(2-((3-(4-bromophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 524.62, a, I & II1205-Amino-3-(4-(2-((3-(2,4-difluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 481.22, a, II1215-Amino-1-(propan-2-yl)-3-[4-([[3-(trifluoromethyl)phenyl]c arbamoyl]methyl) phenyl]-1H-pyrazole-4-carboxamide 446.37, c, III1225-Amino-1-(propan-2-yl)-3-[4-([[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl]carbamoyl]methyl)phe nyl]-1H-pyrazole-4-carboxamide 478.27, c, III1235-Amino-1-(propan-2-yl)-3-[4-([[7-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]methyl)phe nyl]-1H-pyrazole-4-carboxamide 503.18, V1245-Amino-1-tert-butyl-3-[4-([[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phe nyl]pyrazole-4-carboxamide 493.37, c, III1255-Amino-1-cyclopentyl-3-(4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 505.21, c, III1265-Amino-3-(4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, Isomer 1 533.11, c, III1275-Amino-3-(4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)amino)ethyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, Isomer 2 533.11, c, III1285-Amino-3-[3-fluoro-4-([[3-(trifluoromethyl)phenyl]c arbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 464.17, c, III1295-Amino-3-[3-fluoro-4-([[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phenyl]-1-isopropylpyrazole-4-carboxamide 497.31, c, III1305-Amino-3-(3-fluoro-4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl)amino)ethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 496.21, c, 1251315-Amino-3-[3-fluoro-4-([[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]methyl)phe nyl]-1-isopropylpyrazole-4-carboxamide 510.37, c, III1325-Amino-3-[3-fluoro-4-([[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phe nyl]-1-isopropylpyrazole-4-carboxamide 497.31, c, IV1335-Amino-3-(3-fluoro-4-(2-oxo-2-((7-(trifluoromethyl)benzo[d] thiazol-2-yl)amino)ethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 521.28, V1345-Amino-1-cyclopentyl-3-(4-(2-oxo-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 504.21, c, III1355-Amino-1-cyclopentyl-3-(4-(2-(1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-ylamino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 518.37, c, III1365-Amino-1-cyclopentyl-3-[4-([[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phe nyl]pyrazole-4-carboxamide 505.21, c, III1375-Amino-1-cyclopentyl-3-(4-(2-oxo-2-((7-(trifluoromethyl)benzo[d] thiazol-2-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide 529.38, V1385-Amino-1-isopropyl-3-(4-(2-((5-(1-methylcyclopropyl)isoxa zol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 423.31, c, III1395-Amino-3-(3-fluoro-4-[[(5-phenyl-1H-pyrazol-3-yl)carbamoyl]methyl]phe nyl)-1-isopropylpyrazole-4-carboxamide 462.21, c, III1405-Amino-3-(3-fluoro-4-[[(1-methyl-5-phenylpyrazol-3-yl)carbamoyl]methyl]phe nyl)-1-isopropylpyrazole-4-carboxamide 476.27, c, III1415-Amino-3-[2-chloro-4-([[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phe nyl]-1-isopropylpyrazole-4-carboxamide 513.31, c, III1425-Amino-3-(4-(2-((3-(3-chloropyridin-2-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 480.21, c, IV1435-Amino-1-isopropyl-3-[4-([[3-(2-methylpyridin-3-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phe nyl]pyrazole-4-carboxamide 230.6 (M+2H ) / 21, c, IV1445-Amino-1-isopropyl-3-[4-([[3-(4-methylpyridin-3-yl)-1,2-oxazol-5-yl]carbamoyl] methyl)phenyl]pyrazole-4-carboxamide 460.11, c, IV1455-Amino-3-[4-([[3-(2,4-dichlorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)-3-fluorophenyl]-1-isopropylpyrazole-4-carboxamide 531.11, c, IV1465-Amino-3-(4-[[(3-[3-cyanobicyclo[1.1.1]penta n-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phe nyl)-1-isopropylpyrazole-4-carboxamide 460.21, c, IV1475-Amino-3-[3-fluoro-4-[([3-[3-(trifluoromethyl)bicyclo[ 1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phe nyl]-1-isopropylpyrazole-4-carboxamide 521.21, c, IV1485-Amino-3-(3-fluoro-4-[[(3-[3-methylbicyclo[1.1.1]pent an-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phe nyl)-1-isopropylpyrazole-4-carboxamide 467.31, c, IV1495-Amino-1-isopropyl-3-[4-([[5-(pyridin-3-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phe nyl]pyrazole-4-carboxamide 446.21, c, IV1505-Amino-1-isopropyl-3-[4-([[5-(pyridin-4-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phe nyl]pyrazole-4-carboxamide 446.31, c, IV1515-Amino-3-[4-([[3-(1-cyano-1-methylethyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phe nyl]-1-isopropylpyrazole-4-carboxamide 436.21, c, IV1525-Amino-1-isopropyl-3-(4-[[(3-[3-methylbicyclo[1.1.1]pent an-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phe nyl)pyrazole-4-carboxamide 449.21, c IV Example 1535-Amino-1-isopropyl-3-(4-(2-oxo-2-((3-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1H-pyrazole-4-carboxamide

[0323]

[0324] 2-(4-(5-Amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl)phenyl)acetic acid (196 mg, 0.65 mmol) and 3-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine (140.00 mg, 0.65 mmol) are combined in DCM. DIPEA (251.36 mg, 1.95 mmol) and T3P ®< (536.32 mg. 0.84 mmol, 50 wt% in EtOAc) are added dropwise at RT and under N 2 and the reaction is stirred for 1 hr at 50 °C in a sealed tube. The reaction is concentrated under reduced pressure and the residue is purified by reversed phase flash chromatography (C18 column), eluting with a gradient of 40% to 50% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (120 mg). The material is titurated with hexanes (3 mL). The precipitated solids are collected by filtration and washed with hexanes (3x3 mL) to give the title product (85.1 mg, 34%) as a white solid ES / MS (m / z) 503.2 (M+H).Example 1545-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluorophenyl]-1-isopropyl-pyrazole-4-carboxamide

[0325]

