Compounds useful for inhibiting RET kinase

Abstract

The present invention provides RET kinase inhibitors according to formula (I): their pharmaceutically acceptable salts, their pharmaceutical compositions, and methods for their use in the treatment of diseases treatable with RET kinase inhibitors, including RET-related diseases and disorders. A, R1, n, X1, X2, X3, X4, and R2 have the meanings given in the specification.

Description

[0001] Background

[0002] The rearranged during transfection (RET) kinase is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily and is essential for the 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 proper folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.

[0003] 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 persephin (PSPN). Unlike other receptor tyrosine kinases, RET does not bind directly to the GFL and requires an additional co-receptor, which can be one of four GDNF family receptor-α (GFRα) family members linked to the cell surface by a glycosylphosphatidylinositol bond. The GFL and GFRα family members form a binary complex, which then binds to RET and recruits it to cholesterol-rich membrane subdomains where RET signaling occurs.

[0004] Following the binding of the ligand-co-receptor complex, dimerization and autophosphorylation of RET on intracellular tyrosine residues recruit adaptor and signaling proteins to stimulate multiple downstream pathways. The binding of adaptor proteins to these docking sites leads to the activation of the Ras-MAPK and PI3K-Akt / mTOR signaling pathways or to the recruitment of ubiquitin ligases of the CBL family, which play a role in the downregulation of RET in RET-mediated functions.

[0005] Disruption of normal RET activity caused by aberrant RET expression due to genetic alterations attributed to the RET kinase, including protein-gene fusions and activating point mutations, leads to hyperactive RET signaling and uncontrolled cell growth, such as in various cancer types and certain gastrointestinal disorders, such as irritable bowel syndrome (IBS). The ability to inhibit aberrant RET activity in cancer patients or patients with other disorders associated with hyperactive RET signaling would be highly beneficial to these patients. Additionally, some RET kinase genetic alterations cause conformational structural changes in the RET kinase such that a given RET kinase inhibitor may be less effective (or ineffective). In these cases, novel RET kinase inhibitors that are effective against the modified RET kinase would greatly benefit patients.

[0006] Overview

[0007] This disclosure provides compounds of the following formula:

[0008]

[0009] and their pharmaceutically acceptable salts and pharmaceutical compositions. In formula (I), A can be a five- or six-membered aryl or heteroaryl; R1 can be hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -(C0-C4 alkyl)(C5-C6 heteroalkyl), -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C7 cycloheteroalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloheteroalkyl), -(C0-C4 alkyl)(C4-C 10 bicyclo), -(C0-C4 alkyl)(C5-C6 aryl), -(C0-C4 alkyl)(C5-C6 heteroaryl), -(C0-C4 alkyl)(C4-C 10 heterobicyclo), C5-C 12 spiroalkane, C5-C 12 heterospiroalkane, adamantane, difluoromethylthio or pentafluorothio, where each R1 is optionally substituted by one or more groups independently selected from halogen, cyano, hydroxy, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine or mono-, di- or tri-halomethyl, and where two R1 groups can be fused to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4 or 5; X1, X2, X3 and X4 can each independently be N, CH, C-CH3, C-CH2-OH, C-OCH3, C-CH2-OCH3 or C-halogen; and R2 can be C1-C4 alkyl, -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C7 heterocycloalkyl), -(C0-C4 alkyl)(C4-C 10 bicyclo), each optionally substituted by one or more groups independently selected from deuterium, halogen, cyano, hydroxy, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl or mono-, di- or tri-halomethyl. The compounds of formula (I) contain chiral centers to provide the R-enantiomeric form and the S-enantiomeric form as shown herein:

[0010]

[0011] (R-enantiomer)

[0012]

[0013] (S-enantiomer)

[0014] Also provided are the R-enantiomer and S-enantiomer, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof, wherein A, R1, n, X1, X2, X3, X4, and R2 are as defined herein. It is to be understood that Formulas II and III are subclasses of Formula I, and thus references to Formula I throughout this application also apply to Formulas II and III.

[0015] Also provided is a method of treating cancer, particularly cancer having abnormal RET expression (e.g., RET-related cancers such as medullary thyroid cancer or RET fusion lung cancer), using a compound of Formula I, II, or III, its pharmaceutically acceptable salt, or a pharmaceutical composition thereof. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, II, or III or its pharmaceutically acceptable salt.

[0016] Also provided herein are compounds of Formulas I, II, and III and their pharmaceutically acceptable salts for use in therapy. Further provided herein are compounds of Formulas I, II, and III and their pharmaceutically acceptable salts for treating cancer, particularly cancer having abnormal RET expression (e.g., RET-related cancers such as medullary thyroid cancer or RET fusion lung cancer). Also provided is the use of a compound of Formulas I, II, and III or its pharmaceutically acceptable salt in the preparation of a medicament for treating cancer, particularly cancer having abnormal RET expression (e.g., RET-related cancers such as medullary thyroid cancer or RET fusion lung cancer).

[0017] Description

[0018] Novel RET kinase inhibitor compounds are described herein. These novel compounds address the need for a potent and effective treatment for disorders associated with abnormal RET activity, such as IBS or cancer, particularly cancers caused by hyperactive RET signaling (i.e., RET-related cancers). More specifically, these novel compounds address the need for a potent and effective treatment for RET-related cancers such as lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), 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 tumors, lung adenocarcinoma, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal gangliocytomatosis, inflammatory myofibroblastic tumor, or cervical cancer.

[0019] The compounds described herein are compounds of formula (I):

[0020]

[0021] or a pharmaceutically acceptable salt thereof. In formula (I),

[0022] A is a five- or six-membered aryl or heteroaryl;

[0023] Each R1 may be attached to A at various chemically suitable positions and is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -(C0-C4 alkyl)(C5-C6 heteroalkyl), -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C7 cycloheteroalkyl), -(C0-C4 heteroalkyl)(C3-C7 cycloheteroalkyl), -(C0-C4 alkyl)(C4-C 10 bicyclic), -(C0-C4 alkyl)(C5-C6 aryl), -(C0-C4 alkyl)(C5-C6 heteroaryl), -(C0-C4 alkyl)(C4-C 10 heterobicyclic), C5-C 12 spiroalkane, C5-C 12 heterospiroalkane, adamantane, difluoromethylthio or pentafluorothio, wherein each R1 is optionally substituted by one or more groups independently selected from halogen, cyano, hydroxy, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine or mono-, di- or tri-halomethyl, and wherein two R1 groups may be fused to form a ring structure that includes a part of A and is optionally aromatic, and n is 1, 2, 3, 4 or 5;

[0024] X1, X2, X3 and X4 are each independently N, CH, C-CH3, C-CH2-OH, C-OCH3, C-CH2-OCH3 or C-halogen; and

[0025] R2 is C1-C4 alkyl, -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C7 heterocycloalkyl), -(C0-C4 alkyl)(C4-C 10 bicyclic), each optionally substituted by one or more groups independently selected from deuterium, halogen, cyano, hydroxy, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl or mono-, di- or tri-halomethyl.

[0026] Although n is defined as 1, 2, 3, 4 or 5, some A rings have 5 positions available for R1 groups while others do not. For example, phenyl has 5 substitutable positions, pyrazole has three substitutable positions, and isoxazole has only two. Thus, the maximum value of the variable n can depend on what the A ring is.

[0027] The specific chemical naming conventions used herein are familiar to those skilled in the art of chemistry. For greater clarity, certain terms are specifically defined.

[0028] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched-chain monovalent hydrocarbon group having 1 to 4 atoms, such as "C1-C4 alkyl". In the case where 0 is indicated, such as C0-C4 alkyl, this component of the substituent may be absent. Thus, if a C5 heterocycloalkyl substituent is in the R2 position in formula (I), the C5 heterocycloalkyl substituent will be described by a substituent such as -(C0-C4 alkyl)(C4-C7 heterocycloalkyl) as described for R2, i.e., the substituent is -(C0)(C5 heterocycloalkyl). Examples include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, and butyl. Similarly, as used herein, the term "heteroalkyl" refers to a saturated, straight-chain or branched-chain monovalent alkyl molecule containing one or more heteroatoms in place of carbon in the alkyl chain as defined herein.

[0029] As used herein, the term "C5-C6 aryl" refers to a functional group or substituent derived from an aromatic ring containing 5 to 7 carbon atoms and no heteroatoms. As used herein, the term "C5-C6 heteroaryl" refers to a functional group or substituent derived from an aromatic ring containing carbon atoms and one or more heteroatoms (such as nitrogen, oxygen, or sulfur) as part of the aromatic ring such that the ring contains 5 to 7 atoms. Examples of aryl and heteroaryl include, but are not limited to, benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, and thiazole.

[0030] As used herein, the term "C3-C7 cycloalkyl" refers to a cycloalkyl molecule containing 3 to 7 carbon atoms. Examples of C3-C7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl. Similarly, as used herein, the term "C4-C7 cycloheteroalkyl" refers to a cycloalkyl molecule as defined herein containing 4 to 7 total atoms and including one or more heteroatoms in place of carbon in the cycloalkyl chain.

[0031] As used herein, the term "C4-C 10 "bicyclic" refers to a group having two or more fused or bridged rings composed of 4 to 10 carbon atoms. When the C4-C 10 bicyclic group is fused, the two rings share two adjacent atoms. When the C4-C 10 bicyclic group is bridged, the two rings share three or more atoms. Bicyclic molecules can be fully aliphatic, fully aromatic, or mixed aromatic-aliphatic. The term C4-C 10 "heterobicyclic" refers to a C4-C 10 bicyclic group as defined that also includes one or more heteroatoms. Examples of bridged C4-C8 cycloalkyl molecules that can be used in the compounds of formula (I) include, but are not limited to:

[0032] 3-Methyl-bicyclo[1.1.1]pentyl, and

[0033] 3-(Trifluoromethyl)-bicyclo[1.1.1]pentyl.

[0034] As used herein, the term C5-C 12 spiroalkane refers to a group having two or more rings composed of 7 to 12 carbon atoms connected via a single shared carbon atom. Similarly, the term C5-C 12 heterospiroalkane refers to a group having two or more rings composed of 7 to 12 atoms including carbon and at least one heteroatom connected via a spirocyclic linkage through a carbon atom, wherein each ring has 3 to 6 ring atoms (one of which is a carbon atom shared by two rings), and wherein two of the ring atoms are nitrogen atoms. Examples of C5-C 12 spiroalkanes and heterospiroalkanes that can be used in the compounds of formula (I) include, but are not limited to:

[0035] Spiro[3.3]heptyl,

[0036] Spiro[3.3]hept-2-one-yl,

[0037] Spiro[3.3]hept-2-ol-yl,

[0038] 2-Methylspiro[3.3]hept-2-ol-yl,

[0039] 7-Methyl-7-azaspiro[3.5]nonyl, and

[0040] 8-Methyl-8-azaspiro[4.5]decyl.

[0041] As used herein, the term halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0042] As used herein, the term oxo refers to oxygen double-bonded to a carbon atom.

[0043] In the compounds of formula (I), A-(R1) n can be

[0044]

[0045]

[0046] where the wavy line indicates the point of attachment of A to the backbone as shown in formula (I).

[0047] In one embodiment, in the compound of formula (I), A-(R1) n is .

[0048] In one embodiment, in the compound of formula (I), A-(R1) n is .

[0049] In another embodiment, in the compound of formula (I), A-(R1) n is . In a preferred embodiment, the halogen is F or Cl.

[0050] In yet another embodiment, in the compound of formula (I), A-(R1) n is .

[0051] In another embodiment, in the compound of formula (I), A-(R1) n can be

[0052] or .

[0053] In one embodiment, in the compound of formula (I), A-(R1) n is

[0054] ; and n is 1.

[0055] In a further embodiment, in the compound of formula (I), A-(R1) n is or .

[0056] In one embodiment, A-(R1) n is phenyl substituted by (R1) n . In a further embodiment, n is 1-4, or 1-3, or 1-2, or 1, or 2, or 2-4, or 2-5. In some embodiments, when A-(R1) n is phenyl substituted by (R1) n , two R1 groups are fused to form a ring structure that includes a part of A and is optionally aromatic, and the resulting A ring is optionally substituted as described herein.

[0057] In some embodiments, in the compound of formula (I), each R1 is independently selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF 3、 .

[0058] In a further embodiment, in the compound of formula (I), at least one R1 group is H or CH3.

[0059] In another embodiment, in the compound of formula (I), at least one R1 is a halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0060] In yet another embodiment, at least one R1 is a halogen, -CH2C(CH3)3, or .

[0061] In yet another embodiment, at least one R1 is CH3, -CH2C(CH3)3, -C(CH3)2CF3, C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3 or CF3.

[0062] In another embodiment, at least one R1 is an optionally substituted C5-C 12 spiroalkane.

[0063] In yet another embodiment, at least one R1 is difluoromethylthio or pentafluorothio.

[0064] In yet another embodiment, at least one R1 is 2-fluoro-4-chlorophenyl; 2-chloro-4-fluorophenyl; 2,4-dichlorophenyl; or 2,4-difluorophenyl.

[0065] In the compound of formula (I), R2 can be

[0066] , where the wavy line indicates the point of attachment to the main chain.

[0067] In some embodiments, in the compound of formula (I), R2 is -CH(CH3)2, -CH(CF3)CH3, -CH(CH3)CHF2 or .

[0068] In other embodiments, in the compound of formula (I), R2 is .

[0069] In another embodiment, in the compound of formula (I), R2 is .

[0070] In yet another embodiment, in the compound of formula (I), R2 is .

[0071] In some embodiments, in the compound of formula (I), R2 is deuterated, i.e., it contains at least one deuterium. In some further embodiments, deuterated R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3.

[0072] In some embodiments, R2 is -CH(CD3)2.

[0073] In various embodiments, X1, X2, X3 and X4 are CH.

[0074] In other embodiments, X1, X2, X3 and X4 are each independently CH, C-CH3, C-CH2-OH, C-OCH3, C-CH2-OCH3 or C-halogen, where at least one of X1, X2, X3 and X4 is not CH.

[0075] In some embodiments, two of X1, X2, X3 and X4 are CH and the other two are C-halogen. In a further embodiment, X1 and X2 are CF and X3 and X4 are CH.

[0076] In various embodiments, three of X1, X2, X3 and X4 are CH and one is C-halogen. In a further embodiment, X2 is CF and X1, X3 and X4 are CH.

[0077] In still other embodiments, one of X1, X2, X3 and X4 is N.

[0078] In a further embodiment, X2 is N and at least two of X1, X3 and X4 are CH.

[0079] In a still further embodiment, X1 is N and at least two of X2, X3 and X4 are CH.

[0080] In all of the above embodiments, it is to be understood that the definitions of the variables apply to the non-salt form “or a pharmaceutically acceptable salt thereof”.

[0081] Those skilled in the art will recognize that the compound described by formula (I) or a pharmaceutically acceptable salt thereof contains at least one chiral center, the position of which in formula (I) ϕ is designated by ϕ:

[0082]

[0083] (Other chiral centers may also be created by various optional substitution patterns of R1 and R2, and further sets of diastereoisomers may be created). Those skilled in the art will also recognize that the Cahn-Ingold-Prelog (R) or (S) designations of the chiral centers will vary with the substitution pattern around the chiral center. The chiral centers designated in the compounds of formula (I) provide the R-enantiomeric form shown in formula (II) and the S-enantiomeric form shown in formula (III):

[0084]

[0085]

[0086] This text also provides compounds of formula (II) and formula (III) or pharmaceutically acceptable salts thereof, wherein A, R1, n, X1, X2, X3, X4 and R2 are as defined for formula (I). If there are multiple chiral centers, diastereoisomers may also exist.

[0087] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0088] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0089] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0090] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0091] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0092] In a still further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0093] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0094] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0095] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0096] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0097] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0098] In yet a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0099] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0100] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, and .

[0101] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0102] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0103] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0104] In a still further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0105] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0106] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0107] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0108] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0109] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0110] In yet a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0111] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is or , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0112] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0113] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is or , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0114] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , where R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0115] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is or , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0116] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , wherein R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF 3、 , and .