[0326] To tert-butyl N-[4-carbamoyl-5-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluoro-phenyl]-2-isopropyl-pyrazol-3-yl]carbamate (45 mg, 0.078 mmol) in DCM (0.55 mL) is added TFA (0.23 mL, 3.12 mmol) at RT. The mixture is stirred for 3 hr. The reaction mixture is concentrated under reduced pressure, the pH of the residue is made basic with saturated aq. NaHCO 3 and extracted with EtOAc. The organic extract is washed with brine and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM to give a white solid. This solid is triturated in iPr 2 O at RT, filtered, washed with iPr 2 O, and dried under vacuum at 80 °C overnight to give the title compound (26 mg, 70%) as a white solid. ES / MS (m / z) 475 (M+H).Example 1555-Amino-3-(2,3-difluoro-4-(2-((3-(3-fluorobicyclo[11.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide

[0327]

[0328] To tert-butyl (4-carbamoyl-3-(2,3-difluoro-4-(2-((3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazol-5-yl)carbamate (30 mg, 0.051 mmol) in DCM (2 mL) is added TFA (0.39 mL, 5.10 mmol). The reaction mixture is stirred at RT for 2 hr. The reaction mixture is quenched with cold saturated aq. NaHCO 3 and the aqueous layer is extracted with EtOAc. The organic extract is washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 10% to 100% EtOAc in heptane to give the title compound (10 mg, 40%). ES / MS (m / z) 489.4 (M+H).

[0329] The following compounds in Table 30 are prepared essentially as described for 5-amino-3-(2,3-difluoro-4-(2-((3-(3-fluorobicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide adjusting reaction time to determine completion of the reaction, using appropriate chromatography conditions for purification, and / or tituration in an appropriate solvent if needed. TFA can also be added dropwise to the reaction. THF can be substituted for DCM if appropriate for solubility. Table 30Pre p. No.Chemical nameStructureES / MS m / z (M+H)1565-Amino-3-(2,3-difluoro-4-(2-oxo-2-((3-(3-(trifluoromethyl)bicyclo[1.1.1]p entan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 539.41575-Amino-3-[3-chloro-4-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 547.11585-Amino-3-[4-[2-[[3-[2,4-dichloro-5-[(dimethylamino)methyl]phenyl] isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 570.81595-Amino-1-(azetidin-3-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 452.21605-Amino-3-[4-[2-[[3-(2,2-dimethylcyclopropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4371615-Amino-1-isopropyl-3-[4-[2-oxo-2-[(3-spiro[2.2]pentan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]pyrazole-4-carboxamide 435.11625-Amino-3-[4-[2-[[3-[(2,2-difluorocyclopropyl)methyl]isox azol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4591635-Amino-3-[4-[2-[[3-(3,3-difluorocyclopentyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4731645-Amino-1-isopropyl-3-[4-[2-oxo-2-[(3-spiro[2.3]hexan-2-ylisoxazol-5-yl)amino]ethyl]phenyl]pyrazole-4-carboxamide 449.31655-Amino-1-isopropyl-3-[4-[2-oxo-2-[(5-spiro[2.3]hexan-2-ylisoxazol-3-yl)amino]ethyl]phenyl]pyrazole-4-carboxamide 4491665-Amino-3-[4-[2-[[5-(2,2-dimethylcyclobutyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 451.11675-Amino-3-[4-[2-[[3-(2,2-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 451.11685-Amino-1-isopropyl-3-[3-methoxy-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxoethyl]phenyl]pyrazole-4-carboxamide 4811695-Amino-3-[3,5-difluoro-4-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 515.41705-Amino-3-[2-(hydroxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4811715-Amino-3-[4-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-methoxy-phenyl]-1-isopropyl-pyrazole-4-carboxamide 543.21725-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-1-isopropyl-pyrazole-4-carboxamide 457.21735-Amino-3-[3-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-1-isopropyl-pyrazole-4-carboxamide 491.11745-Amino-3-[2-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-fluorophenyl]-1-isopropyl-pyrazole-4-carboxamide 491.11755-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-methyl-phenyl]-1-isopropyl-pyrazole-4-carboxamide 453.11765-Amino-3-[4-[2-[[3-(cyclobutylmethyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4371775-Amino-3-[2-chloro-4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4731785-Amino-1-isopropyl-3-[4-[2-[[3-[(1-methylcyclobutyl)methyl]isoxaz ol-5-yl]amino]-2-oxoethyl]phenyl]pyrazole-4-carboxamide 451.21795-Amino-3-[4-[2-[[3-(3,3-difluoro-1-methylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 473.11805-Amino-3-[4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-fluorophenyl]-1-isopropyl-pyrazole-4-carboxamide 469.21815-Amino-3-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 485.11825-Amino-3-[2-chloro-4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-fluorophenyl]-1-isopropyl-pyrazole-4-carboxamide 503.11835-Amino-3-[4-[2-[[3-(1,1-difluoro-2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4751845-Amino-3-[2-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4671855-Amino-3-[4-[2-[[3-(3,3-dimethylcyclobutyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,3-difluoro-phenyl]-1-isopropyl-pyrazole-4-carboxamide 4871865-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2,5-difluoro-phenyl]-1-isopropyl-pyrazole-4-carboxamide 475.11875-Amino-3-[4-[2-[[5-(3,3-dimethylcyclobutyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4511885-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3,5-difluoro-phenyl]-1-isopropyl-pyrazole-4-carboxamide 475.11895-Amino-3-[2-chloro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 483.11905-Amino-3-[2-chloro-3-fluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 5011915-Amino-3-[4-[2-[[3-(3,3-dimethylcyclobutyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 469.11925-Amino-3-[3,5-difluoro-4-[2-[[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4851935-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 457.11945-Amino-3-[4-[2-[[4-fluoro-3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 4671955-Amino-1-isopropyl-3-[4-[2-oxo-2-[[5-[1-(trifluoromethyl)cyclopropyl]iso xazol-3-yl]amino]ethyl]phenyl]pyrazole-4-carboxamide 477.4 Example 1965-Amino-1-isopropyl-3-[2-(methoxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]pyrazole-4-carboxamide

[0330]

[0331] To 2-[4-bromo-3-(methoxymethyl)phenyl]-N-[5-(1-methylcyclopentyl)isoxazol-3-yl]acetamide (0.130 g, 0.319 mmol) in THF (3 mL) is added bis(pinacolato)diboron (89 mg, 0.350 mmol) and KOAc (95 mg, 0.968 mmol). The reaction mixture is degassed with Ar for 10 min, Pd(dppf)Cl 2 ·CH 2 Cl 2 (27 mg, 0.032 mmol) is added, the mixture is stirred at 50 °C overnight, and cooled to RT. 5-Amino-3-bromo-1-isopropyl-pyrazole-4-carboxamide (95 mg, 0.384 mmol) in THF (1.2 mL) is added followed by K 3 PO 4 (0.206 g, 0.970 mmol) in H 2 O (1.2 mL). The mixture is degassed with Ar for 10 min and XantPhos Pd G3 (95%, 16 mg, 0.016 mmol) is added. The mixture is heated to 50 °C for 20 hr, cooled to RT, and filtered through talcum powder. The filtrate is diluted with EtOAc / H 2 O and the aqueous layer is extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM, followed by a second chromatography, eluting with a gradient of 90% to 100% EtOAc in DCM and by reversed-phase chromatography (C18Aq column), eluting with a gradient of 0% to 100% ACN (0.1% HOAc) in H 2 O to give the title compound. The residue is dissolved in DCM and added dropwise to pentane. The suspension is stirred at RT for 2 hr and filtered. The solid is dried under vacuum at 38 °C for 3 days to give the title compound (35 mg, 22%). ES / MS (m / z) 495 (M+H).

[0332] The following compounds in Table 31 are prepared essentially as described for , 5-amino-1-isopropyl-3-[2-(methoxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]pyrazole-4-carboxamide adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification. The reaction temperature can range from about 50-55 °C. Table 31Ex No.Chemical nameStructureES / MS m / z (M+H)1975-Amino-1-isopropyl-3-[3-(methoxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxoethyl]phenyl]pyrazole-4-carboxamide 4951985-Amino-3-[3-(hydroxymethyl)-4-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 481 Example 1995-Amino-3-(4-(2-((3-(2-chloro-4-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide

[0333]

[0334] 2-(4-(5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl)phenyl)-N-(3-(2-chloro-4-fluorophenyl)isoxazol-5-yl)acetamide (66 mg, 0.134 mmol) and Parkins catalyst (69.2 mg, 0.161 mmol) are stirred in EtOH (1.0 mL) and H 2 O (1.0 mL) at 60 °C for 4 hr, then 50 °C for 4 hrs and RT overnight. The reaction mixture and extracted with EtOAc and washed with H2O (3x). The combined organic extracts are concentrated, and purified by silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes followed by 0% to 20% MeOH (with 1% NH 4 OH) in EtOAc to give the title compound (35 mg, 51%). ES / MS (m / z) 509.1

[0335] The following compounds in Table 32 are prepared essentially as described for 5-amino-3-(4-(2-((3-(2-chloro-4-fluorophenyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification. Table 32Ex. No.Chemical nameStructureES / MS m / z (M+H)2005-Amino-1-(1-cyclopropylethyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 465.22015-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide, 467.22025-Amino-1-cyclopentyl-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 465.22035-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, 481.42045-Amino-3-[4-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide 525.12055-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide 481.22065-Amino-1-(3-ethoxycyclobutyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 495.22075-Amino-1-(1-hydroxypropan-2-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide, 455.22085-Amino-1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 469.22095-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-(3,3,3-trifluoro-2,2-dimethylpropyl)isoxazol-5-yl]amino]ethyl]phenyl]pyrazole-4-carboxamide 492.22105-Amino-3-(4-(2-((3-(4-fluorobicyclo[2.2.2]octan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 495.42115-Amino-1-cyclobutyl-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 451.22125-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide 479.22135-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-4-carboxamide 481.42145-Amino-1-(tert-butyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 453.22155-Amino-1-cyclopropyl-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxoethyl]phenyl]pyrazole-4-carboxamide 437.22165-Amino-3-[4-[2-[(3-benzylisoxazol-5-yl)amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 459.22175-Amino-1-(bicyclo[1.1.1]pentan-1-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 463.22185-Amino-3-[4-[2-[[3-(3-bicyclo[1.1.1]pentanylmethyl)isoxa zol-5-yl]amino]-2-oxoethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide 449.22195-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide 451.22205-Amino-1-(3-hydroxypropyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 455.2 Example 2215-Amino-3-[2,3-difluoro-4-[2-[[3-(3-fluoro-1-bicyclp[1.1.1]pentanyl)isoxazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

[0336]

[0337] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]-N-(3-[3-fluorobicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide (60 mg, 0.124 mmol), NaOH (25 mg, 0.625 mmol) in EtOH:DMSO (6 mL, 5:1), and H 2 O 2 (0.38 mL, 3.72 mmol, 30% in H 2 O) are added together and stirred for 1 hr at 50 °C. The solution is allowed to cool to RT, quenched with saturated aq. Na 2 SO 3 (10 mL) and extracted with EtOAc (3x20 mL). The organic extracts are dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed- phase chromatography (C18 column), eluting with a gradient of 40% to 60% ACN in H 2 O (0.1% FA) to give the title compound (45 mg, 73%). ES / MS (m / z) 501.2 (M+H).Example 2225-Amino-3-(2,3-difluoro-4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

[0338]

[0339] To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-2,3-difluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)acetamide (70 mg, 0.146 mmol) and NaOH (29 mg, 0.725 mmol) in EtOH (3 mL) and DMSO (0.60 mL) is added H 2 O 2 (0.22 mL, 2.15 mmol, 30% in H 2 O). The reaction is stirred for 1 hr at 50 °C. The mixture is allowed to cool to RT and quenched with saturated aq. Na 2 SO 3 (10 mL) at 0 °C. The aqueous layer is extracted with EtOAc (2x30 mL). The combined organic extracts are washed with brine (2x20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 column), eluting with a gradient of 40% to 60% ACN in H 2 O (0.1% NH 4 HCO 3 ) to give the title compound (36 mg, 50%) as a white solid. ES / MS (m / z) 497.3 (M+H).Example 2235-Amino-1-isopropyl-3-[4-([[3-(pyridin-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl]pyrazole-4-carboxamide

[0340]

[0341] To a stirred solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(pyridin-2-yl)-1,2-oxazol-5-yl]acetamide (60 mg, 0.140 mmol) and NaOH (28 mg, 0.700 mmol) in EtOH (1.5 mL), DMSO (0.30 mL), and H 2 O (0.60 mL) is added H 2 O 2 (0.22 mL, 2.15 mmol, 30% in H 2 O) at RT. The mixture is stirred for 3 hr at 40 °C. The reaction is quenched with saturated aq. Na 2 SO 3 (10 mL). The mixture is extracted with EtOAc (3x100 mL). The combined organic extracts are washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reversed-phase chromatography, eluting with a gradient of 10% to 30% ACN in H 2 O (0.1% NH 3 H 2 O) to give the title compound (26 mg, 40%) as a white solid. ES / MS (m / z) 446.2 (M+H).