[0117] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0118] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0119] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , wherein each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0120] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0121] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0122] In yet a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is selected from H, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, , and .

[0123] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0124] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0125] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0126] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0127] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0128] In yet a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0129] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0130] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0131] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0132] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0133] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0134] In a still further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0135] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0136] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0137] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0138] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; Three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0139] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0140] In a still further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0141] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0142] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0143] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0144] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0145] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0146] In a still further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where at least one R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0147] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is or , wherein R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0148] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , wherein R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0149] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is or , wherein R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0150] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0151] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is or , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0152] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is or , where R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0153] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0154] In another aspect, in the compounds of formula (I), (II) and / or (III), R2 is isopropyl; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0155] In one aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0156] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is ; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0157] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; X1, X2, X3 and X4 are CH; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0158] In a further aspect, in the compounds of formula (I), (II) and / or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2 or -CD(CH3)CD3; three of X1, X2, X3 and X4 are CH, and one of X1, X2, X3 and X4 is N; A-(R1) n is , where each R1 is halogen, , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , , , -C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3.

[0159] Whenever a variable is defined as "each", e.g., "each R1 is...", it is to be understood that the definition of the variable at each occurrence is independently selected from the groups contained in the definition. Thus, for example, if a phenyl group is substituted by four R1 groups, the identity of each R1 group is independently selected from the groups listed in the definition of R1. Accordingly, all four R1 groups can be the same or they can all be different, or some groups can be the same while others are different.

[0160] Specific enantiomers can be prepared starting with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, a single enantiomer can be separated from a mixture of different chiral forms at any convenient point in the synthesis of the compounds of formula (I), formula (II) and formula (III) by standard chiral chromatography or crystallization techniques. This text is intended to include all individual enantiomers, as well as mixtures of enantiomers of the compounds of formula (II) and formula (III), including racemates.

[0161] Specific examples of the compounds of formula (I), including the forms of formula (II) and formula (III), are shown in the examples below. A subset of the molecules available in the examples is shown in Table A.

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] The structures depicted in Table A do not indicate the absolute stereochemistry at the chiral positions of the main chain (as indicated by ϕ in formula (I)). However, the isomers can be separated by chiral chromatography as described in the examples below and often different activities are noted between the isomers. Thus, in each example in Table A, the designated isomer (i.e., isomer 1 or isomer 2) can be the R - enantiomeric form of the molecule as distinct from the S - enantiomeric form (or vice versa). The R - enantiomeric form and the S - enantiomeric form are both indicated in the examples below and both forms are intended to be included within the present disclosure. ϕ Compounds of formula (I), including the forms of formula (II) and formula (III), can also be deuterated at specific positions, and such deuterated forms are understood to be disclosed herein, where hydrogen in the disclosed molecules can be replaced by deuterium.

[0168] The compounds of formula (I), (II) and (III) described herein may form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts of the compounds of formula (I), (II) and (III) are intended to be included. Pharmaceutically acceptable salts and their common preparation methods are well - known in the art (see, for example, P. Stahl et al.

[0169] , Second Revised Edition (Wiley - VCH, 2011); S.M. Berge et al., “Pharmaceutical Salts,” Handbook of Pharmaceutical Salts: Properties, Selection and Use , Vol. 66, No. 1, January 1977). Journal of Pharmaceutical Sciences

[0170] The compounds of formula (I), (II) and (III) as described herein are generally effective over a wide dosage range. For example, the daily dosage ranges from about 1 mg / kg to about 200 mg / kg. In addition, the compounds of formula (I), (II) and (III) as described herein can be administered, for example, in an amount from about 1 mg / kg to about 150 mg / kg, from about 1 mg / kg to about 100 mg / kg, from about 5 mg / kg to about 150 mg / kg, from about 5 mg / kg to about 100 mg / kg, from about 20 mg / kg to about 40 mg / kg, from about 25 mg / kg to about 35 mg / kg, from about 50 mg / kg to about 70 mg / kg, from about 55 mg / kg to about 65 mg / kg, from about 90 mg / kg to about 110 mg / kg, from about 95 mg / kg to about 105 mg / kg, or from about 50 mg / kg to about 150 mg / kg. Additionally, the compounds of formula (I), (II) and (III) as described herein can be administered, for example, in an amount of about 5 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. The daily administration can be once daily or in multiple doses, for example, twice daily (BID). It is to be understood that the amount of the compound actually administered is determined by the physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.

[0171] The compounds of formula (I), (II) and (III) as described herein can be formulated into pharmaceutical compositions for administration by various routes. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, for example Remington:The Science and Practice of Pharmacy (A. Gennaro et al., 21st Edition, Mack Publishing Co., 2005)). Specifically, the compounds of formula (I), (II) and (III) as described herein or their pharmaceutically acceptable salts can be combined with one or more pharmaceutically acceptable carriers, diluents or excipients. More particularly, the compounds of formula (I), (II) and (III) as described herein can be formulated into pharmaceutical compositions. In addition, the compounds of formula (I), (II) and (III) as described herein or their pharmaceutically acceptable salts can be combined with one or more other therapeutic agents. For example, the compounds of formula (I), (II) and (III) as described herein or their pharmaceutically acceptable salts can be components 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. The pharmaceutical compositions containing the compounds of formula (I), (II) and (III) as described herein or their pharmaceutically acceptable salts can be used in the methods described herein.

[0172] As used herein, the term "treatment" refers to inhibiting, slowing down, stopping or reversing the progression or severity of an existing symptom, condition or disorder.

[0173] As used herein, the term "irritable bowel syndrome" or "IBS" refers to 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.

[0174] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition of a patient that is typically characterized by unregulated cell proliferation. Benign and malignant cancers are included in this definition. "Early cancer" or "early tumor" refers to a cancer that is not advanced or metastatic or is classified as stage 0, I, or II cancer. Examples of cancers include, but are not limited to, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), 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 tumors, lung adenocarcinoma, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, inflammatory myofibroblastic tumor, and cervical cancer.

[0175] As used herein, the term "RET-related disease or disorder" refers to a disease or disorder associated with or having an aberration in the regulation of the RET gene, the RET kinase (also referred to herein as the RET kinase protein), or the expression or activity or amount of either (e.g., any type of aberration in the expression or activity or amount of the RET gene, the RET kinase, the RET kinase domain, or either as described herein).

[0176] As used herein, the term "RET-related cancer" refers to a cancer associated with or having an aberration in the regulation of the RET gene, the RET kinase (also referred to herein as the RET kinase protein), or the expression or activity or amount of either. Non-limiting examples of RET-related cancers are described herein.

[0177] The phrase "abnormal regulation of the expression, activity or amount of the RET gene, RET kinase or any of them" refers to gene mutations. Examples of such gene mutations that cause abnormal regulation of the expression, activity or amount of the RET gene, RET kinase or any of them include, but are not limited to, RET gene translocations that result in the expression of a fusion protein, RET gene deletions that result in the expression of a RET protein that includes the deletion of at least one amino acid compared to the wild-type RET protein, RET gene mutations that result in the expression of a RET protein with one or more point mutations, or alternative splicing versions of RET mRNA that result in the production of a RET protein that deletes at least one amino acid in the RET protein compared to the wild-type RET protein, or RET gene amplifications that result in overexpression of the RET protein or autocrine activity caused by overexpression of the RET gene in cells to cause a pathogenic increase in the activity of the kinase domain of the RET protein in the cells (e.g., constitutively active kinase domain of the RET protein). Abnormal regulation of the expression, activity or amount of the RET gene, RET protein or any of them can be a mutation in the RET gene encoding the RET protein that is constitutively active or has increased activity compared to the protein encoded by the RET gene that does not include the mutation. For example, abnormal regulation of the expression, activity or amount of the RET gene, RET protein or any of them can be the result of a gene or chromosomal translocation such that a fusion protein is expressed that contains a first part of RET that includes a functional kinase domain and a second part of a partner protein (i.e., non-RET). In some instances, abnormal regulation of the expression, activity or amount of the RET gene, RET protein or any of them can be the result of a gene translocation of one RET gene with another non-RET gene.

[0178] Methods of treating RET-related diseases or disorders, particularly treating IBS or cancer with abnormal RET expression, using the compounds of formulas (I), (II) and (III) as described herein are provided. Examples of cancers with abnormal RET expression include cancers caused by abnormal regulation of the expression, activity or amount of the RET gene, RET kinase or any of them. One such method of treating a RET-related disease or disorder, such as IBS or cancer, includes administering a therapeutically effective amount to a patient in need thereof. Another method of treating a RET-related disease or disorder, such as IBS or cancer, includes a) detecting abnormal regulation of the expression, activity or amount of the RET gene, RET kinase or any of them in a sample from a patient; and b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt.

[0179] Deregulation of the expression, activity, or amount of the RET gene, RET kinase, or either thereof can be the result of one or more chromosomal translocations or inversions that result in RET gene fusions (i.e., gene translocations that result in a fusion protein that contains residues from a non-RET partner protein and includes a minimal amount of the 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 known as PTC1, D10S170, or H4) (NSCLC, colon cancer, papillary thyroid cancer, adenocarcinoma, lung adenocarcinoma, metastatic colorectal cancer, adenosquamous carcinoma, breast cancer); CCDC88C (NSCLC); 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 known as 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 known as PTC5) (papillary thyroid cancer, Spitzoid tumor); H4L (various); HOOK3 (papillary thyroid cancer); HRH4-RET (thyroid cancer and / or papillary thyroid cancer); HTIF1 (various); KIAA1217 (also known as SKT) (papillary thyroid cancer, lung adenocarcinoma, NSCLC); KIAA1468 (also known as PTC9 and RFG9) (papillary thyroid cancer, lung adenocarcinoma); KIF13A (NSCLC); KIF5B (NSCLC, ovarian cancer, Spitzoid tumor, lung adenocarcinoma, adenosquamous carcinoma); KTN1 (also known as PTC8) (papillary thyroid cancer); MBD1 (also known as PCM1) (papillary thyroid cancer); MPRIP (NSCLC); MYH10 (infantile fibromatosis); MYH13 (medullary thyroid cancer); NCOA4 (also known as PTC3, ELE1, and RFG) (papillary thyroid cancer, NSCLC, colon cancer, salivary adenocarcinoma, metastatic colorectal cancer, lung adenocarcinoma, adenosquamous carcinoma of the diffuse sclerosing variant of papillary thyroid cancer, breast cancer, acinar cell carcinoma, mammary-like secretory carcinoma); OLFM4 (small intestine cancer); PARD3 (NSCLC); PCM1 (papillary thyroid cancer); PIBF1 (bronchioloalveolar cell carcinoma); PICALM (NSCLC); PPFIBP2 (papillary thyroid cancer);PRKAR1A (also known as PTC2) (papillary thyroid carcinoma); PTC1ex9 (novel CCDC6 rearrangement) (metastatic papillary thyroid carcinoma); PTC4 (novel NCO4 / ELE1 rearrangement) (papillary thyroid carcinoma); RAB61P2 (papillary thyroid carcinoma); RASAL2 (sarcoma); RASGEF1A (breast cancer); RBPMS (NSCLC); RFG8 (papillary thyroid carcinoma); RRBP1 (colon cancer); RUFY1 (colorectal cancer); RUFY2 (NSCLC; papillary thyroid carcinoma); RUFY3 (papillary thyroid carcinoma); SLC12A2 (NSCLC); SORBS2 (papillary thyroid carcinoma); SPECC1L (papillary thyroid carcinoma; thyroid carcinoma); SQSTM1 (papillary thyroid carcinoma); TAF3 (pancreatic cancer); TBL1XR1 (papillary thyroid carcinoma, thyroid carcinoma); TFG (pancreatic cancer); TIF1G (various); TRIM24 (also known as PTC6) (papillary thyroid carcinoma); TRIM27 (also known as RFP) (papillary thyroid carcinoma); AKAP13 (papillary thyroid carcinoma); TRIM33 (also known as PTC7 and RFG7) (NSCLC, papillary thyroid carcinoma); and UEVLD (papillary thyroid carcinoma). The fusion protein can be, for example, KIF5B-RET. Some other RET fusion proteins may not be included in this list or are yet unknown; however, the compounds of formulas (I), (II) and (III) as described herein and their methods of use are expected to be effective inhibitors.;

[0180] Aberrant regulation of the RET gene, the RET kinase or the expression or activity or amount of either thereof can be caused by one or more point mutations, insertions or deletions in the RET gene (compared to wild-type RET). As a reference, the sequence of the mature human RET protein is provided herein (SEQ ID NO: 1:

[0181] .

[0182] Non-limiting examples of activating RET kinase protein point mutations, insertions or deletions 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., glutamate to stop codon), 145 (e.g., V145G), amino acid position 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 frameshift), 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 GermlineDeletion), 633 (e.g., 9-base pair duplication), 634 (e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T, or insertion of ELCR, or 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 (such as V804L, V804M, V804E, V804G, V804S) (such as causing MTC), 804 / 918 (such as V804M / M918T, V804L / M918T), 805 (such as E805K), 804 / 805 (such as V804M / E805K), 806 (such as Y806F, Y806C, Y806H, Y806Y), 810 (such as G810R, G810S, G810A, G810C, G810V), 818 (such as E818K), 819 (such as S819I), 823 (such as G823E), 826 (such as Y826M, Y826S), 833 (such as R833C), 841 (such as P841L, P841P), 843 (such as E843D), 844 (such as R844W, R844Q, R844L), 848 (such as M848T), 852 (such as I852M), 865 (such as L865V), 870 (such as L870F), 873 (such as R873W), 876 (such as A876V), 881 (such as L881V), 882, 883 (such as A883F, A883P, A883S, A883T, A883Y), 884 (such as E884K), 886 (such as R886W), 891 (such as S891A), 897 (such as R897Q), 898 (such as D898V), 900 (such as Y900F), 901 (such as E901K), 904 (such as S904F, S904C), 905 (such as Y905F), 907 (such as K907E, K907M), 908 (such as R908K), 911 (such as G911D), 912 (such as R912P, R912Q), 918 (such as M918T, M918V, M918L, M918R) (such as causing MTC), 919 (such as A919V), 921 (such as E921K), 922 (such as S922P, S922Y), 930 (such as T930M), 961 (such as F961L), 972 (such as R972G), 981 (such as Y981F), 982 (such as R982C), 1009 (such as M1009V), 1015 (such as Y1015F), 1017 (such as D1017N), 1041 (such as V1041G), 1064 (such as M1064T), 1096 (such as Y1096F), RET+3, in-frame deletions in exons 6 and 11, 3bp in-frame deletion in exon 15, nucleotide position 2136+2 (such as 2136+2T>G), del632-636ins6. Point mutations / insertions / deletions in the RET kinase protein can be, for example, M918T, M918V, C634W, V804L or V804M. Some other point mutations / insertions / deletions in the RET kinase protein may not be included in this list or may still be unknown; however, the compounds of formulas (I), (II) and (III) as described herein and their methods of use are expected to be effective inhibitors.

[0183] Dysregulation of the expression or activity or amount of the RET gene, RET kinase or either of them may also include splicing changes in the RET mRNA, which results in an alternative splice variant of RET in which the expressed protein has deleted at least one residue (compared to the wild-type RET kinase) to cause constitutive activation of the RET kinase domain.

[0184] "RET kinase inhibitor" as defined herein refers to a compound that inhibits RET activity using a measurement method, such as the bioassay described below in the examples.

[0185] In some cases, the RET kinase containing a mutation, insertion or deletion is more resistant to the inhibition of its phosphotransferase activity by one or more first RET kinase inhibitors compared to the wild-type RET kinase or a RET kinase that does not include the same mutation. Such a mutation may not reduce the sensitivity of cancer cells or tumors having the RET kinase to treatment with the compounds of formulas (I), (II) and (III) as described herein (e.g., compared to cancer cells or tumors that do not include a specific RET inhibitor-resistant mutation). In these cases, compared to the wild-type RET kinase or a RET kinase that does not have the same mutation in the presence of the same first RET kinase inhibitor, the RET inhibitor-resistant mutation can result in the RET kinase having increased V max , decreased K m for ATP and increased K D for the first RET kinase inhibitor, one or more of which.

[0186] In other cases, the RET kinase containing a mutation, insertion or deletion has increased resistance to the compounds of formulas (I), (II) and (III) as described herein compared to the wild-type RET kinase or a RET kinase that does not include the same mutation. In such cases, compared to the wild-type RET kinase or a RET kinase that does not have the same mutation in the presence of the same compounds of formulas (I), (II) and (III) as described herein, the RET inhibitor-resistant mutation can result in the RET kinase having increased V max , decreased K m and increased K D , one or more of which.

[0187] Examples of RET inhibitor resistant mutations can include point mutations, insertions or deletions in and near the ATP binding site in the tertiary structure of the RET kinase (including but not limited to the gatekeeper residue, P-loop residues, residues in or near the DFG motif, and the 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 not limited to residues in the activation loop, residues near or interacting with the activation loop, residues contributing to the active or inactive enzyme conformation, changes including mutations, deletions and insertions in the loop proceeding the C-helix and in the C-helix. Specific residues or residue regions known to form RET inhibitor resistance upon mutation herein include but are not limited to the following amino acids (based on the human wild-type 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 resistant mutation positions include but are not limited to the following amino acids (based on the human wild-type 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 sequence, and deletions within or flanking the sequence) are thought to induce steric and / or active conformational effects that alter inhibitor binding characteristics.

[0188] The compounds of formulas (I), (II), and (III) as described herein can be used to treat patients suffering from cancers with certain RET inhibitor-resistant mutations. For example, resistant mutations that result in increased resistance to RET inhibitors, such as substitutions at amino acid position 804 (e.g., V804M, V804L, or V804E), and / or one or more other RET inhibitor-resistant mutations, such as those discussed above, can be treated by combination administration or as a follow-up treatment to existing drug therapy. For example, if a patient is treated with a first RET kinase inhibitor and the patient develops a RET inhibitor-resistant mutation, the patient can subsequently be treated with a compound of formulas (I), (II), and (III) as described herein or a pharmaceutically acceptable salt thereof (assuming the compound of formulas (I), (II), and (III) as described herein is a suitable inhibitor of the specific RET kinase inhibitor mutation present). As another example, if a patient is known to have a specific RET kinase inhibitor mutation (or mutations), the patient can be treated simultaneously with multiple RET kinase inhibitors, including a compound of formulas (I), (II), and (III) as described herein or a pharmaceutically acceptable salt thereof, which are effective against the RET kinase inhibitor mutation(s) present. Examples of currently known RET kinase inhibitors include alectinib, BLU6864, cabozantinib, dovitinib, foretinib, lenvatinib, ponatinib, pralsetinib, selpercatinib, sorafenib, sunitinib, and vandetanib.

[0189] The types of cancer that can be treated using the methods described herein include blood cancers or solid tumor cancers. Examples of the types of cancer that can be treated using the compounds of formulas (I), (II), and (III) as described herein include lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), 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 tumors, lung adenocarcinoma, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary carcinoma, breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, inflammatory myofibroblastic tumor, and cervical cancer. Specifically, the cancer type can be lung cancer or thyroid cancer. More specifically, the cancer can be non-small cell lung cancer or medullary thyroid cancer. Further examples of the types of cancer that can be treated using the compounds and methods of formulas (I), (II), and (III) as described herein include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, cancer of unknown primary site, cardiac tumors, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, neoplasmsbysite, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, 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 tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic tumor, head and neck tumor, CNS tumor, primary central nervous system tumor, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, 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, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratory tract tumor, bronchial cancer, bronchial tumor, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, kidney cancer, colon cancer, colon tumor, renal cell carcinoma, 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, gastric cancer, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of unknown primary site, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms tumor.

[0190] Examples of types of blood cancers that can be treated with the compounds and methods of Formulas (I), (II), and (III) as described herein include leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with myelodysplasia in all three lineages (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), and multiple myeloma (MM). Additional examples of blood cancers include myeloproliferative disorders (MPD), such as polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In one embodiment, the blood cancer (e.g., a blood cancer that is a RET-related cancer) is AML or CMML.

[0191] Examples of types of solid tumor cancers that can be treated with the compounds and methods of Formulas (I), (II), and (III) as described herein include thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma, and melanoma.

[0192] The compounds of formula (I), (II) and (III) as described herein, or a pharmaceutically acceptable salt thereof, can be used to prepare a medicament for treating RET-related diseases or disorders, such as IBS or cancer. The cancers that can be treated with such a medicament are described above. The use of the compounds of formula (I), (II) or (III) as described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament may further comprise the steps of: performing an in vitro assay using a biological sample from a patient to determine the presence of an abnormality in the regulation of the expression, activity or amount of the RET gene, RET kinase or any of them, and if there is an abnormality in the regulation of the expression, activity or amount of the RET gene, RET kinase or any of them, administering to the patient a therapeutically effective amount of the compounds of formula (I), (II) and (III) as described herein. In these uses, the biological sample can be a tumor sample, and methods known to those skilled in the art, such as genomic / DNA sequencing, can be used to analyze the tumor sample. Additionally, in these uses, the sample can be obtained from the patient prior to the first administration of the compounds of formula (I), (II) and (III) as described herein. These uses of the compounds of formula (I), (II) and (III) as described herein in the treatment can be based on selecting patients for treatment by having at least one abnormality in the regulation of the expression, activity or amount of the RET gene, RET kinase or any of them. Furthermore, in these uses, the compounds of formula (I), (II) and (III) as described herein, or a pharmaceutically acceptable salt thereof, can be administered to the patient at a dose of about 1 mg / kg to 200 mg / kg (the sub-range of the effective dose is as described above).

[0193] The compounds of formula (I), (II) and (III) as described herein, or a pharmaceutically acceptable salt thereof, can be prepared by various procedures known in the art as well as the "Preparation Examples and Examples" below. The specific synthetic steps of each of the routes can be combined in different ways or with steps from different protocols to prepare the compounds of formula (I), (II) and (III), or a pharmaceutically acceptable salt thereof. The products of each step in the following protocols can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration and crystallization. The reagents and starting materials are readily available to those of ordinary skill in the art.

[0194] For clarity, certain stereochemical centers are not specified in the following protocols and certain substituents have been removed, and it is not intended to limit the teachings of the protocols in any way. Additionally, those of ordinary skill in the art can separate or resolve individual isomers, enantiomers and diastereomers at any convenient point in the synthesis of the compounds of the present 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). For example, the following molecule has two chiral centers, designated by ϕ (as above in formula (I) ϕ ), and an asterisk (*) (to indicate the second chiral center). This molecule has four possible isomers, which can be separated without determining the absolute stereochemistry, i.e., these diastereomeric pairs can be RR, RS, SR, and SS. Without determining the stereochemistry, the molecules can be distinguished by their retention times on a chiral column.

[0195]

[0196] For example, the names "isomer 1" and "isomer 2" refer to the first and second compounds, respectively, eluting from chiral chromatography under the conditions described herein, and if chiral chromatography is started early in the synthesis, the same names apply to subsequent intermediates and examples. Similarly, when diastereomers are also present, the names "diastereomer A" and "diastereomer B" are used in addition to the names isomer 1 and isomer 2. Additionally, the intermediates described in the following schemes may contain numerous nitrogen protecting groups. The variable protecting groups can be the same or different at each occurrence, depending on the specific reaction conditions and the particular transformation to be carried out. Protecting and deprotecting conditions are well known to those skilled in the art and are described in the literature (see, for example, " Greene’s Protective Groups in Organic Synthesis ", 4th Edition, Peter G.M. Wuts and Theodora W.Greene, John Wiley and Sons, Inc. 2007).

[0197] Certain abbreviations are defined as follows: "ACN" means acetonitrile; "ATP" means adenosine triphosphate; "BSA" means bovine serum albumin; "n-BuLi" means n-butyllithium; "DCM" means dichloromethane or methylene chloride; "DEA" means diethylamine; "DIPEA" means N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine; "DMA" means dimethylamine; "DMF" means N,N-dimethylformamide; "DMSO" means dimethyl sulfoxide; "DTT" means dithiothreitol; "Et3N" means triethylamine; "EtOAc" means ethyl acetate; "ee" means enantiomeric excess; "Et2O" means diethyl ether; "EtOH" means ethanol or ethyl alcohol; "FA" means formic acid; "GST" means glutathione S-transferase; "HEK" means human embryonic kidney; "hr" or "hrs" means hour; "HTRF" means homogeneous time-resolved fluorescence; "IgG" means immunoglobulin G; "IPA" means isopropyl alcohol or isopropanol; "KOAc" means potassium acetate; "LDA" means lithium diisopropylamide; "MeOH" means methanol or methyl alcohol; "MeTHF" means 2-methyltetrahydrofuran; "min" means minute; "Mn(dpm)3" means manganese(3+) tris[(3Z)-2,2,6,6-tetramethyl-5-oxo-3-hepten-3-olate]; "MtBE" means methyl tert-butyl ether; "NaOAc" means sodium acetate; "NBS" means N-bromosuccinimide; "NMI" means 1-methylimidazole or N-methylimidazole; "PBS-T" means phosphate buffered saline + Tween® 20; "Pd(dppf)Cl2)" means dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II); "PE" means petroleum ether; "PhSiH3" means phenylsilane; "RT" means room temperature; "TCHF" means tetramethylammonium hexafluorophosphate chloride; tert -BuOH" means tert-butyl alcohol; "TCFH" means N,N,N',N'-tetramethylammonium hexafluorophosphate chloride; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; and "T3P ® " means propanephosphonic anhydride, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide or PPACA; "t (R) " means retention time and "WT" means wild type.

[0198] In the following schemes, unless otherwise specified, all substituents are as defined above. Reagents and starting materials are generally available to those of ordinary skill in the art. Others can be prepared by standard techniques of organic and heterocyclic chemistry similar to the synthesis of known structurally related compounds and by the procedures described in the "Preparation Examples and Examples" below, including any novel procedures. It is intended to include in this specification intermediates and methods useful for the synthesis of the compounds of formula (I).

[0199] Scheme 1

[0200]

[0201] Scheme 1 depicts the preparation of the compound of (13), which can be used to prepare the compounds of formula (I), (II), and (III). Those of ordinary skill in the art will recognize that the aryl aldehyde (1) can be condensed with the alkyl hydrazine (4) to provide the hydrazone (2). The hydrazone (2) can be halogenated using reagents well known in the art to provide the hydrazide bromide (3). The aminopyrazole (6) can be formed by the condensation of the hydrazide bromide (3) with malononitrile and subsequent cyclization. The aminopyrazole (6) can also be synthesized by reacting a suitably substituted hydrazine (4) with a suitable dinitrile Michael acceptor (5). Boronation of the aryl bromide (6) under typical Miyaura reaction conditions can provide the boronicester (7). Treatment of the boronicester (7) with a suitable metal catalyst and halide can provide the α,β-unsaturated ester (8). Reduction of the alkene (8) can be achieved under reducing conditions, such as a hydrogen atmosphere and a suitable metal catalyst, preferably Pd / C, to provide the α-methyl ester (13).

[0202] Scheme 2

[0203]

[0204] Scheme 2 depicts the preparation of the compounds of formulas (I), (II) and (III) as described herein. One skilled in the art will recognize that an alternative synthesis of the α-methyl ester (13) can be achieved by α-methylation of methyl acetate (9) under typical enolate alkylation conditions to provide the α-methyl ester (10). Arylbromide (10) can be borated by Miyaura conditions to provide boronate (11) in substantially the same manner as described for boronate (7) in Scheme 1. Treatment of boronate (11) with an appropriate bromopyrazole (12) and a metal catalyst under Suzuki coupling conditions provides the α-methyl ester (13). Carboxylic acid (14) can be obtained by saponification of ester (13) with an appropriate nucleophilic base. The enantiomers of carboxylic acid (14) can be separated using chiral separation techniques well known in the art or at a later step in the synthesis. Carboxylic acid (14) and primary amine (15) can be linked using an appropriate amide coupling agent under conditions suitable for amide bond formation to provide (16). The nitrile moiety of aminopyrazole (16) can be converted to the compounds of formulas (I), (II) and (III) as described herein under various conditions such as metal-catalyzed hydration, acidic hydrolysis and oxidation. The enantiomers can be separated using chiral separation techniques well known in the art to afford the compounds of formulas (I), (II) and (III) as described herein.

[0205] Preparation Examples and Examples

[0206] Preparation Example 1

[0207] Methyl 2-(5-bromo-2-pyridyl)propionate

[0208]

[0209] Under N2 and at -20 °C, 60% NaH (w / w) in mineral oil (771 mg, 19.3 mmol) was added to methyl 2-(5-bromopyridin-2-yl)acetate (4.20 g, 17.5 mmol) in THF (84 mL). The mixture was stirred at -20 °C until gas evolution subsided. Then methyl iodide (4.4 mL, 70.1 mmol) was added to the reaction mixture. The mixture was stirred at -20 °C for 5 minutes, after which it was allowed to warm to room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure and dried in vacuo. DCM (15 mL), H2O (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added to the residue. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of EtOAc / DCM from 0% to 20% to yield the title compound as a colorless oil (3.16 g, 68.59%).

[0210] Production Example 2

[0211] Methyl 2-[4-(2,2-dicyano-1-hydroxyethenyl)phenyl]propionate

[0212]

[0213] 60% NaH (w / w) (3.85 g, 96.091 mmol) in mineral oil was added portionwise to THF (180 mL) at room temperature and under N2. Malononitrile (3.17 g, 48.046 mmol) in THF (20 mL) was added dropwise to the mixture at 0 - 10 °C. The mixture was stirred at room temperature for 30 minutes. Methyl 2-(4-chlorocarbonylphenyl)propionate (13 g, crude) in THF (30 mL) was added dropwise to this mixture at 0 °C. The mixture was stirred at room temperature for 2 hours. The resulting mixture was used directly without further purification.

[0214] Production Example 2a

[0215] 2-[(4-Bromo-2,3-difluorophenyl)-hydroxy-methylene]malononitrile

[0216]

[0217] Malononitrile (1.53 g, 23.160 mmol) in THF (100 mL) was added dropwise to a stirred mixture of NaH (1.68 g, 42.13 mmol, 60%) in THF (100 mL) at 0 °C and under N2. The mixture was stirred at room temperature and under N2 for 30 minutes. 4-Bromo-2,3-difluorobenzoyl chloride in THF (10 mL) was added dropwise to the above mixture at 0 °C. The mixture was stirred at room temperature for an additional 2 hours. The mixture was used without further purification.

[0218] Production Example 3

[0219] Methyl 2-[4-(2,2-dicyano-1-methoxyethyl-1-en-1-yl)phenyl]propionate

[0220]

[0221] At room temperature and under N2, dimethyl sulfate (7.67 g, 60.810 mmol) was added dropwise to methyl 2-[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]propionate in THF solution, and the mixture was stirred overnight at 80 °C and under N2. The mixture was cooled to room temperature and quenched with H2O (300 mL). The mixture was extracted with EtOAc (3 × 300 mL), and the combined organic extracts were washed with saturated aqueous NaCl solution (3 × 500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (6:1 - 1:1) to afford the title compound as a yellow oil (5 g, 36.49% over 3 steps). 1 H NMR (d6-DMSO) δ 7.71 –7.62 (m,2H), 7.59 –7.50 (m, 2H), 4.00 –3.93 (m, 1H), 3.90 (s, 3H), 3.63 (s,3H), 1.44(d, 3H).

[0222] Preparation Example 3a

[0223] 2-[(4-Bromo-2,3-difluoro-phenyl)-methoxy-methylene]malononitrile

[0224]

[0225] At room temperature, dimethyl sulfate (3.35 g, 26.56 mmol) was added dropwise to crude 2-[(4-bromo-2,3-difluoro-phenyl)-hydroxy-methylene]malononitrile. The mixture was stirred overnight at 80 °C and under N2. The mixture was cooled to room temperature. The reaction was quenched with H2O at room temperature. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1 - 2:1) to afford the title compound as a light grey solid (5.0 g, 75.5% over 3 steps). 1 H NMR (300 MHz, CDCl3) δ 7.64-7.54 (m, 1H), 7.18-7.11 (m,1H), 3.99 (d, 3H).