[0342] The following compounds in Table 33 are prepared essentially as described 5-amino-1-isopropyl-3-[4-([[3-(pyridin-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl]pyrazole-4-carboxamide, 0.3 formic acid, using the appropriate reagents, adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification. The salt formation depends on purification conditions. H 2 O 2 (about 15-30 equiv) can be added dropwise or portionwise, H 2 O can be added if necessary, and temperature can range from about RT to 50 °. Table 33Ex. No.Chemical nameStructureES / MS m / z (M+H)2245-Amino-1-isopropyl-3-[4-([[5-(2-methylbutan-2-yl)-1,2-oxazol-3-yl]carbamoyl]methyl)phenyl] pyrazole-4-carboxamide 439.42255-Amino-3-[4-([[3-(3,5-dichloropyridin-2-yl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 514.12265-Amino-3-[4-([[5-(2,2-dimethylpropyl)-1,2-thiazol-3-yl]carbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 455.32275-Amino-3-[4-([[5-(2,2-dimethylpropyl)-1,3-thiazol-2-yl]carbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 455.42285-Amino-3-[4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazole-4-carboxamide 507.32295-Amino-3-[4-([[3-(3,3-dimethylcyclobutyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-(1-methylcyclopropyl)pyrazole-4-carboxamide 485.4 M+Na2305-Amino-1-(1-methylcyclopropyl)-3-(4-(2-((5-neopentylisoxazol-3-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide 451.42315-Amino-3-[4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-(1-methoxy-2-methylpropan-2-yl)pyrazole-4-carboxamide 483.22325-Amino-1-(1-methylcyclopropyl)-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 515.52335-Amino-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] -1-[1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide 557.22345-Amino-3-(4-(2-oxo-2-((3-(3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide 543.32355-Amino-1-cyclobutyl-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 515.32365-Amino-1-[1-hydroxypropan-2-yl]-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl) pyrazole-4-carboxamide 465.22375-Amino-1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl) pyrazole-4-carboxamide 479.22385-Amino-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl) -1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazole-4-carboxamide 517.32395-Amino-1-tert-butyl-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl) pyrazole-4-carboxamide 463.32405-Amino-3-[4-([[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-(1-hydroxypropan-2-yl)pyrazole-4-carboxamide 513.12415-Amino-3-[4-([[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-(1-hydroxy-2-methylpropan-2-yl)pyrazole-4-carboxamide 527.22425-Amino-1-(1-hydroxypropan-2-yl)-3-[4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 547.32435-Amino-1-(1-methylcyclopropyl)-3-[4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 543.22445-Amino-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-[4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 599.12455-Amino-1-tert-butyl-3-[4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 545.02465-Amino-1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] pyrazole-4-carboxamide 561.12475-Amino-3-(2-fluoro-4-(2-((3-(3-methylbicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide 479.12485-Amino-3-(2-fluoro-4-(2-oxo-2-((3-(3-(trifluoromethyl)bicyclo[1.1.1 ]pentan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide 5332495-Amino-3-[2,3-difluoro-4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1 ] pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] -1-(1-methylcyclopropyl)pyrazole-4-carboxamide 551.12505-Amino-3-[2,3-difluoro-4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] -1-(1-methylcyclopropyl)pyrazole-4-carboxamide 579.22515-Amino-3-(2-fluoro-4-(2-oxo-2-((3-(4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl)isoxazol-5-yl)amino)ethyl)phenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide 561.22525-Amino-3-[2,3-difluoro-4-[([3-[4-(trifluoromethyl)bicyclo[2.2.1 ]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] -1-isopropylpyrazole-4-carboxamide 567.32535-Amino-3-[2,3-difluoro-4-[([3-[4-(trifluoromethyl) bicyclo[2.2.1] heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl] -1-isopropylpyrazole-4-carboxamide 485.22545-Amino-3-(4-(2-((3-(1,1-difluoroethyl)isoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-isopropyl-1H-pyrazole-4-carboxamide 433.52555-Amino-3-[4-([[5-(2,2-dimethylpropyl)-4-methyl-1,3-thiazol-2-yl]carbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 491.4 M+Na2565-Amino-3-(4-[[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]phenyl) -1-(1-methylcyclopropyl)pyrazole-4-carboxamide 461.22575-Amino-3-[4-([[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]methyl)phenyl] -1-isopropylpyrazole-4-carboxamide 439.4 Example 2585-Amino-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl]-1-[1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide, Isomer 1

[0343] Example 2595-Amino-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl]-1-[1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide, Isomer 2

[0344] 5-Amino-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl]-1-[1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide (70 mg) is purified by Prep-CHIRAL-HPLC with the following conditions: Column: Lux 5 µ Cellulose-4, AXIA Packed, 2.12*25 cm, 5 µm eluting with 80% hexanes (0.1%TFA) and 20% IPA; flow rate 20 mL / min in 37 min 205 / 250 nm to give the title compound of Isomer 1 t (R) 18.6 min (15.4 mg, 22.0%, ee=100%) as a light brown solid, ES / MS (m / z) 557.2 (M+H) and the title compound of Isomer 2 t (R) 29.8 min (14.9 mg, 21.2%, ee=99.5%) as a light brown solid, ES / MS (m / z) 557.2 (M+H).