[0226] Preparation Example 3b

[0227] 2-[(4-Bromo-2-fluorophenyl)(methoxy)methylene]malononitrile

[0228]

[0229] To a solution of 2-(4-bromo-2-fluorobenzoyl)malononitrile (23.40 g, 87.62 mmol) in THF (300 mL) was added dimethyl sulfate (13.26 g, 105.13 mmol), and the mixture was stirred overnight at 80 °C under N2. The solution was cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and diluted with H2O (200 mL). The mixture was extracted with EtOAc (3 × 200 mL), and the organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of 5:1 to 3:1 PE to EtOAc to afford the title product as a brown semi-solid (23.5 g, 95.4%). ES / MS m / z( 79 Br / 81 Br) 265.0 / 267.0 [M+H] + 。

[0230] Preparation Example 4

[0231] 5,5-Difluoro-4,4-dimethyl-3-oxohexanenitrile

[0232]

[0233] To a stirred mixture of LDA (20.81 mL, 41.62 mmol) in THF (100 mL) at -70 °C was added dropwise ACN (1.82 g, 44.33 mmol) in THF. The mixture was stirred at -70 °C for 30 minutes. To the above mixture was added dropwise ethyl 3,3-difluoro-2,2-dimethylbutyrate (5 g, 27.75 mmol) in THF at -70 °C, and the mixture was slowly warmed to room temperature. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) (30 mL) at 0 °C and extracted with PE (200 mL). The aqueous phase was acidified to pH = 3 with HCl (aqueous solution) (1 N) and extracted with EtOAc (3 × 100 mL). The EtOAc extracts were washed with saturated aqueous NaCl solution (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil (1.9 g, 39.09%), which was used without further purification. 1 H NMR(CDCl3) δ 3.79 (s, 2H), 1.63 (t, 3H), 1.34 (s,6H).

[0234] Preparation Example 5

[0235] 4-(3-Bicyclo[1.1.1]pentyl)-3-oxo-butyronitrile

[0236]

[0237] At room temperature, 60% NaH (w / w) (140 mg, 3.5 mmol) in mineral oil in THF (1 mL) was added dropwise to a stirred solution of benzyl 2-(3-bicyclo[1.1.1]pentyl)acetate (504 mg, 2.33 mmol) and ACN (134 μL, 2.56 mmol) in THF (8 mL, 0.3 M). The reaction mixture was heated and stirred at 60 °C for 25 minutes. The reaction mixture was quenched with ice H2O (10 mL), acidified to pH 5 with HCl (c) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (350 mg).

[0238] Preparation Example 5a

[0239] 3-[3-Methylbicyclo[1.1.1]pent-1-yl]-3-oxopropanenitrile

[0240]

[0241] n-BuLi (1.71 mL, 4.28 mmol, 2.5 M in THF) was added to THF (5.00 mL) at 0 °C and under N2. ACN (187.42 mg, 4.56 mmol) in THF (5 mL) was added dropwise to this mixture over 5 minutes at -78 °C and under N2. The mixture was stirred at -78 °C for 1 hour. Methyl 3-methylbicyclo[1.1.1]pentane-1-carboxylate (400.00 mg, 2.85 mmol) in THF (5 mL) was added dropwise to this mixture at -78 °C and under N2. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (20 mL) at 0 °C. The mixture was acidified to pH 4 with aqueous HCl (1 N) and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a brown liquid (360 mg, 84.5%).

[0242] Preparation Example 5b

[0243] 3-Oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]propanenitrile

[0244]

[0245] n-BuLi (0.83 mL, 2.087 mmol, 2.5 M in hexanes) was added to THF (10 mL) at 0 °C under N2. ACN (91.34 mg, 2.23 mmol) in THF (2 mL) was added dropwise over 2 minutes at -78 °C under N2, and the reaction was stirred at -78 °C for 1 h. Methyl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (270.00 mg, 1.39 mmol) in THF (2 mL) was added dropwise to the reaction mixture at -78 °C, and the reaction was stirred at room temperature for 12 h. The reaction was quenched by addition of saturated aqueous NH4Cl (20 mL), acidified to pH = 4 with concentrated HCl, and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product (290 mg) was used without further purification. 1 1H NMR (300 MHz, CDCl3) δ 3.54 (s, 2H), 2.39 (s, 6H).

[0246] The following compounds in Table 1 were prepared substantially as described for 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]propanenitrile, adjusting the reaction time to determine reaction completion and appropriate purification conditions. After addition of the carboxylic acid ester, the reaction was allowed to warm to room temperature. n-BuLi in hexanes or THF could be added.

[0247]

[0248] Preparation Example 6

[0249] tert-Butyl N-(tert-butoxycarbonylamino)-N-(2-methoxy-1,1-dimethylethyl)carbamate

[0250]

[0251] To Mn(dpm) at 0 °C under N2 3(60.31 mg, 0.100 mmol) was added portionwise to a stirred solution of 3-methoxy-2-methyl-prop-1-ene (860.00 mg, 9.984 mmol), PhSiH3 (1.08 g, 9.984 mmol), and (E)-N-[(tert-butoxycarbonyl)imino](tert-butoxy)formamide (3.45 g, 14.98 mmol) in IPA (20.00 mL). The resulting mixture was stirred at room temperature and under N2 for 2 h and concentrated in vacuo. H2O (15 mL) was added and the resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of PE / EtOAc (10:1 to 7:3) to afford the title compound as a colorless oil (1.8 g, 56.62%). 1 1H NMR (CDCl3) δ 3.38 - 3.32 (m, 5H), 1.49 - 1.46 (m, 24H).

[0252] Preparation Example 7

[0253] tert-Butyl N-(1-methylcyclopropyl)-N-nitroso-carbamate

[0254]

[0255] tert-Butyl nitrite (2.40 g, 23.36 mmol) was added portionwise to a stirred solution of tert-butyl N-(1-methylcyclopropyl)carbamate (2.00 g, 11.68 mmol) in DCM (20.00 mL) at room temperature and under N2. The mixture was stirred at room temperature and under N2 for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (25 / 1 to 20 / 1) to afford the title compound as a brown liquid (1.3 g, 55.59%). 1 1H NMR (d6-DMSO) δ 1.59 (s, 9H), 1.10 (s, 3H), 0.86 - 0.84 (m, 2H), 0.70 - 0.65 (m, 2H).

[0256] Preparation Example 8

[0257] (1-Methylcyclopropyl)hydrazine hydrochloride

[0258]

[0259] To a stirred solution of N-(1-methylcyclopropyl)-N-nitroso-carbamic acid tert-butyl ester (1.20 g, 5.99 mmol) in 4 N HCl (8.00 mL) at 0 °C and under N2 was added portionwise Zn (783.98 mg, 11.99 mmol). The mixture was stirred at room temperature and under N2 for 12 h. The mixture was filtered and the cake was washed with H2O (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford the title compound (2 g, crude) as an off-white solid, which was used directly without further purification. 1 1H NMR (d6-DMSO) δ 1.30 (s, 3H), 0.77 - 0.73 (m, 2H), 0.54 - 0.50 (m, 2H).

[0260] Preparation Example 9

[0261] (1-Methoxy-2-methylpropan-2-yl)hydrazine hydrochloride

[0262]

[0263] A solution of N-(tert-butoxycarbonylamino)-N-(2-methoxy-1,1-dimethylethyl)carbamic acid tert-butyl ester (1.6 g, 5.00 mmol) in HCl (gas) in 1,4-dioxane (15.00 mL) was stirred at room temperature and under N2 for 6 h. The mixture was concentrated in vacuo and triturated with Et2O (3 × 10 mL) to afford the title compound (400 mg, 52%) as a semi-solid. 1 1H NMR (d6-DMSO) δ 3.36 (s, 2H), 3.32 (s, 3H), 1.17 (s, 6H).

[0264] Preparation Example 10

[0265] (1,1,1-Trifluoro-2-methylpropan-2-yl)hydrazine dihydrochloride

[0266]

[0267] To a stirred mixture of N'-(1,1,1-trifluoro-2-methylpropan-2-yl)benzohydrazide (7.50 g) in H2O (40.00 mL) at room temperature and under N2 was added portionwise HCl(c) (40.00 mL). The resulting mixture was stirred at 80 °C and under N2 for 12 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting solid was triturated with Et2O (30 mL), and the precipitated solid was collected by filtration and washed with Et2O (3 × 30 mL) to afford the title compound (4.0 g, 61%) as an off-white solid.1 1H NMR (d 6 -DMSO) δ 9.55 (br, s, 2H), 5.60 (br, s, 3H), 1.34 (s, 6H).

[0268] Production Example 11

[0269] N-[(E)-(4-Bromophenyl)methylideneamino]propan-2-amine

[0270]

[0271] A solution of 4-bromobenzaldehyde (100.00 g, 540.48 mmol), isopropylhydrazine hydrochloride (65.75 g, 594.53 mmol) and DIPEA (76.84 g, 594.53 mmol) in DMF (500 mL) was stirred at 80 °C under N2 for 3 hours. The reaction was cooled to room temperature. The resulting mixture was used directly without work-up or further purification. ES / MS m / z( 79 Br / 81 Br) 241.1 / 243.1 [M+H] + .

[0272] The following compounds in Table 1a were prepared substantially as described for N-[(E)-(4-bromophenyl)methylideneamino]propan-2-amine, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0273]

[0274] Production Example 13a

[0275] N'-[(2Z / E)-1-Bromo-1,1-difluoropropan-2-ylidene]benzohydrazide

[0276]

[0277] To a crude solution of 1-bromo-1,1-difluoro-propan-2-one (200 mL of 3 / 1 Et2O / toluene) at room temperature under N2 was added benzohydrazide (23.62 g) in a sealed tube. The mixture was stirred at 50 °C under N2 for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with toluene (3 × 100 mL) to give the title compound as a white solid (28 g, 34%, over 2 steps, purity 62% on 1 1H-NMR).

[0278] Production Example 13b

[0279] (Z / E)-N-[(2,2,2-trideuterio-1-methylethylidene)amino]benzamide

[0280]

[0281] At -78 °C and under N2, benzohydrazide (2.14 g, 15.71 mmol, dissolved in THF (10 mL)) was added dropwise to a stirred mixture of 1,1,1-trideuterio-propan-2-one (0.24 g, 3.93 mmol) in THF (50 mL). The mixture was stirred at -78 °C for 2 h. The mixture was diluted with EtOAc (200 mL). The organic phase was washed with H2O (2 × 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound, which was used directly without further purification. ES / MS (m / z) 180.1 (M+H).

[0282] Preparation Example 13c

[0283] N-[[2,2,2-trideuterio-1-(trideuteriomethyl)ethylidene]amino]benzamide

[0284]

[0285] At room temperature, 1,1,1,3,3,3-hexadeuterio-propan-2-one (2.35 g, 36.723 mmol) was added dropwise to a stirred solution of benzohydrazide (5.00 g, 36.723 mmol) in MeOH (100.00 mL). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure to afford the title compound as a white solid (5 g, 74.70%). ES / MS (m / z) 183.3 (M+H).

[0286] Preparation Example 13d

[0287] N'-(2,2,2-trideuterio-1-methylethyl)benzohydrazide

[0288]

[0289] At 0 °C, NaBH4 (293.40 mg, 7.76 mmol) was added portionwise to a stirred mixture of (Z / E)-N-[(2,2,2-trideuterio-1-methylethylidene)amino]benzamide (695 mg, 3.88 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (100 mL), washed with H2O (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1~1:3) to afford the title compound as a white solid (280 mg, 39.8%). ES / MS (m / z) 182.2(M+H).

[0290] Preparation Example 13e

[0291] N’-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]benzohydrazide

[0292]

[0293] At room temperature, NaBH4 (0.81 g, 21.95 mmol) was added portionwise to a stirred solution of N-[[2,2,2-trideuterio-1-(trideuteriomethyl)ethylidene]amino]benzamide (2.00 g, 10.97 mmol) in MeOH (30.00 mL). The mixture was stirred for 2 h. The reaction was quenched with H2O (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts were washed with H2O (3×50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a white solid (1.9 g, 93.96%). ES / MS (m / z) 185.3 (M+H).

[0294] Preparation Example 13f

[0295] N’-(1,2,2,2-tetradeuterio-1-methylethyl)benzohydrazide

[0296]

[0297] At 0 °C, NaBD4 (326.15 mg, 7.77 mmol) was added portionwise to a stirred mixture of (Z / E)-N-[(2,2,2-trideuterio-1-methylethylidene)amino]benzamide (695.00 mg, 3.88 mmol) in CD3OD (5 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (100 mL) and washed with H2O (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:EtOAc (3:1 to 1:3) to afford the title compound as a white solid (260 mg, 36.6%). ES / MS (m / z) 183.2 (M+H).

[0298] The following compounds in Table 1b were prepared essentially as described for N'-(1,2,2,2-tetradeuterio-1-methylethyl)benzohydrazide, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction. NaBD4 can be added at room temperature and used without further purification.

[0299]

[0300] Preparation Example 13h

[0301] N'-(2-Bromo-2,2-difluoro-1-methylethyl)benzohydrazide

[0302]

[0303] At 0 °C and under N2, BH3-THF (82.45 mL, 82.45 mmol, 1 M in THF) was added dropwise to a stirred solution of N'-[(2E)-1-bromo-1,1-difluoroprop-2-ylidene]benzohydrazide (12 g, 41.22 mmol) in THF (100 mL). The mixture was stirred at room temperature and under N2 for 12 h. The reaction was quenched by the addition of MeOH (5 mL) at 0 °C. The mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8 / 1 to 6 / 1) to afford the title compound as a white solid (7 g, 57%). 11H NMR (400 MHz, CDCl3) δ 7.78 - 7.73 (m, 2H), 7.60 - 7.53 (m, 1H), 7.52 - 7.45 (m, 2H), 3.57 - 3.49 (m, 1H), 1.45 (d, 3H).

[0304] Preparation Example 13i

[0305] [2,2,2-Trideuterio-1-(trideuteriomethyl)ethyl]hydrazine·HCl

[0306]

[0307] A mixture of N'-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]benzohydrazide (500 mg, 2.71 mmol) in HCl (5.00 mL, concentrated) was stirred overnight at 80 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was triturated with Et2O (3 mL). The resulting precipitate was filtered and the filter cake was washed with Et2O (3 × 2 mL) to afford the title compound as a white solid (180 mg, 56.88%).

[0308] The following compounds in Table 1c were prepared substantially as described for [2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]hydrazine·HCl, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0309]

[0310] Preparation Example 14

[0311] (1Z)-4-Bromo-N-isopropyl-benzohydrazide bromide

[0312]

[0313] NBS (106.04 g, 595.77 mmol) in DMF was added dropwise to N-[(E)-(4-bromophenyl)methylideneamino]propan-2-amine and the mixture was stirred at 0 °C and under N2 for 3 hours. The resulting mixture was used directly without work-up or further purification.

[0314] The following compounds in Table 2 were prepared substantially as described for (1Z)-4-bromo-N-isopropyl-benzohydrazide bromide, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0315]

[0316] Preparation Example 17

[0317] 5-Amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile

[0318]

[0319] At 0 °C and under N2, a solution of sodium ethoxide (91.88 g, 1.351 mol) and malononitrile (39.24 g, 594.53 mmol) in EtOH (400 mL) was stirred for 1 h. A crude solution of (1Z)-4-bromo-N-isopropyl-benzohydrazonoyl bromide was added to this mixture. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 L), and the resulting precipitated solid was collected by filtration, washed with H2O (3 × 200 mL), and the solid was dried in an oven at 50 °C to give the title compound (127 g, 73.7% over 3 steps). ES / MS (m / z) ( 79 Br / 81 Br 305 / 307 (M+H).

[0320] The following compounds in Table 3 were prepared essentially as described for 5-amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction and purification conditions where appropriate. The crude reaction can be diluted with H2O, extracted with EtOAc, and purified by chromatography under appropriate conditions.

[0321]

[0322] Preparation Example 20

[0323] 5-Amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

[0324]

[0325] (1-Methylcyclopropyl)hydrazine hydrochloride (1.63 g, 13.30 mmol), THF (20 mL), Et3N (3.08 g, 30.41 mmol), and 2-[(4-bromophenyl)(methoxy)methylene]malononitrile (1.00 g, 3.80 mmol) were combined and stirred at 50 °C for 6 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 30 mL) and saturated aqueous NaCl solution (20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: C18; ACN in H2O (0.1% NH4HCO3), UV 254 nm, eluting with a gradient of 70% to 100% in 15 min to afford the title compound as an off-white solid (375 mg, 31%). ES / MS m / z( 79 Br / 81 Br) 317.0 / 319.0 [M+H] + 。

[0326] The following compounds in Table 3a were prepared essentially as described for 5-amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction. Et3N can be added dropwise. The crude reaction can be concentrated to dryness and purified where appropriate.

[0327]

[0328] Preparation Example 20c

[0329] 5-Amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

[0330]

[0331] A solution of 2-[(4-bromo-2-fluorophenyl)(methoxy)methylene]malononitrile (1.50 g, 5.34 mmol), (1-methylcyclopropyl)hydrazine HCl (1.96 g, 15.99 mmol), and Et3N (2.70 g, 26.682 mmol) in EtOH (20.00 mL) was stirred at room temperature and under N2 for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 3:1 to 2:1 PE:EtOAc to afford the title compound as a pale yellow solid (1.2 g, 67.09%). ES / MS m / z( 79 Br / 81 Br) 335.1 / 337.1 [M+H] + 。

[0332] The following compounds in Table 3b were prepared substantially as described for 5-amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile, using appropriate reagents and adjusting the reaction time to determine completion of the reaction and purification conditions where appropriate. The reaction can be stirred at 50 °C and, if available, the hydrazine can be the free amine.

[0333]

[0334] Preparation Example 20h

[0335] 5-Amino-3-(4-bromophenyl)-1-(2-deuterio-2,2-difluoro-1-methylethyl)pyrazole-4-carbonitrile

[0336]

[0337] To a stirred solution of 5-amino-1-(1-bromo-1,1-difluoropropan-2-yl)-3-(4-bromophenyl)pyrazole-4-carbonitrile (300.00 mg, 0.71 mmol, co-evaporated with 2×CD3OD) in CD3COOD (3.00 mL) at room temperature and under N2 was added portionwise Zn (467.14 mg, 7.14 mmol, co-evaporated with 2×CD3OD). The mixture was stirred at 80 °C and under N2 for 1 h. The mixture was allowed to cool to room temperature and quenched with EtOAc. The mixture was filtered, the cake was washed with EtOAc (3×10 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1 - 1:1) to afford the title compound as a yellow solid (100 mg, 40.92%). 1 1H NMR (300 MHz, d6-DMSO) δ 7.79 - 7.65 (m,4H), 7.00 (s, 2H), 4.93 - 4.68 (m, 1H), 1.48 (d, 3H).

[0338] Preparation Example 20i

[0339] Methyl 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propionate

[0340]

[0341] Methyl 2-[4-(2,2-dicyano-1-methoxyethen-1-yl)phenyl]propionate (500 mg, 1.85 mmol), [2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]hydrazine·HCl (648 mg, 5.56 mmol), and Et3N (936 mg, 9.25 mmol) in EtOH (20 mL) were stirred for 1 h. The solution was diluted with H2O (30 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a pale yellow solid (650 mg, crude). The crude product was used without further purification. ES / MS (m / z) 319.40 (M+H).

[0342] Preparation Example 21

[0343] tert-Butyl N-(4-cyano-2-isopropylpyrazol-3-yl)carbamate

[0344]

[0345] To a stirred solution of 5-amino-1-isopropylpyrazole-4-carbonitrile (13.58 g, 85.0 mmol) in THF (170 mL) was added successively N,N-dimethylpyridin-4-amine (1.05 g, 8.50 mmol), Et3N (36 mL, 0.255 mol), and di-tert-butyl dicarbonate (40.81 g, 0.187 mol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (15 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of EtOAc in cyclohexane from 2% to 30% to afford the title compound as a pale yellow solid (9.29 g, 31%) and a second batch as a pale yellow solid (4.86 g, 16%), which were combined to give 14.15 g, 47% yield.

[0346] Preparation Example 22

[0347] Methyl 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropylpyrazol-3-yl]-2-pyridyl]propionate

[0348]

[0349] and

[0350] Preparation Example 23

[0351] Methyl 2-[5-[5-[Bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propionate

[0352]

[0353] tert-Butyl N-(4-cyano-2-isopropylpyrazol-3-yl)-N-(tert-butoxycarbonyl)carbamate (4.02 g, 11.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.39 g, 9.42 mmol), di-µ-methyloxobis(1,5-cyclooctadiene)dirhodium(I) (1:2) (CAS# 12148-71-9) (136 mg, 0.21 mmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (112 mg, 0.41 mmol) were added together under vacuum. THF (11.60 mL) was added and the reaction was maintained under N2. The mixture was stirred and heated at 80 °C for 6 h. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of DCM / EtOAc 3:1 (10 mL). The solution was passed through a silica gel pad and washed with DCM / EtOAc 3:1 (2 × 10 mL). The filtrates were combined, concentrated under reduced pressure, and dried under vacuum to afford a crude residue. Cs2CO3 (8049 mg, 24.6 mmol), methyl 2-(5-bromo-2-pyridyl)propionate (2.00 g, 8.19 mmol), Pd(dppf)Cl2) DCM (342 mg, 0.410 mmol), and 4 Å molecular sieves (5 g) were added to the crude material. The reaction mixture was then degassed by vacuum / N2 (3×) and heated at 100 °C for 2 h. The reaction was cooled to room temperature, filtered through a bed of perlite, and the perlite bed was washed with THF (3 × 60 mL). The organic solutions were combined, concentrated under reduced pressure, and dried under vacuum. DCM (60 mL), H2O (80 mL), and saturated aqueous NaHCO3 solution (60 mL) were added to the residue. The organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure, and dried under vacuum. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of EtOAc in DCM from 0% to 20% to afford the title compound of Preparation Example 22 (2.47 g, 68.53%) and the title compound of Preparation Example 23. The material of Preparation Example 23 was further purified by column chromatography on silica gel eluting with a gradient of 10% to 80% EtOAc in cyclohexane to yield the title compound of Preparation Example 23.

[0354] Preparation Example 24

[0355] 5-Amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile

[0356]

[0357] 5-Amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile (100 g, 327.68 mmol), bis(pinacolato)diboron (91.53 g, 360.444 mmol), KOAc (48.24 g, 491.52 mmol) and Pd(dppf)Cl2 (11.99 g, 16.38 mmol) in 1,4-dioxane (1 L) were stirred at 80 °C under N2 for 6 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, washed with EtOAc (3 × 100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 - 5:1) to afford the title compound as a brown solid (100 g, 86.6%). ES / MS (m / z) 353.2 (M+H).

[0358] The following compounds in Table 4 were prepared substantially as described for 5-amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and adjusting the purification conditions under appropriate conditions. The material was also filtered without work-up and used without further purification.

[0359]

[0360]

[0361] Alternative Preparation Example 26

[0362] 5-Amino-1-(1-methylcyclopropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile

[0363]

[0364] 5-Amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carbonitrile (350 mg, 1.10 mmol), bis(pinacolato)diboron (560.41 mg, 2.21 mmol), KOAc (325 mg, 3.31 mmol) and Pd(dppf)Cl2 (121 mg, 0.17 mmol.) were combined in dioxane (5.00 mL). The solution was stirred at 80 °C under N2 for 2 h. The mixture was filtered and used directly without purification. ES / MS (m / z) 365.2 (M+H).

[0365] Preparation Example 29f

[0366] 5-Amino-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carbonitrile

[0367]

[0368] A solution of 5-amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)-1H-pyrazole-4-carbonitrile (700 mg, 2.09 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (636.40 mg, 2.51 mmol), Pd(dppf)Cl2·CH2Cl2 (341.10 mg, 0.42 mmol) and KOAc (614.89 mg, 6.26 mmol) in dioxane (10.00 mL) was stirred at 80 °C under N2 for 1 h. The solution was cooled to room temperature, filtered, and the cake was washed with 1,4-dioxane (2 × 3 mL). The mixture was used directly without further purification. ES / MS (m / z) 383.3 (M+H).

[0369] Preparation Example 29g

[0370] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-3-fluorophenyl]prop-2-enoate

[0371]

[0372] 5-Amino-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carbonitrile (980 mg, 2.56 mmol), methyl 2-(trifluoromethanesulfonyloxy)acrylate (1200.61 mg, 5.13 mmol), Pd(dppf)Cl2·CH2Cl2 (418.73 mg, 0.51 mmol) and K2CO3 (708.65 mg, 5.128 mmol) in dioxane / H2O (4:1, 10 mL) were stirred at 80 °C under N2 for 1 h. The solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 3:1 to 2:1 PE:EtOAc to afford the title compound as a yellow solid (430 mg, 49.28%). ES / MS (m / z) 341.2 (M+H).

[0373] Preparation Example 30

[0374] Methyl 2-[4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)phenyl]acrylate

[0375]

[0376] 5-Amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole-4-carbonitrile (100.00 g, 283.89 mmol), methyl 2-(trifluoromethanesulfonyloxy)acrylate (99.71 g, 425.83 mmol), K2CO3 (117.71 g, 851.67 mmol) and Pd(dppf)Cl2 (10.39 g, 14.19 mmol) in 1,4-dioxane (1 L) and H2O (250 mL) were stirred overnight at 90 °C under N2. The mixture was cooled to room temperature. The resulting mixture was filtered and the cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure, diluted with H2O (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (3 × 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 - 3:1) to afford the title compound as a yellow solid (43 g, 48.8%). ES / MS (m / z): 311.2 (M+H).

[0377] The following compounds in Table 5 were prepared substantially as described for methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]prop-2-enoate, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction. The temperature was 80 - 90 °C and dioxane and H2O were used as solvents.

[0378] Table 5

[0379]

[0380]

[0381] The title compound was purified by reverse phase combinatorial chromatography using the following conditions: C18; gradient elution with ACN in H2O (0.1% NH4HCO3) from 70% to 100% over 15 minutes; UV 254 nm.

[0382] Alternative Preparation Example 32

[0383] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]prop-2-enoate

[0384]

[0385] 5-Amino-1-(1-methylcyclopropyl)-3-[4-(4,4,5,5–tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile (400 mg, 1.10 mmol), methyl 2-(trifluoromethanesulfonyloxy)prop-2-enoate (642.95 mg, 2.75 mmol), K2CO3 (455 mg, 3.30 mmol) and Pd(dppf)Cl2 (85 mg, 0.09 mmol) were added together in dioxane (6.00 mL) and H2O (1.50 mL). The solution was stirred at 80 °C for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with H2O (2 x 30 mL) and brine (20 mL). The organic phase was separated and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial chromatography using the following conditions: C18; gradient elution with ACN in H2O (0.1% NH4HCO3) to give the title compound as a brown solid (280 mg, 78.5). ES / MS (m / z) 323.1 (M+H).

[0386] Preparation Example 36

[0387] Methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, isomer 1

[0388] and

[0389] Preparation Example 37

[0390] Methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 2

[0391]

[0392] Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)pyrazol-3-yl]phenyl]prop-2-enoate (2.00 g) was purified by Prep-HPLC under the following conditions: column: N-(R,R)-Whelk-O1 4.6 * 50 mm, 3.5 µm; mobile phase A: mobile phase B: MeOH (0.1% DEA), flow rate 2 mL / min; eluted with 10% B, UV 254 nm; t (R) For Isomer 1, t was 6.7 min; t (R) For Isomer 2, t was 7.2; as a yellow solid (700 mg, 35.0%, 100% ee) and as a yellow solid (700 mg, 35.0%, 100% ee).

[0393] The following compounds in Table 6 were prepared substantially as described for methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 1 and methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 2, using appropriate purification conditions.

[0394] Table 6

[0395]

[0396]

[0397] 1 CHIRALPAK IG, 2 * 25 cm, 5 µm; eluted with 30% EtOH in hexane (10 mM NH3-MeOH), flow rate: 20 mL / min, UV 234 / 274 nm.

[0398] 2CHIRAL ART Amylose-SA, 2*25 cm, 5 µm; eluted with 10% EtOH in hexane (0.5% 2 M NH3-MeOH), flow rate: 20 mL / min, 210 / 220 nm.

[0399] 3 CHIRALPAK IH, 2.0*2.5 cm, 5 µm eluted with 40% EtOH in hexane (10 mM NH3-MeOH), flow rate: 20 mL / min, UV 235.275.

[0400] Preparation Example 40

[0401] Methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propionate

[0402]

[0403] A mixture of methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]prop-2-enoate (43.00 g, 138.55 mmol) and 50% Pd / C (43.00 g) in MeOH (1 L) was stirred at room temperature and under N2 for 4 h. The resulting mixture was filtered (through Celite if necessary), and the filter cake was washed with MeOH (300 mL). The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (40 g, 92.4%). ES / MS (m / z) 313.2 (M+H).

[0404] The following compounds in Table 7 were prepared substantially as described for methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propionate, using the appropriate reagents, a hydrogen balloon where appropriate, 10-50% Pd / C, and adjusting the reaction time to determine completion of the reaction. The products were also purified by silica gel chromatography eluting with a solvent system such as 2:1 to 1:1 PE:EtOAc.

[0405] Table 7

[0406]

[0407]

[0408] 1 PD(OH)2 / C is the catalyst and DCM is the solvent used.

[0409] Alternative Preparation Example 42

[0410] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]phenyl]propionate

[0411]

[0412] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]phenyl]acrylate (260 mg, 0.81 mmol), MeOH (15.00 mL), and 50% Pd / C (275 mg) were added together. The solution was stirred at room temperature under H2 for 2 h. The mixture was filtered and the solution was concentrated in vacuo to afford the title compound as a pale yellow solid (240 mg, 91%). The crude product was used directly without further purification. ES / MS (m / z) 325.1 (M+H).

[0413] Alternative Preparation Example 42

[0414] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]phenyl]propionate

[0415] Et3N (7.49 g, 73.99 mmol) was added dropwise to a stirred solution of methyl 2-[4-(2,2-dicyano-1-methoxyethylidene)phenyl]propionate (4.00 g, 14.80 mmol) and (1-methylcyclopropyl)hydrazine hydrochloride (1.81 g, 14.80 mmol) in THF (50.00 mL) at room temperature under N2. The mixture was stirred at 50 °C under N2 for 1 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (5:1 - 1:1) to afford the title compound as an off-white solid (3.8 g, 79.16%). ES / MS (m / z) 325.2 (M+H).

[0416] Preparation Example 47h

[0417] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-3-fluorophenyl]propionate

[0418]

[0419] To a solution of methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-3-fluorophenyl]acrylate (410 mg, 1.21 mmol) in MeOH (10 mL) was added Pd / C (10%, 0.64 g). The mixture was hydrogenated at room temperature for 1 h using a H2 balloon. The mixture was filtered and the cake was washed with MeOH (3×50 mL). The filtrate was concentrated under reduced pressure to afford the title compound as a dark yellow solid (340 mg, 82.44%). ES / MS (m / z) 343.2 (M+H).

[0420] Preparation Example 48

[0421] Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl]phenyl]propionate

[0422]

[0423] To a stirred mixture of methyl 2-[4-(2,2-dicyano-1-methoxyethenyl)phenyl]propionate (400.00 mg, 1.48 mmol) and (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazine dihydrochloride (210.33 mg, 1.48 mmol) in EtOH (5.00 mL) at room temperature and under N2 was added Et3N (449.25 mg, 4.44 mmol) portionwise. The resulting mixture was stirred at 50 °C and under N2 for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of PE / EtOAc (2 / 1 to 1 / 1) to afford the title compound as an off-white solid (270 mg, 47%). ES / MS (m / z) 381.2 (M+H).