[0345] The following compounds in Table 34 are prepared essentially as described 5-amino-3-[4-[([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]phenyl]-1-[1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2 and adjusting the purification system as appropriate. Table 34Ex. No.Chemical nameStructureES / MS m / z (M+H)t (R) min 1< 2605-Amino-1-[1-hydroxypropan-2-yl]-3-(4-[[(3-[3-methylbicyclo[1.1.1]pe ntan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]p henyl)pyrazole-4-carboxamide, Isomer 1 465.15.25 1< 2615-Amino-1-[1-hydroxypropan-2-yl]-3-(4-[[(3-[3-methylbicyclo[1.1.1]pe ntan-1-yl]-1,2-oxazol-5-yl)carbamoyl]methyl]p henyl)pyrazole-4-carboxamide, Isomer 2 465.111.5 1< 2625-Amino-3-[4-([[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)p henyl]-1-(1-hydroxypropan-2-yl)pyrazole-4-carboxamide, Isomer 1 8.12 1< 2635-Amino-3-[4-([[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]carbamoyl]methyl)p henyl]-1-(1-hydroxypropan-2-yl)pyrazole-4-carboxamide, Isomer 2 16.3 2< 2645-Amino-1-[1-hydroxypropan-2-yl]-3-[4-[([3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]p henyl]pyrazole-4-carboxamide, Isomer 1 547.211.4 3 2< 2655-Amino-1-[1-hydroxypropan-2-yl]-3-[4-[([3-[4-(trifluoromethyl)bicyclo [2.2.1]heptan-1-yl]-1,2-oxazol-5-yl]carbamoyl)methyl]p henyl]pyrazole-4-carboxamide, Isomer 2 547.318.0 5 3< 2665-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[2,2-dimethylcyclopropyl]is oxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 4378.70 3< 2675-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[2,2-dimethylcyclopropyl]is oxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 43712.8 4< 2685-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[spiro[2.2]pentan-2-yl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 435.18.29 4< 2695-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[spiro[2.2]pentan-2-yl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 435.110.1 5 5< 2705-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[[2,2-difluorocyclopropyl]me thyl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 4595.35 5< 2715-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[[2,2-difluorocyclopropyl]me thyl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 459.16.352725-Amino-3-[4-[2-[[3-[3,3-difluorocyclopentyl]iso xazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, Isomer 1 47328.52735-Amino-3-[4-[2-[[3-[3,3-difluorocyclopentyl]iso xazol-5-yl]amino]-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, Isomer 2 47332.8 4 4< 2745-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[spiro[2.3]hexan-2-yl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 44910.6 4< 2755-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[spiro[2.3]hexan-2-yl]isoxazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 44913.5 4 6< 2765-Amino-1-isopropyl-3-[4-[2-oxo-2-[[5-[spiro[2.3]hexan-2-yl]isoxazol-3-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 449.12.222775-Amino-1-isopropyl-3-[4-[2-oxo-2-[[5-[spiro[2.3]hexan-2-yl]isoxazol-3-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 449.13.792785-Amino-1-isopropyl-3-[4-[2-oxo-2-[[5-[2,2-dimethylcyclobutyl]iso xazol-3-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 451.120.9 52795-Amino-1-isopropyl-3-[4-[2-oxo-2-[[5-[2,2-dimethylcyclobutyl]iso xazol-3-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 45121.9 42805-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[2,2-dimethylcyclobutyl]iso xazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 1 451.15.27 7< 2815-Amino-1-isopropyl-3-[4-[2-oxo-2-[[3-[2,2-dimethylcyclobutyl]iso xazol-5-yl]amino]ethyl]phenyl] pyrazole-4-carboxamide, Isomer 2 451.45.76 8< 2825-Amino-1-(1-cyclopropylethyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide, Isomer 1 465.22.37 8< 2835-Amino-1-(1-cyclopropylethyl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide, Isomer 2 465.22.96 9< 2845-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide, Isomer 1 467.21.7 9< 2855-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide, Isomer 2 467.22.22865-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, Isomer 1 481.44.92875-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, Isomer 2 481.47.1 10< 2885-Amino-1-(1-hydroxypropan-2-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide, Isomer 1 455.21.11 10< 2895-Amino-1-(1-hydroxypropan-2-yl)-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1H-pyrazole-4-carboxamide, Isomer 2 455.21.46 11< 2905-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-4-carboxamide, Isomer 1 481.41.71 11< 2915-Amino-3-(4-(2-((3-neopentylisoxazol-5-yl)amino)-2-oxoethyl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-4-carboxamide, Isomer 2 481.42.38 1< CHIRAL ART Amylose-SA, 2*25 cm, 5 µm, 70% hexanes (10 mM NH 3 in MeOH and 30% EtOH. 2< CHIRALPAK IA 2*25 cm, 5 µm, 70% hexanes (10 mM NH 3 in MeOH) and 30% EtOH. 3< CHIRALPAK AD 250 mm x 4.6, 5 µm, 70% to 30% CO 2 with EtOH (0.5% IPAm). 4< Waters Prep SFC200 Chiralpak AD-H 5µm, 250 x 30 mm 70 30 CO 2 / EtOH (0.5% IPAm). 5< CHIRALPAK AD-H 5 µm, 250x30 mm, 78% CO 2 / MeOH (0.5% IPAm). 6< Chiralcel OD 500x76.5 mm, 20 µm, 100% ACN (0.05% IPA). 7< Waters Prep SFC80 (Pirkle (R,R) Whelk-01 5 µm, 250x21.1 mm, 70% CO 2 / MeOH (0.5% IPAm). 8< ChiralPak IC, 4.6x150 mm, 30% MeOH / CO 2 . 9< ChiralPak AD-H, 4.6x150 mm, 35% EtOH / CO 2 . 10< ChiralCel OJ-H, 4.6x150 mm, 15% MeOH / CO 2 . 11< ChiralPak IA, 4.6x150 mm, 30% EtOH / CO 2 . Example 2925-Amino-1-isopropyl-3-[5-[2-oxo-2-[3-(trifluoromethyl)anilino]ethyl]-2-pyridyl]pyrazole-4-carboxamide

[0346]

[0347] To a stirred solution of 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]acetic acid (0.070 g, 0.24 mmol), 3-(trifluoromethyl)aniline (0.047 g, 0.29 mmol), and DIPEA (0.16 g, 1.22 mmol) in DMF (2 mL) is added T3P ®< (0.46 g, 0.73 mmol, 50% in DMF). The mixture is stirred for 2 hr at RT under N 2 then concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 40% to 60% ACN in H 2 O (0.1% FA) to give 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]-N-[3-(trifluoromethyl)phenyl]acetamide (0.050 g, 45%) as a white solid. ES / MS (m / z) 429.1 (M+H).