[0424] The following compounds in Table 8 were prepared substantially as described for methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl]phenyl]propionate, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and adjusting the purification conditions as necessary. The reaction can be stirred at RT - 50 °C and used without purification.

[0425]

[0426] Preparation Example 50

[0427] Lithium 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-1H-pyrazol-3-yl]pyridin-2-yl]propionate

[0428]

[0429] Methyl 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propionate (100 mg, 0.227 mmol) and methyl 2-[5-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propionate (958 mg, 1.87 mmol) were combined in MeOH (8.20 mL). LiOH (142 mg, 5.69 mmol) was dissolved in H2O (2.46 mL) and added to the mixture. The reaction mixture was stirred at room temperature for 18 h and concentrated under reduced pressure to afford the title compound (926 mg, 111.39%).

[0430] Preparation Example 51

[0431] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid

[0432]

[0433] A mixture of methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propionate (40.00 g, 128.05 mmol) and NaOH (25.61 g, 640.26 mmol) in MeOH (500 mL) and H2O (500 mL) was stirred at 50 °C for 5 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure, diluted with H2O (500 mL), and the aqueous layer was extracted with EtOAc (2 × 300 mL). The aqueous layer was acidified to pH 3 - 4 with 6 N HCl, and the resulting precipitated solid was collected by filtration, washed with H2O (3 × 50 mL), and dried in vacuo to afford the title compound as a pale yellow solid (34 g, 89.0%). ES / MS (m / z) 299.2 (M+H).

[0434] The following compounds in Table 9 were prepared essentially as described for 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, stirred at room temperature until complete.

[0435] Table 9

[0436]

[0437] 1Using 2 M NaOH, without additional H2O, after acidification with potassium bisulfate, the mixture was cooled at 0 °C for 1 hour. The title compound was filtered, collected, dried and used directly without further purification.

[0438] Preparation Example 54

[0439] 2-(6-[5-Amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, isomer 1

[0440]

[0441] To a stirred solution of methyl 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoate, isomer 2 (1.30 g, 3.53 mmol) in THF (16.00 mL) and H2O (4.00 mL) at room temperature and under N2 was added portionwise LiOH (253.56 mg, 10.59 mmol). The resulting mixture was stirred at room temperature and under N2 for 2 hours. The mixture was concentrated under reduced pressure, diluted with H2O (20 mL) and acidified to pH 3 with HCl (c). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (1.2 g, 96%). ES / MS (m / z) 353.9 (M+H).

[0442] The following compounds in Table 10 were prepared substantially as described for 2-(6-[5-amino-4-cyano-1-[-1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, isomer 1, using the appropriate reagents, at room temperature to 50 °C and adjusting the reaction time to determine completion of the reaction. LiOH can be added portionwise or in a single amount, depending on the scale of the reaction.

[0443]

[0444]

[0445]

[0446] Preparation Example 60k

[0447] 2-[4-[5-Amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoic acid

[0448]

[0449] At room temperature, a solution of methyl 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propionate (630 mg, 1.98 mmol) and LiOH (143 mg, 5.94 mmol) in MeOH / H2O (25 mL, 4:1) was stirred for 1 hour. The solution was extracted with EtOAc (2 × 5 mL). The aqueous layer was acidified with HCl (2 M) and extracted with EtOAc (3 × 50 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a pale yellow solid (460 mg, crude). The product was washed with Et2O (10 mL) and used directly without further purification. ES / MS (m / z) 305.20 (M+H).

[0450] Preparation Example 60l

[0451] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid

[0452]

[0453] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propionate (220.00 mg, 0.68 mmol), MeOH (2.00 mL), H2O (2.00 mL) and NaOH (109 mg, 2.71 mmol) were added together. The solution was stirred at 50 °C for 2 hours, and then MeOH was removed under reduced pressure. The pH of the mixture was adjusted to 4 with 4 N HCl, and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with H2O (2 × 15 mL), washed with brine (10 mL) and concentrated to give the title compound as an off-white solid (240 mg, 100% crude). The crude product was used directly without further purification. ES / MS (m / z) 311.2 (M+H).

[0454] Preparation Example 60m

[0455] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoic acid

[0456]

[0457] Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propionate (340 mg, 0.99 mmol) and LiOH (118.91 mg, 4.96 mmol) in a solution of THF / H2O (4:1, 5.00 mL) were stirred at 50 °C under N2 for 1 hour. The solution was cooled to room temperature and the mixture was acidified to pH = 3 with HCl (aqueous solution, 1 N). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (280 mg, 85.87%). ES / MS (m / z) 329.2 (M+H).

[0458] Preparation Example 61

[0459] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 1

[0460] and

[0461] Preparation Example 62

[0462] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 2

[0463]

[0464] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (500 mg) was separated by preparative chiral HPLC under the following conditions: column: (R,R)Whelk-O1, 21.1*250 mm, 5 µm; mobile phase A: hexane (0.1% FA), mobile phase B: IPA; eluted at 20 mL / min with a gradient of 0 - 30% B in 17 minutes; UV 254 nm; t (R) Isomer 1 9.2 minutes (209.6 mg, 41.2%, 100% ee), as a white solid, ES / MS (m / z) 299.1 (M+H),t (R) Isomer 2 12 minutes (206.8 mg, 41.03%, 100% ee) as a white solid, ES / MS (m / z) 299.1(M+H).

[0465] Preparation Example 63

[0466] 2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid, isomer 1

[0467] and

[0468] Preparation Example 64

[0469] 2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid, isomer 2

[0470]

[0471] 2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid (290.00 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK AD-H, 2.0 * 25 cm L; mobile phase A: hexane (0.1% TFA), mobile phase B: IPA; eluted with a gradient of 30 - 0% B in 9.5 minutes; flow rate 20 mL / min; UV 230 / 254 nm, t (R) Isomer 1 6.2 minutes (102.5 mg, 35.3%), as a white solid, 100% ee; ES / MS (m / z) 300.1 (M + H), t (R) Isomer 2 7.8 minutes (104.8 mg, 36.1%), as a white solid, 100% ee, ES / MS (m / z) 300.1 (M + H).

[0472] Preparation Example 64a

[0473] 2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid

[0474]

[0475] At 50 °C, a mixture of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (1.00 g, 3.352 mmol), NaOH (671 mg, 16.759 mmol), and H2O2 (7.81 mL, 68.873 mmol, 30%) in EtOH (20.00 mL) / DMSO (2.00 mL) was stirred overnight. The reaction was quenched at 0 °C with saturated aqueous Na2SO3 (20 mL). The resulting mixture was diluted with H2O (200 mL) and acidified to pH 3 - 4 with 6 N HCl. The precipitated solid was collected by filtration and washed with H2O (2 × 10 mL). The solid was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O, eluting with a gradient of 30% to 60% in 25 minutes; detector, UV 220 nm, followed by lyophilization to yield the title compound as an off-white solid (670 mg, 62.5%). ES / MS (m / z) 317.2 (M+H).

[0476] Preparation Example 64b

[0477] 2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 1

[0478] and

[0479] Preparation Example 64c

[0480] 2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 2

[0481]

[0482] 2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (280 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK AD-H, 2.0 * 25 cm; mobile phase A: hexane (0.1% FA), mobile phase B: IPA; flow rate: 20 mL / min, eluting with 15% B in 21 minutes; UV 210 / 254 nm; t (R) Isomer 1 16 min, (106.2 mg, 37.6%, 100% ee) as a white solid, ES / MS (m / z) 317.1 (M+H); t (R)Isomer 2 19 min, (94.96 mg, 33.3%, 98.3% ee) as a white solid, ES / MS (m / z) 317.1 (M+H).

[0483] Preparation Example 65

[0484] (Z / E)-5,5-difluoro-N'-hydroxy-4,4-dimethyl-3-oxohexanamidine

[0485]

[0486] A solution of 5,5-difluoro-4,4-dimethyl-3-oxohexanenitrile (1.50 g, 8.56 mmol), NaHCO3 (1.80 g, 21.427 mmol), and bis(hydroxyammonium) sulfate (1.69 g, 10.30 mmol) in H2O (27.00 mL) and MeOH (3.00 mL) was stirred overnight at 65 °C and under N2. The mixture was used directly without further purification. ES / MS m / z 209.2 (M+H).

[0487] Preparation Example 66

[0488] 3-(3,3-dimethylcyclobutyl)-1,2-oxazol-5-amine

[0489]

[0490] A solution of 3-(3,3-dimethylcyclobutyl)-3-oxopropanenitrile (1.50 g, 9.92 mmol), NH2OH·HCl (0.76 g, 10.94 mmol), and NaOH (0.79 g, 19.84 mmol) in H2O (15.00 mL) was stirred at 100 °C and under N2 for 2 h. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with H2O (3 × 30 mL). The resulting mixture was concentrated under reduced pressure to give the title compound as an off-white solid (1.5 g, 90.97%). ES / MS (m / z) 167.3 (M+H).

[0491] The following compounds in Table 11 were prepared essentially as described for 3-(3,3-dimethylcyclobutyl)-1,2-oxazol-5-amine, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction. The base can be added in portions, and the reaction mixture can be extracted with DCM or filtered where appropriate.

[0492]

[0493] Preparation Example 67b

[0494] 3-(3-Methyl-1-bicyclo[1.1.1]pentyl)isoxazol-5-amine

[0495]

[0496] At room temperature and under N2, NaOH (192.38 mg, 4.81 mmol) was added portionwise to a stirred mixture of 3-[3-methylbicyclo[1.1.1]pent-1-yl]-3-oxopropanenitrile (350.00 mg, 2.41 mmol) and hydroxylamine HCl (183.83 mg, 2.65 mmol) in H2O (8.00 mL). The mixture was stirred at 100 °C under N2 for 1 h. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with H2O (3 × 20 mL) to afford the title compound as a pale yellow solid (300 mg, 77.9%). ES / MS m / z (M+H) 165.1.

[0497] Preparation Example 67c

[0498] 3-(2,2-Dimethylpropyl)-4-fluoro-1,2-oxazol-5-amine

[0499]

[0500] A solution of 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (5.00 g, 32.42 mmol) and Selectfluor™ (13.78 g, 38.90 mmol) in MeOH (100 mL, 780.04 mmol) was stirred at 50 °C under N2 for 30 min. The reaction was cooled to room temperature, diluted with H2O (100 mL), and extracted with EtOAc (3 × 100 mL). The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound as a pale yellow solid (1.55 g, 27.7%). LC-MS: (ES+H, m / z): [M+H]+ = 173.10

[0501] Preparation Example 67d

[0502] 3-(3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl)isoxazol-5-amine

[0503]

[0504] At room temperature and under N2, NaOH (110.25 mg, 2.76 mmol) was added portionwise to a mixture of 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile (280.00 mg, 1.38 mmol), hydroxylamine HCl (105.35 mg, 1.52 mmol), and H2O (10 mL). The resulting mixture was heated to 100 °C for 1 hour. The mixture was cooled to room temperature and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with Et2O (10 mL). The resulting solid was collected by filtration and washed with Et2O to afford the title compound (220 mg, 73%). ES / MS m / z (M+H) 219.2.

[0505] Preparation Example 68

[0506] 5-(3,3-Difluoro-2-methylbutan-2-yl)-1,2-oxazol-3-amine

[0507]

[0508] The crude solution of (Z)-5,5-difluoro-N'-hydroxy-4,4-dimethyl-3-oxohexanimidamide was acidified to pH = 1 with HCl (c), and the resulting mixture was stirred at 100 °C and under N2 for 1 hour. The mixture was slowly cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O, eluted with a gradient of 30% to 50% in 20 minutes; UV 220 nm to afford the title compound as a yellow solid (230 mg, 14%). ES / MS (m / z) 191.2 (M+H).

[0509] Preparation Example 69

[0510] 3-(2-Chloro-4-fluorophenyl)-1,2-oxazol-5-amine

[0511]

[0512] To a crude mixture of 3-(2-chloro-4-fluorophenyl)-3,2-oxopropanenitrile (2.8 g, 14. mmol) was added NH2OH.HCl (0.98 g, 14.17 mmol), KOAc (2.09 g, 21.30 mmol) and 1,4-dioxane (30.00 mL). The resulting mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature and diluted with H2O (30 mL) and EtOAc (30 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of PE / EtOAc (9:1 - 2:1) to afford the title compound as a yellow solid (1.2 g, 39.83%). ES / MS (m / z) ( 35 Cl / 37 Cl) 213.0 / 215.0(M+H).

[0513] The following compounds in Table 12 were prepared essentially as described for 3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-amine, using the appropriate reagents and adjusting the reaction time to determine completion of the reaction, and determining purification conditions where appropriate. The reaction temperature can be about 70 °C to 100 °C. NaOAc can be substituted for KOAc and EtOH can be substituted for 1,4-dioxane.

[0514]

[0515] Preparation Example 71

[0516] 5-(2-Methylbutan-2-yl)-1,2-oxazol-3-amine

[0517]

[0518] At room temperature and under N2, NaHCO3 (4.53 g, 53.88 mmol) was added portionwise to a stirred mixture of 4,4-dimethyl-3-oxohexanenitrile (3.00 g, 21.55 mmol) and hydroxylamine sulfate (3.89 g, 23.71 mmol) in MeOH (5.00 mL) and H2O (45 mL). The resulting mixture was stirred at 65 °C and under N2 for 5 h. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 1 with HCl (c) and stirred at 130 °C and under N2 for 20 min. The mixture was allowed to cool to room temperature and the pH was adjusted to 8 with NaOH. The resulting mixture was extracted with DCM (3 × 200 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (2 × 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN (0.1% NH4HCO3) in H2O, eluted with a 30% to 40% gradient over 10 min; UV 220 nm, to afford the title compound as a pale yellow solid (1.2 g, 36%). 1 1H NMR (CDCl3) δ 5.53 (s, 1H), 1.66 (q, 2H), 1.27 (s, 6H), 0.82 (t, 3H).

[0519] Preparation Example 72

[0520] 3-(2,4-Dichlorophenyl)-1,2-oxazol-5-amine

[0521]

[0522] A solution of NH2OH.HCl (535.66 mg, 7.71 mmol) and KOAc (756.53 mg, 7.71 mmol) in MeOH (10.00 mL) was stirred at room temperature and under N2 for 1 h. 3-(2,4-Dichlorophenyl)-3-oxopropanenitrile (550.00 mg, 2.57 mmol) was added to the mixture and the reaction was stirred at room temperature for an additional 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and the precipitated solid was collected by filtration, washed with H2O (3 × 20 mL), and dried under reduced pressure to afford the title compound as a yellow solid (200 mg, 35.0%). ES / MS m / z ( 35 Cl / 37 Cl) 229.0 / 231.0 (M+H).

[0523] Preparation Example 72a

[0524] 5-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

[0525]

[0526] A solution of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500.0 mg, 2.59 mmol), hexane-2,5-dione (886.3 mg, 7.77 mmol) and HOAc (15.5 mg, 0.26 mmol) in toluene (10.00 mL) was stirred at 100 °C under N2 for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography eluting with the following conditions: column, C18 gel, ACN (0.1% FA) in H2O, eluting with a gradient of 30% to 50% over 10 minutes; UV 254 nm to give the title compound as a yellow solid (610 mg, 87%). ES / MS m / z (M+H) 272.1.

[0527] Preparation Example 72b

[0528] 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

[0529]

[0530] A solution of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (500.0 mg, 1.84 mmol), MeI (1046.4 mg, 7.37 mmol) and K2CO3 (509.4 mg, 3.69 mmol) in ACN (10.00 mL) was stirred at 80 °C under N2 for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluting with 5:1 PE / EtOAc, 254 nm to give the title compound as a white solid (95 mg, 18%). ES / MS m / z (M+H) 286.2.

[0531] Preparation Example 72c

[0532] 1-Methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-amine

[0533]

[0534] A solution of KOH (53.1 mg, 0.95 mmol) in EtOH (1.00 mL) and H2O (1.00 mL) was added to a solution of hydroxylamine HCl (131.5 mg, 1.89 mmol) in EtOH (2.00 mL). 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (90.0 mg, 0.32 mmol) was added and the mixture was stirred at 100 °C under N2 for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18 gel, ACN (0.1% FA) in H2O, eluting with a gradient of 10% to 30% over 10 min; UV 254 nm to afford the title compound as a white solid (45 mg, 68%). ES / MS m / z (M+H) 208.1.

[0535] Preparation Example 73

[0536] tert-Butyl N-[4-cyano-5-[6-[2-[[5-(1,1-dimethylpropyl)isoxazol-3-yl]amino]-1-methyl-2-oxoethyl]-3-pyridinyl]-2-isopropylpyrazol-3-yl]carbamate

[0537]

[0538] Under N2, MeTHF (1.85 mL) and 5-(1,1-dimethylpropyl)isoxazol-3-amine (171 mg, 1.11 mmol) were added to a suspension of lithium 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropylpyrazol-3-yl]-2-pyridinyl]propionate (300 mg, 0.740 mmol) in pyridine (1.85 mL), followed by the addition of T3P ® solution (50%, 1413 mg, 2.22 mmol) in MeTHF. The reaction mixture was stirred overnight at room temperature and then poured into a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography eluting with a gradient of acetone in DCM from 1 to 10% to afford the title compound (181.3 mg, 43%). 1 H NMR (d 6-DMSO) δ 11.17 (s, 1H), 9.91(s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.2, 2.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 6.61 (s, 1H), 4.58 (p, J = 6.5 Hz, 1H), 4.16 (q, J = 6.9 Hz,1H), 1.61 (q, J = 7.5Hz, 2H), 1.50 (d, J = 8.4 Hz, 13H), 1.41 (d, J = 6.6 Hz,7H), 1.24 (s, 7H), 1.08 (s, 1H), 0.73 (t, J = 7.5 Hz, 3H).

[0539] The following compounds in Table 13 were prepared substantially as described for tert-butyl N-[4-cyano-5-[6-[2-[[5-(1,1-dimethylpropyl)isoxazol-3-yl]amino]-1-methyl-2-oxoethyl]-3-pyridinyl]-2-isopropylpyrazol-3-yl]carbamate, adjusting the reaction time to determine completion of the reaction and using appropriate chromatographic conditions for purification.

[0540] Table 13

[0541]

[0542] a1 H NMR (400 MHz, d 6 -DMSO) δ 8.95 –8.90 (m, 1H), 8.58 (dd, J =5.8, 1.6Hz, 1H), 8.17 (dd, J = 8.2, 2.4 Hz, 1H), 7.60 (d, J = 8.2Hz, 1H), 7.39 (ddd,J = 7.6, 4.3, 1.5 Hz, 1H), 6.38 (s, 1H), 4.58 (p, J = 6.5 Hz, 1H), 4.17 (q, J= 7.0 Hz, 1H), 1.55 –1.46(m, 20H), 1.41 (d, J = 6.6 Hz, 8H).

[0543] b1 H NMR (400 MHz, d 6-DMSO) δ 11.76 (s, 1H), 9.91 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 8.2, 2.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 6.12 (s, 1H), 4.58 (p, J = 6.6 Hz, 1H), 4.15 (q, J = 7.0 Hz, 1H), 2.45 (s, 2H), 1.52 - 1.49 (m, 12H), 1.41 (d, J = 6.6 Hz, 6H), 0.93 (s, 9H).

[0544] c Use the lithium salt of 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propionic acid.

[0545] Preparation Example 80

[0546] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide

[0547]

[0548] To a mixture of 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (62 mg, 0.402 mmol), 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propionic acid (120 mg, 0.402 mmol) and NMI (99 mg, 1.206 mmol) in ACN (5.00 mL) was added TCFH (338 mg, 1.206 mmol). The resulting mixture was stirred at 50 °C under N2 for 2 h and then concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O (0.1% NH4CO3), eluted with a gradient of 0% to 50% in 25 min; UV 254 nm to give the title compound as a white solid (130 mg, 74.41%). ES / MS (m / z) 435.2 (M+H).

[0549] The following compounds in Table 14 were prepared substantially as described for 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide, using appropriate reagents, adjusting the reaction time to determine completion of the reaction, and determining purification conditions where appropriate. The reaction temperature can be from about 50 °C to 80 °C.

[0550] Table 14

[0551]

[0552]

[0553]

[0554]

[0555]

[0556] *4 Å molecular sieve was added to the reaction.

[0557] Alternative Preparation Example 82

[0558] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide

[0559]

[0560] To a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (220 mg, 0.71 mmol) and 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (131 mg, 0.85 mmol) in ACN (3.00 mL) was added NMI (291 mg, 3.54 mmol) and TCFH (995 mg, 3.54 mmol). The mixture was stirred at 50 °C for 3 hours. The mixture was purified by reverse phase combinatorial flash chromatography under the following conditions: C18; ACN (0.1% FA) in H2O, eluting with a gradient of 50% to 80% to afford the title compound as an off-white solid (200 mg, 63.1%). ES / MS (m / z) 447.3 (M+H).

[0561] Preparation Example 96l

[0562] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]phenyl]-N-(3-(3-methylbicyclo[1.1.1]pentan-1-yl)-1,2-oxazol-5-yl)propanamide

[0563]

[0564] At room temperature and under N2, NMI (119.05 mg, 1.45 mmol) and TCFH (271.22 mg, 0.97 mmol) were added portionwise to a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (150 mg, 0.48 mmol) and 3-(3-methylbicyclo[1.1.1]pentan-1-yl)-1,2-oxazol-5-amine (79.36 mg, 0.48 mmol) in ACN (5.00 mL). The mixture was stirred at 50 °C under N2 for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3 / 1 to 2 / 1) to afford the title compound as an off-white solid (130 mg, 58.9%). ES / MS (m / z) 457.2 (M+H).

[0565] Preparation Example 96m

[0566] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-3-fluorophenyl]-N-(3-(3-methylbicyclo[1.1.1]pentan-1-yl)-1,2-oxazol-5-yl)propanamide

[0567]

[0568] To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoic acid (150 mg, 0.46 mmol), 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (90.02 mg, 0.55 mmol) and NMI (112.52 mg, 1.37 mmol) in ACN (5.00 mL) was added TCFH (192.27 mg, 0.68 mmol). The reaction was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: column, C18; ACN in H2O (0.1% NH4HCO3), eluting with a gradient of 20% to 40% to afford the title compound as a white solid (110 mg, 50.74%). ES / MS (m / z) 475.1 (M+H).

[0569] Preparation Example 96n

[0570] 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamide

[0571]

[0572] To a solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (300 mg, 1.01 mmol), 3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (264 mg, 1.21 mmol) and NMI (248 mg, 3.02 mmol) in ACN (20 mL) was added TCFH (1.41 g, 5.03 mmol). The mixture was stirred in a sealed tube at 50 °C under N2 for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: column, C18, ACN in H2O (0.1% NH4HCO3), eluting with a gradient of 10% to 50% to afford the title compound as a light brown solid (250 mg, 49.9%). ES / MS (m / z) 499.10 (M+H).

[0573] Preparation Example 96o

[0574] 2-[4-[5-Amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]propanamide

[0575]

[0576] At room temperature and under N2, NMI (1.89 g, 22.99 mmol) and TCFH (6.45 g, 22.99 mmol) were added dropwise to a stirred solution of 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoic acid (700 mg, 2.30 mmol) and 3-(2,2-dimethylpropyl)-4-fluoro-1,2-oxazol-5-amine (435.62 mg, 2.53 mmol) in ACN (5.00 mL). The mixture was stirred at 50 °C under N2 for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:2 - 1:1) to afford the title compound as an off-white solid (400 mg, 39.93%). ES / MS (m / z) 459.2 (M+H).

[0577] Preparation Example 97

[0578] 2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-bicyclo[1.1.1]pentylmethyl)isoxazol-5-yl]propanamide, isomer 1

[0579]

[0580] Add T3P ®(250 μL, 0.427 mmol, 50% solution in EtOAc) was added dropwise to a stirred solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 1 (51 mg, 0.171 mmol), 3-(3-bicyclo[1.1.1]pentylmethyl)isoxazol-5-amine (28.1 mg, 0.171 mmol) and pyridine (27.7 μL, 0.342 mmol) in EtOAc (2 mL, 0.1 M). The reaction was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc (5 mL) and saturated aqueous NaCl solution (5 mL). The organic layer was separated and concentrated to dryness. The crude product was purified by C18 HPLC eluting with H2O:ACN (5-95%) containing 0.1% TFA to afford the title compound as a salt. The free base of the desired product was formed by eluting the desired product through a cartridge of carbonate resin to afford the title compound (10 mg, 0.0225 mmol, 13%). ES / MS (m / z) 445.2 (M+H).

[0581] Preparation Example 98

[0582] 2-(6-[5-Amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]propanamide, isomer 2

[0583]

[0584] To a solution of 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, isomer 2 (200 mg, 0.57 mmol), 3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-amine (180 mg, 0.84 mmol) and DIPEA (273 mg, 2.11 mmol) in DCM (15 mL) was added T3P ® (2.24 g, 3.52 mmol, 50% in EtOAc), and the mixture was stirred overnight at 50 °C. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O (0.1% NH4HCO3), eluting with a gradient of 10% to 50% in 10 min; UV 254 nm to afford the title compound as an off-white solid (100 mg, 32.2%). ES / MS (m / z) 548.10 (M+H).

[0585] The following compounds in Table 15 were prepared substantially as described for 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]propanamide, isomer 2, using appropriate reagents, adjusting the reaction time to determine completion of the reaction, and using appropriate chromatography conditions for purification. The temperature can be from room temperature to 80 °C and can be carried out in a sealed tube where appropriate. Dimethylacetamide (DMA) can be used in place of DCM.

[0586]

[0587]

[0588]

[0589]

[0590] Preparation Example 119g

[0591] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamide

[0592]

[0593] To a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (400 mg, 1.29 mmol) and 3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (281.20 mg, 1.29 mmol) in DCM (5.00 mL) at room temperature and under N2 in a sealed tube was added dropwise DIPEA (499.72 mg, 3.87 mmol) and T3P ® (4.10 g, 6.44 mmol, 50 wt% in EtOAc). The mixture was stirred at 80 °C and under N2 for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: C18; ACN in H2O, eluting with a gradient of 30% to 50% to afford the title compound as a pale yellow solid (230 mg, 34%). ES / MS (m / z) 511.2 (M+H).

[0594] Preparation Example 119h

[0595] 2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-methyl-1-bicyclo[1.1.1]pentyl)isoxazol-5-yl]propanamide, isomer 1

[0596]

[0597] Combine 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, isomer 1 (78 mg, 0.25 mmol), 3-(3-methylbicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine (34 mg, 0.21 mmol) and 1-methylimidazole (39 mg, 0.038 mL, 0.48 mmol) in EtOAc (3 mL). The orange solution was stirred at room temperature for 2 minutes, then T3P ® (0.31 g, 0.29 mL, 50 wt% in EtOAc, 0.49 mmol) was added. The reaction was stirred for 16 h. The reaction was then diluted with 5 mL H2O and extracted with EtOAc (3 × 25 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was used without further purification. ES / MS (m / z) 511.2 (M+H). ES / MS (m / z) 445.2 (M+H).

[0598] Preparation Example 120

[0599] tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]amino]ethyl]-3-pyridinyl]pyrazol-3-yl]carbamate

[0600]

[0601] In tertA mixture of -BuOH (2.6 mL) and H2O (1.3 mL) was charged with tert-butyl N-[4-cyano-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]amino]ethyl]-3-pyridinyl]pyrazol-3-yl]carbamate (130 mg, 0.226 mmol) and platinate(2-), tris(dimethylphosphinito-P)hydro-, dihydrogen (Parkins catalyst, CAS# 173416-05-2) (116 mg, 0.271 mmol). The reaction mixture was stirred overnight at 60 °C, filtered through a pad of talc, and washed with EtOAc. The organic phase was washed with H2O and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (147.8 mg, 104.73%). The material was used without further purification.

[0602] The following compounds in Table 16 were prepared substantially as described for tert-butyl N-[4-carbamoyl-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethylethyl)isoxazol-3-yl]amino]ethyl]-3-pyridinyl]pyrazol-3-yl]carbamate, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and using appropriate chromatographic conditions for purification if desired. The temperature can be about 60 to 70 °C.

[0603] Table 16

[0604]

[0605]

[0606] 1 EtOH can be substituted tert -BuOH.

[0607] Preparation Example 129a

[0608] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide

[0609]

[0610] To a mixture of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (120 mg, 0.276 mmol), NaOH (55 mg, 1.38 mmol), H2O (2.00 mL), and DMSO (1.00 mL) in EtOH (5.00 mL) was added H2O2 (187.86 mg, 5.523 mmol, 30% aqueous solution). The resulting mixture was stirred at 40 °C for 4 h. The mixture was cooled to room temperature and quenched by the addition of saturated aqueous Na2SO3 solution (10 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN (0.1% NH4CO3) in H2O, eluting with a gradient of 0% to 50% in 25 min; UV 254 nm to afford the title compound as a white solid (100 mg, 80.02%). ES / MS (m / z) 453.4 (M+H).

[0611] The following compounds in Table 17 were prepared essentially as described for 5-amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and using appropriate chromatographic conditions for purification. NaOH and H2O2 may be added in portions and the relative amounts of the solvents H2O, EtOH, and DMSO may be varied. The temperature may be from room temperature to 50 °C.

[0612] Table 17

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622] * After quenching, the mixture was acidified to pH = 3 - 6 with HCl (aqueous solution).

[0623] Alternative Preparation Example 129

[0624] 5 - Amino - 3 - [4 - (1 - [[3 - (2,2 - dimethylpropyl)-1,2 - oxazol - 5 - yl]carbamoyl]ethyl)phenyl]-1 - isopropylpyrazole - 4 - carboxamide

[0625] A mixture of 2 - [4 - (5 - amino - 4 - carbamoyl - 1 - isopropylpyrazol - 3 - yl)phenyl]propanoic acid (1.30 g, 4.109 mmol), 3 - (2,2 - dimethylpropyl)-1,2 - oxazol - 5 - amine (0.70 g, 4.520 mmol), NMI (2.12 g, 16.437 mmol) and TCFH (2.31 g, 8.218 mmol) in DMF (50 mL) was stirred at room temperature and under N2 for 4 hours. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (3 × 100 mL) and concentrated under reduced pressure. The residue was purified by reverse - phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN (0.1% FA) in H2O, eluted with a gradient of 55% to 65% in 10 minutes; UV 220 nm to give the title compound as a pale yellow solid (500 mg, 26.9%). ES / MS (m / z) 453.4(M + H).

[0626] Alternative Preparation Example 130

[0627] 5 - Amino - 3 - [5 - (1 - [[3 - (2,2 - dimethylpropyl)-1,2 - oxazol - 5 - yl]carbamoyl]ethyl)pyridin - 2 - yl]-1 - isopropylpyrazole - 4 - carboxamide

[0628]

[0629] To a mixture of 2-[6-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (120 mg, 0.28 mmol), NaOH (55 mg, 1.38 mmol), DMSO (0.40 mL), H2O (0.80 mL) in EtOH (2.00 mL) was added H2O2 (937 mg, 8.27 mmol, 30%). The mixture was stirred at 40 °C for 4 h. The mixture was cooled to room temperature, quenched by addition of saturated aqueous Na2SO3 solution (30 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: column, C18, eluted with a gradient of 0 to 50% ACN (0.1% NH4CO3) in H2O to afford the title compound as a white solid (100 mg, 80%). ES / MS (m / z) 454.2 (M+H).