[0348] To a stirred solution of 2-[6-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)-3-pyridyl]-N-[3-(trifluoromethyl)phenyl]acetamide (0.050 g, 0.11 mmol) and NaOH (0.13 g, 0.58 mmol) in EtOH:DMSO (1.2 mL, 5:1) at 0 °C is added H 2 O 2 (0.13 g, 1.16 mmol, 30% in H 2 O). The mixture is stirred for 4 hr at 40 °C. The solution is cooled to 0 °C, quenched with saturated aq. Na 2 SO 3 , and extracted with EtOAc (2x10 mL). The combined organic extracts are washed with brine (2x30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue is purified by reversed-phase chromatography (C18 gel column), eluting with a gradient of 35% to 45% ACN in H 2 O (0.1% NH 3 H 2 O) to give the title compound (0.021 g, 40%) as a white solid. ES / MS (m / z) 447.1 (M+H).

[0349] The compounds in Table 35 are prepared essentially as described for 5-amino-1-isopropyl-3-[5-[2-oxo-2-[3-(trifluoromethyl)anilino]ethyl]-2-pyridyl]pyrazole-4-carboxamide, using the appropriate amine and carboxylic acid (or lithium salt) and adjusting the reaction time as needed to complete the reaction. Table 35Ex. No.Chemical NameStructureES / MS m / z (M+H)2935-Amino-1-isopropyl-3-[5-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]-2-pyridyl]pyrazole-4-carboxamide 480.22945-Amino-1-isopropyl-3-[5-[2-[[3-(1-methylcyclopentyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]pyrazole-4-carboxamide 4522955-Amino-1-isopropyl-3-[5-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]-2-pyridyl]pyrazole-4-carboxamide 452.22965-Amino-3-[5-[2-[[3-(2-chlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4802975-Amino-3-[5-[2-[(5-tert-butylisoxazol-3-yl)amino]-2-oxoethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4262985-Amino-1-isopropyl-3-[5-[2-oxo-2-[(5-phenylisoxazol-3-yl)amino]ethyl]-2-pyridyl]pyrazole-4-carboxamide 4462995-Amino-1-isopropyl-3-[5-[2-oxo-2-[(3-phenylisoxazol-5-yl)amino]ethyl]-2-pyridyl]pyrazole-4-carboxamide 4463005-Amino-3-[5-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 514.13015-Amino-3-[5-[2-[(3-cyclohexylisoxazol-5-yl)amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 452.43025-Amino-3-[5-[2-[[3-(2-chloro-4-fluoro-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4983035-Amino-3-[5-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4403045-Amino-1-isopropyl-3-[5-[2-[[3-(1-methylcyclopropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]pyrazole-4-carboxamide 4243055-Amino-3-[5-[2-[(5-tert-butylisothiazol-3-yl)amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4423065-Amino-3-[5-[2-[[3-(1,1-difluoroethyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-2-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4343075-Amino-1-isopropyl-3-[5-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]pyrazin-2-yl]pyrazole-4-carboxamide 481.13085-Amino-3-[5-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]pyrazin-2-yl]-1-isopropyl-pyrazole-4-carboxamide 515.13095-Amino-1-isopropyl-3-[5-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]pyrazin-2-yl]pyrazole-4-carboxamide 453.23105-Amino-3-[5-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]pyrazin-2-yl]-1-isopropyl-pyrazole-4-carboxamide 441.33115-Amino-3-[5-[2-[(5-tert-butylisoxazol-3-yl)amino]-2-oxoethyl]pyrazin-2-yl]-1-isopropyl-pyrazole-4-carboxamide 425.3 (M-H)3125-Amino-1-isopropyl-3-[6-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazole-4-carboxamide 480.33135-Amino-1-isopropyl-3-[6-[2-oxo-2-[(3-phenylisoxazol-5-yl)amino]ethyl]-3-pyridyl]pyrazole-4-carboxamide 4463145-Amino-1-isopropyl-3-[6-[2-[[5-(1-methylcyclopentyl)isoxazol-3-yl]amino]-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide 4523155-Amino-3-[6-[2-[[3-(1,1-difluoroethyl)isoxazol-5-yl]lamino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4343165-Amino-3-[6-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]lamino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 5143175-Amino-3-[6-[2-[[3-(2-chlorophenyl)isoxazol-5-yl]lamino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 480.23185-Amino-3-[6-[2-[(5-tert-butylisoxazol-3-yl)amino]-2-oxoethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 426.43195-Amino-1-isopropyl-3-[6-[2-[[3-(1-methylcyclopropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide 4243205-Amino-3-[6-[2-[[3-(4-chloro-3-fluoro-phenyl)isoxazol-5-yl]lamino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 498.23215-Amino-3-[6-[2-[[3-(4-chloro-2-fluoro-phenyl)isoxazol-5-yl]lamino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 498.23225-Amino-3-[6-[2-[[3-(4-chloro-2-methoxy-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 510.23235-Amino-3-[6-[2-[[3-(2-chloro-4-fluoro-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 4983245-Amino-3-[6-[2-[[3-(2-chloro-4-methyl-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 494.23255-Amino-3-[6-[2-[[3-[2-chloro-4-(trifluoromethyl)phenyl]isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 548.13265-Amino-3-[6-[2-[[5-(2,4-dichlorophenyl)-1H-pyrazol-3-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 513.23275-Amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 440.43285-Amino-3-[6-[2-[[3-(3,5-dichloro-2-pyridyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 515.03295-Amino-1-isopropyl-3-[6-[2-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)anilino]-2-oxoethyl]-3-pyridyl]pyrazole-4-carboxamide 559.33305-Amino-3-[6-[2-[[3-(2,4-dichloro-3-fluorophenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 532.13315-Amino-3-[6-[2-[[3-(4-chloro-2-methyl-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 494.13325-Amino-3-[6-[2-[[3-(2,2-dimethylpropyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 440.23335-Amino-3-[6-[2-[[5-(2,4-dichlorophenyl)-1-methyl-pyrazol-3-yl]amino]-2-oxoethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 527.13345-Amino-3-[6-[2-[[3-(2-chloro-4-methoxy-phenyl)isoxazol-5-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 510.13355-Amino-1-isopropyl-3-[6-[2-oxo-2-[[5-(3,3,3-trifluoro-1,1-dimethyl-propyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazole-4-carboxamide 494.23365-Amino-3-[6-[2-[[5-(2,2-dimethylpropyl)isoxazol-3-yl]amino]-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide 440.13375-Amino-1-ethyl-3-[6-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazole-4-carboxamide 466.13385-Amino-1-isopropyl-3-[2-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]pyrimidin-5-yl]pyrazole-4-carboxamide 481.33395-Amino-3-[2-[2-[[3-(2,4-dichlorophenyl)isoxazol-5-yl]amino]-2-oxoethyl]pyrimidin-5-yl]-1-isopropyl-pyrazole-4-carboxamide 515.13405-Amino-1-isopropyl-3-[5-[2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]pyrimidin-2-yl]pyrazole-4-carboxamide 481.1 Biological Assays

[0350] The following assays demonstrate that the compounds described herein are RET kinase inhibitorsAssay A: RET Enzyme Assay

[0351] Compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx are screened for their ability to inhibit wildtype, V804M, and G810S mutant RET kinase using CisBio's HTRF ®< KinEASE ™< -TK assay technology. N-terminal GST tagged recombinant human RET cytoplasmic domain (aa 658-end) from Eurofins (1.25 nM RET; Catalog No. 14-570M) or N-terminal GST tagged recombinant human V804M mutant RET cytoplasmic domain (aa 658-end) from Millipore (1.25 nM enzyme; Catalog No. 14-760) or N-Terminal GST-tagged recombinant human G810S (aa-658-end) (1.25 nM Enzyme; produced in insect cells) is incubated with 62.5 nM TK-substrate biotin (CisBio, part of Catalog No. 62TK0PEC) and 1 mM ATP along with test compound (0.4% final DMSO in the assay) in a 1X Cisbuio enzymatic buffer consisting of 1 nM DTT, 5 mM MgCl 2 , 0.04% BSA and 0.05% Tween20 in a volume of 10 µL. Compounds are typically prepared in a threefold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 40-60 min (40 min for V804M, 60 min for WT and G810S) incubation at 22 °C, the reaction is quenched by adding quench solution (10 µL) containing 7.8 nM Streptavidine-XL665 and 0.5X TK-ab-Cryptate in HTRF detection buffer (all from CisBio, part of Cat. No. 62TK0PEC). After a 60-80 min incubation (60 minutes for WT, 80 minutes for V804M and G810S) at 22 °C, the extent of reaction is determined using a PHERastar plate reader via HTRF detection at excitation / emission 337 / 665 nm. Percent of inhibition is calculated with 0% inhibition referring to control conditions containing no compound (0.4% DMSO only) and 100% inhibition represented by conditions containing no enzyme. The % inhibition values are fit to a 4 parameter logistic curve, and the determined IC 50 value is defined as the estimated concentration of inhibitor at the inflexion point of the fitted curve. The compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 153, 154, 199, 221, 222, 292, 293, 294, 299, 300, 301, 302, 303, 306, 308, 310, 311, 316, 317, 318, 321, 324, 329, 330, and 335 all exhibited IC 50 values of less than 150 nM in at least one of wildtype, V804M, and G810S mutant RET kinases in these assays. This data demonstrates these compounds are RET inhibitors, as are the other compounds disclosed herein.Assay B: RET cell assay

[0352] Compounds of formulas I, Ia to Ix, IIa to IIx, and / or IIIa to IIIx are screened for their ability to inhibit the intracellular autophosphorylation of RET at tyrosine 1062 as detected by In-Cell Western. HEK293 cells containing a doxycycline-inducible plasmid for inducible expression of KIF5B-RET WT and RET mutant forms V804M and G810S are seeded at 25,000 cells / well into black poly-D-lysine pre-coated 384-well plates (Corning, Catalog No. 356697). Expression of KIF5B-RET is induced with doxycycline at 1 µg / mL and cells are incubated at 37 °C overnight. Compounds are prepared in a threefold serial dilution in DMSO before further diluting 1:100 in media prior to the addition to the cells (0.1% final DMSO concentration). Compound treatment is performed for 1 hr at 37 °C followed by fixation of cells with 4% formaldehyde for 20 min at RT and cell permeabilisation with ice-cold MeOH for 10 min at RT. Cells are incubated with Intercept ®< blocking buffer (Li-COR, Catalogue No. 927-70010) for 1 hr at RT. Incubation with primary antibodies against human phospho-RET (Y1062) (R&D, Catalogue No. AF5009, 1 / 250 dilution) and human glyceraldehyde-3-phosphate dehydrogenase (clone 6C5, Merck, Catalog No. MAB374, 1 / 1000 dilution) are performed overnight at 4 °C. Incubation with secondary antibodies IRDye ®< 800CW goat anti-rabbit IgG (Li-COR, Catalogue No. 926-32211, 1 / 1000 dilution) and IRDye ®< 680CW goat anti-mouse IgG (Li-COR, Catalogue No. 926-68070, 1 / 1000 dilution) are performed for 1 hr at RT. All antibody dilutions are done in Intercept ®< blocking buffer containing 0.05% Tween20. After washing cells with PBS-T (Cell Signaling technology, Catalogue No. 9809), the images are acquired on a Li-COR Odyssey LCx at 700 and 800 nm. Percent of DMSO control is calculated with 100% signal referring to control conditions containing no compound (0.4% DMSO only) and 0% signal represented by conditions containing control compound. The % of DMSO control values are fit to a 4 parameter logistic curve, and the determined EC 50 value is defined as the estimated concentration of inhibitor at the inflexion point of the fitted curve. The compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 153, 154, 199, 221, 222, 292, 293, 294, 299, 300, 301, 302, 303, 306, 308, 310, 311, 316, 317, 318, 321, 324, 329, 330, and 335 all inhibited the intracellular autophosphorylation of RET at tyrosine 1062 with EC 50 values of less than 150 nM in at least one of wildtype, V804M, and G810S RET mutant cell assays. This data demonstrates these compounds are RET inhibitors, as are the other compounds disclosed herein.

Claims

1. A compound of the formula: wherein A is C6-C10 aryl or C5-C6 heteroaryl; each R1 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -(C1-C4 alkyl)(C5-C6 heteroalkyl), -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C3-C7 cycloheteroalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloheteroalkyl), -(C0-C4 alkyl)(C4-C10 bicyclyl), -(C0-C4 alkyl)(C5-C6 aryl), -(C0-C4 alkyl)(C5-C6 heteroaryl), -(C0-C4 alkyl)(C4-C10 heterobicyclyl), C5-C12 spiranyl, C5-C12 heterospiranyl, dimethylphosphoryl, adamantyl, C1-C6 alkoxy, -(C1-C4 alkyl)-SO2-(C1-C4 alkyl), difluoromethylsulfanyl, or pentafluorosulfanyl, wherein each R1 is unsubstituted or when it is capable of being substituted, it is substituted with one or more substituents that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, mono-, di, or trihalomethoxy, mono-, di-, or tri-halomethyl, and C0-C3 alkyl-pyrrolidinyl, where the pyrrolidinyl group is unsubstituted or substituted with one, two or 3 independently selected halogen atoms, and wherein two R1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4, 5, or 6; X1, X2, X3, and X4 are each independently N, CH, C-CH3, C-CH2-OH, C-OCH3, C-CH2-OCH3, or C-halogen; and R2 is C1-C6 alkyl, -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C7 heterocycloalkyl), -(C0-C4 alkyl)(C4-C10 bicyclic) each optionally substituted with one or more of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl; or a pharmaceutically acceptable salt thereof.

2. The compounds or a pharmaceutically acceptable salts thereof according to claim 1, wherein A-(R1)n is wherein a wavy line indicates connection to the backbone and the maximum value of n depends on the number of substitutable positions on the A-ring.

3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein A-(R1)n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

4. The compound or a pharmaceutically acceptable salts thereof according to any one of claims 1-2, wherein A-(R1)n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein A-(R1)n is 6. The compound or a pharmaceutically acceptable salts thereof according to any one of claims 1-2, wherein A-(R1)n is and the maximum value of n depends on the number of substitutable positions on the A-ring.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of and 8. The compound according to any one of claims 1 to 7, wherein each R1 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C10 bicyclyl and C5-C12 spiranyl, wherein the C4-C10 bicyclyl is a C4-C8 bridged bicycloalkyl, and wherein each R1 is optionally substituted with one or more of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, or mono-, di-, or tri-halomethyl.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R1 is independently 2,2-dimethylpropyl; 2-chloro-4-fluorophenyl; 2,4-dichlorophenyl; 1,1-dimethyl-2,2,2-trifluoroethyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; trifluoromethyl; 1,1-dimethyl-2,2-difluoropropyl; 1,1-dimethyl-3,3,3-trifluoropropyl; 1-methylcyclopropyl; (1-methylcyclopropyl)methyl; 3-methylbicyclo[1.1.1]pentan-1-yl; 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl; or (3,3-dimethylcyclobutyl)methyl.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R1 is a C4-C8 bridged bicycloalkyl that is unsubstituted or substituted with 1 or 2 groups independently selected from the group consisting of methyl, ethyl, CF3, halo, and CN.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or claim 10, wherein each R1 is independently 12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R1 is independently -CH2C(CH3)3, -CH(CH2CH3)2, -CF2CH3, -CH2CH2CF3, -C(CH3)2F, -C(CH3)2CF3, -CH2-cyclopentyl, -CH2-cyclohexyl, - CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-morpholinyl, -CH2-pyrrolidinyl, phenyl, naphthyl, pyran-4-yl, 4-methylphenyl, 4-methoxyphenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 3-trifluoromethylphenyl, 3-fluoro-S-trifluoromethylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2,4-dimethylphenyl, 4-chlorophenyl, 2-methylphenyl, 3-fluorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-difluoromethoxyphenyl, -C(CH3)2SO2CH3, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3-chlorophenyl, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, 3-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 2,4,6-trifluoromethylphenyl, 3-tetrahydrofuranyl, -C(CH3)2CH2CH3, -C(CH3)2OH, 3,3-dimethylcyclobut-1-yl, 2,3-dichlorobenzyl, 3,3-difluoromethylcyclobutyl, 2,2-dimethylcycloprop-1-yl, 2,2-difluorocyclopropyl, N-methylimidazolyl, 2-methyl-4-chlorophenyl, 2,4-dichloro-3-fluorophenyl, -CH2OCH3, -CH2CF3, -CF2CH3, -CF2C(CH3)3, -CH(CH3)cyclopropyl, 2,6-difluorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 3-chloropyrid-2-yl, 2-methylpyrid-3-yl, 4-methylpyrid-3-yl, 3,5-dichloropyrid-2-yl, 3,3-difluorocyclopentyl, fluoro, chloro, bromo, 2-methoxy-4-chloro-phenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, benzyl, piperidinyl, 4-methyl-piperidinyl, 4-methoxy-piperidinyl, N-methylpyrazol-3-yl, - C(O)-piperidinyl, -OCHF2, 13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein n is 1 and R1 is 2,2-dimethylpropyl or 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R1 is independently 15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein R2 is -C1-C6 alkyl, -C1-C4 alkyl-tetrahydrofuranyl, C3-C6 cycloalkyl, tetrahydrofuranyl, pyranyl, -C1-C4 alkyl - tetrahydropyranyl, -C1-C4 alkyl - C3-C6 cycloalkyl, and azetidinyl, wherein each is unsubstituted or substituted with one or two groups that are independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein R2 is of tert-butyl, -CH(CH3)-cyclopropyl, -2-tetrahydrofuranyl, - 3-tetrahydrofuranyl, -3-pyranyl, -4-pyranyl, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2-(2-tetrahydrofuranyl), -CH2-(3-tetrahydrofuranyl), -(CH2)3OH, -C(CH3)2CH2OCH3, -CH(CH3)CF3, -CH2CF3, -C(CH3)2CH2OCH3, cyclopentyl, 17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein R2 is 18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein R2 is 19. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 that is: or 20. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 that is or 21. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in therapy.

22. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 for use in the treatment of cancer.

23. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 22, wherein the cancer is a RET-associated cancer.

24. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 22 or 23, wherein the cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

25. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 22-24, wherein the cancer is medullary thyroid cancer.

26. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 22-24, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

27. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20 and at least one pharmaceutically acceptable carrier, diluent, or excipient.