[0630] Alternative Preparation Example 138

[0631] 5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

[0632] 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (190 mg, 0.43 mmol), EtOH (5.00 mL), H2O (2.00 mL), DMSO (1.00 mL), NaOH (170.00 mg, 4.26 mmol) and H2O2 (2.43 g, 21.30 mmol, 30%) were added together. The solution was stirred at 40 °C for 5 h. The reaction was quenched by saturated Na2SO3 (10 mL). The solution was diluted with EtOAc (100 mL) and washed with H2O (2 × 30 mL) and brine (20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by reverse phase combinatorial flash chromatography under the following conditions: C18; eluted with a gradient of 50 to 80% ACN (0.1% NH4HCO3) in H2O to afford the title compound as a white solid (190 mg, 95.9%). ES / MS (m / z) 465.3 (M+H).

[0633] Preparation Example 167p

[0634] 5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide

[0635]

[0636] At room temperature and under N2, NaOH (176.28 mg, 4.41 mmol) and H2O2 (30%, 999.40 mg, 8.82 mmol, 30 wt%) were added portionwise to a stirred solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]propanamide (225.00 mg, 0.44 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL). The mixture was stirred at 50 °C for 2 h in a sealed tube under N2. The mixture was cooled to room temperature. The reaction was quenched by the addition of saturated Na2SO3 (20 mL) at room temperature. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; elution with a gradient of 40 to 50% ACN (0.1% NH4HCO3) in H2O to give the title compound as a white solid (70 mg, 30%). ES / MS (m / z) 529.2 (M+H)

[0637] Preparation Example 167q

[0638] 5-Amino-3-(4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

[0639]

[0640] At room temperature and under N2, NaOH (113.89 mg, 2.85 mmol) and H2O2 (30%, 645.70 mg, 5.70 mmol, 30 wt%) were added portionwise to a stirred solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)propanamide (130 mg, 0.29 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL). The mixture was stirred at 50 °C under N2 for 4 h. The mixture was cooled to room temperature and quenched by the addition of saturated Na2SO3 (30 mL) at room temperature. The mixture was extracted with DCM (3 × 50 mL), and the combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; elution with a gradient of 40 to 50% ACN (0.1% NH4HCO3) in H2O to afford the title compound as a pink solid (95 mg, 70%). ES / MS (m / z) 497.2 (M+Na).

[0641] Preparation Example 167r

[0642] 5-Amino-1-isopropyl-3-[4-(1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide

[0643]

[0644] To a solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]propanamide (130 mg, 0.27 mmol), NaOH (53.33 mg, 1.33 mmol) in EtOH / DMSO (6 mL, 5:1) was added H2O2 (907 mg, 7.99 mmol, 30%) and the mixture was stirred at 50 °C for 2 h. The solution was cooled to room temperature, quenched with saturated Na2SO3 solution (10 mL) and extracted with EtOAc (3×20 mL). The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; elution with a gradient of 40 to 60% ACN (0.1% NH4HCO3) in H2O to afford the title compound (100 mg, 74.18%). ES / MS (m / z) 506.4 (M+H).

[0645] Preparation Example 167s

[0646] 5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

[0647]

[0648] To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)propanamide (100 mg, 0.21 mmol) and NaOH (42.14 mg, 1.05 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL) was added H2O2 (358.39 mg, 3.161 mmol, 30%). The reaction was stirred at 50 °C for 2 h. The reaction was quenched with saturated aqueous Na2SO3 (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; elution with a gradient of 20 to 40% ACN (0.1% NH4HCO3) in H2O to afford the title compound as a white solid (70 mg, 67.44%). ES / MS (m / z) 493.2 (M+H).

[0649] Preparation Example 167t

[0650] 5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide

[0651]

[0652] A solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]propanamide (230 mg, 0.46 mmol), H2O2 (1.05 g, 9.23 mmol, 30%) and NaOH (93 mg, 2.31 mmol) in EtOH / DMSO (20 mL, 4:1) was stirred at 40 °C for 2 h. The solution was cooled to room temperature, saturated Na2SO3 solution (10 mL) was added, and the mixture was stirred at room temperature for 10 min. The mixture was concentrated under reduced pressure and purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; elution with a gradient of 20 to 50% MeOH (0.1% NH4HCO3) in H2O to afford the title compound as a white solid (166 mg, 69.7%). ES / MS (m / z) 517.10 (M+H).

[0653] Preparation Example 167u

[0654] 5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide

[0655]

[0656] At room temperature and under N2, NaOH (174.44 mg, 4.36 mmol) and H2O2 (1.98 g, 17.45 mmol, 30 wt%) were added dropwise to a stirred solution of 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]propanamide (400 mg, 0.87 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL). The mixture was stirred at 50 °C under N2 for 1 h and then quenched with saturated Na2SO3. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column C18; elution with 30 to 50% ACN in H2O to give the title compound as a yellow solid (120.00 mg, 28.87%). ES / MS (m / z) 477.3 (M+H).

[0657] Preparation Example 168

[0658] 5-Amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridinyl]-1-isopropyl-pyrazole-4-carboxamide

[0659]

[0660] To tert-butyl N-[4-carbamoyl-5-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridinyl]-2-isopropyl-pyrazol-3-yl]carbamate (134 mg, 0.242 mmol) in DCM (1.45 mL) was added TFA (0.72 mL, 9.68 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with a cold saturated aqueous solution of NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of MeOH in DCM from 0% to 5% to afford the title compound (68 mg, 61.95%).

[0661] The following compounds in Table 18 were prepared substantially as described for 5-amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridinyl]-1-isopropyl-pyrazole-4-carboxamide, adjusting the reaction time to determine completion of the reaction and using appropriate chromatographic conditions for purification. The products can also be triturated in isopropyl ether, filtered, and dried under vacuum.

[0662]

[0663] Example 1

[0664] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, isomer 1

[0665] and

[0666] Example 2

[0667] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, isomer 2

[0668]

[0669] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide (100.00 mg, 0.22 mmol) was separated by preparative chiral chromatography under the following conditions: column: CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 µm; mobile phase A: hexane (10 mM NH3), mobile phase B: IPA; flow rate 20 mL / min; 30% B eluted in 15 minutes; 254 nm; t (R) Isomer 1 was at 8.2 minutes (33.3 mg, 33.3%), [α] D 20 = 0.22696º (C = 0.1, MeOH) as a white solid with 100% ee. t (R) Isomer 2 was at 11.0 minutes (33.1 mg, 33.1%), [α] D 20 = -0.2113º (C = 0.1, MeOH) as a white solid with 100% ee. ES / MS (m / z) 453.4 (M+H).

[0670] The following compounds in Table 19 were prepared substantially as described for 5-amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 1 and Isomer 2, adjusting the purification system as appropriate.

[0671] Table 19

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678] 1 Column: Chiralpak AD-H, 2 * 25 cm, 5 µm.

[0679] 2Column: (R,R)Whelk-O 1, 21.1*250 mm, 5 µm.

[0680] 3 Column: (R,R)Whelk-O 1, Kromasil(02), 5*25 cm, 5 µm.

[0681] 4 CHIRALPAK IF, 2*25 cm, 5 µm.

[0682] 5 CHIRALPAK IA, 2*25 cm, 5 µm.

[0683] 6 CHIRALPAK IA, 2*25 cm, 5 µm.

[0684] 7 Mobile phase B, EtOH.

[0685] 8 (R,R)-Whelk-01, 2.12*25, 5 µm, Mobile phase B, EtOH.

[0686] 9 Elute with 25% IPA, 246 / 210 nm.

[0687] Alternative Example 1

[0688] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 1

[0689] 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide (17 g) was separated by preparative chiral chromatography under the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 µm; Mobile phase A hexane (10 mM NH3-MeOH), Mobile phase B IPA; Flow rate 20 mL / min; Elute with 30% B in 12 minutes; UV 254 / 220 nm; t (R)Isomer 1 was 7.0. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase combinatorial flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O (0.1% FA), eluted with a gradient of 55% to 65% in 10 minutes; UV 220 nm, (6.1315 g, 35.7%) as a white solid, with 99.8% ee, MP 128 °C, ES / MS (m / z) 453.2 (M+H).

[0690] Example 36c

[0691] 5-Amino-3-[4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, isomer 1

[0692] and

[0693] Example 36d

[0694] 5-Amino-3-[4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, isomer 2

[0695]

[0696] 5-Amino-3-(4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (93 mg) was purified by preparative HPLC under the following conditions: column CHIRAL ART Cellulose-SB, 2*25 cm, 5 µm; eluted with 20% IPA in hexane (10 mM NH3-MeOH), flow rate 20 mL / min; 254 / 210 nm to obtain isomer 1 as a white solid, t (R) 12.22, (30.8 mg, 33% yield, 100% ee), ES / MS (m / z) 475.3 (M+H) and isomer 2 as a white solid, t (R) 16.56, (30.5 mg, 33% yield 100% ee), ES / MS (m / z) 475.3 (M+H).

[0697] Example 36e

[0698] 5-Amino-1-isopropyl-3-[4-[1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl]phenyl]pyrazole-4-carboxamide, isomer 1

[0699] and

[0700] Example 36f

[0701] 5-Amino-1-isopropyl-3-[4-[1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl]phenyl]pyrazole-4-carboxamide, isomer 2

[0702]

[0703] 5-Amino-1-isopropyl-3-[4-(1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide (90 mg) was purified by preparative chiral HPLC under the following conditions: column CHIRALPAK IC, 2 * 25 cm, 5 µm; eluted with 30% IPA (10 mM NH3-MeOH) in hexane, flow rate 20 mL / min; 240 / 210 nm to give the title compound of isomer 1 as a white solid, t (R) 15.48, (35.2 mg, 39.22% yield, 100% ee), ES / MS (m / z) 506.3 (M + H) and the title compound of isomer 2 as a white solid, t (R) 20.74, (32.3 mg, 35.89% yield, 97.7% ee), ES / MS (m / z) 506.3 (M + H).

[0704] Example 36g

[0705] 5-Amino-1-isopropyl-3-(4-(1-((3-(3-methylbicyclo[1.1.1]pent-1-yl)isoxazol-5-yl)amino)-1-oxopropan-2-yl)phenyl)-1H-pyrazole-4-carboxamide, isomer 1

[0706]

[0707] 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-methyl-bicyclo[1.1.1]pent-1-yl)isoxazol-5-yl]propanamide, isomer 1 (110 mg, 247 μmol) and Parkins catalyst (106 mg, 247 μmol) were mixed in EtOH (4 mL) and H2O (1 mL). The mixture was heated at 60 °C for 24 h. The mixture was filtered through a 0.45 μM filter and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 - 100% heptane:EtOAc to afford the title compound as a yellow solid (26 mg, 23%). ES / MS (m / z) 463.2 (M+H).

[0708] Example 36h

[0709] 5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, isomer 1

[0710] and

[0711] Example 36i

[0712] 5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, isomer 2

[0713]

[0714] 5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide (68 mg) was purified by preparative chiral HPLC under the following conditions: column: CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 μm; eluting with 15% EtOH in hexane (10 mM NH3-MeOH), flow rate 20 mL / min, over 18 min, 254 / 210 nm to afford the title compound of isomer 1 as a white solid, t (R) 11.72, (15.3 mg, 22% yield, 100% ee), ES / MS (m / z) 529.2 (M+H) and the title compound of isomer 2 as a white solid, t(R) 14.41, (16.8 mg, 24% yield, 100% ee). ES / MS (m / z) 529.2 (M+H).

[0715] The following compounds in Table 19a were prepared substantially as described for 5-amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2, and the chromatographic conditions were adjusted where appropriate.

[0716] Table 19a

[0717]

[0718]

[0719] 1 Eluted with 10% EtOH (0.5% 2 M NH3-MeOH) in 1:1 hexane:MTBE.

[0720] 2 Eluted with 10% EtOH (10 mM NH3-MeOH) in hexane, 245 / 210 nm.

[0721] 3 Column: CHIRALPAK ID 2*25 cm, 5 µm; eluted with 8% IPA (0.5% 2 M NH3-MeOH) in 1:1 hexane:MTBE, 245 / 210 nm.

[0722] 4 UV 245 / 210 nm.

[0723] Example 36t

[0724] 5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 1

[0725] and

[0726] Example 36u

[0727] 5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 2

[0728]

[0729] 5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (70 mg) was purified by preparative chiral HPLC under the following conditions: column CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 µm, eluted with 30% IPA in hexane (10 mM NH3-MeOH), 250 / 210 nm to give the title compound t of isomer 1 as a white solid. (R) 7.04, (20.3 mg, 29.0%, 99.76% ee), ES / MS (m / z) 454.2 (M+H) and the title compound t of isomer 2 as a white solid. (R) 9.48, (18.9 mg, 27.0%, 99.26% ee), ES / MS (m / z) 454.2 (M+H).

[0730] Example 36v

[0731] 5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, isomer 1

[0732] and

[0733] Example 36w

[0734] 5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, isomer 2

[0735]

[0736] 5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide (162 mg) was purified by preparative chiral HPLC under the following conditions: column CHIRAL ART Cellulose-SB, 2 * 25 cm, 5 µm, eluted with 20% EtOH in hexane (10 mM NH3-MeOH), 254 / 210 nm to give the title compound of isomer 1 as a white solid t (R) 10.66, (48.1 mg, 29.6%, 100% ee), ES / MS (m / z) 517.05 (M+H) and the title compound of isomer 2 as a white solid t (R) 13.23, (50.4 mg, 30.6%, 99.74% ee), ES / MS (m / z) 517.05 (M+H).

[0737] The following compounds in Table 19b were prepared essentially as described for 5-amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, isomer 1 and isomer 2, and the chromatographic conditions were adjusted where appropriate.

[0738] Table 19b

[0739]

[0740]

[0741] 1 UV was 210 / 237 nm.

[0742] Example 36zf

[0743] 5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide, isomer 1

[0744] and

[0745] Example 36zg

[0746] 5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide, isomer 2

[0747]

[0748] 5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide (120 mg) was purified by preparative chiral HPLC under the following conditions: column CHIRAL ARTCellulose-SB, 2 * 25 cm, 5 µm eluted with 20% EtOH in hexane (10 mM NH3-MeOH), 213 / 237 nm to give the title compound t of isomer 1 as a beige solid (R) 7.78, (22.2 mg, 18.5%, 100% ee), ES / MS (m / z) 477.25(M+H) and the title compound t of isomer 2 as a beige solid (R) 9.43, (27.1 mg, 22.6%, 98.14% ee), ES / MS (m / z) 477.25(M+H).

[0749] Example 37

[0750] 5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, isomer 1

[0751] and

[0752] Example 38

[0753] 5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, isomer 2

[0754]

[0755] 5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide (97.00 mg, 0.21 mmol) was separated by preparative chiral chromatography under the following conditions: column: CHIRALART Cellulose-SB, 2 * 25 cm, 5 µm; mobile phase A: hexane (10 mM NH3), mobile phase B: EtOH; flow rate 20 mL / min; eluted with 40% B in 11 minutes; 254 / 220 nm; t (R) Isomer 1 was at 5.2 minutes (35.8 mg, 36.9%) as a white solid, 100% ee. ES / MS (m / z) 454.2 (M+H). t (R) Isomer 2 was at 7.5 minutes (42.1 mg, 43.4%) as a white solid, 100% ee. ES / MS (m / z) 454.2 (M+H).

[0756] The following compounds in Table 20 were prepared substantially as described for 5-amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, Isomer 1 and Isomer 2, and the purification system was adjusted as appropriate.

[0757] Table 20

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767] 1 Column CHIRAL ART Cellulose-SB, S-5 µm, 50 * 250 mm, 5 µm.

[0768] 2 Column CHIRAL ART Cellulose-SB S-5 µm, 2*25 cm.

[0769] 3 Column CHIRALCEL OD-H, 2*25 mm.

[0770] 4 Column CHIRALCEL OD-H, 4.6X150 mm, 5 µm, 25% EtOH / CO2, 5 mL / min, 225 nm.

[0771] 5 Column CHIRAL ART Cellulose-SC.

[0772] 6 Column: (R,R)Whelk-O 1, 21.1*250 mm, 5 µm.

[0773] 7 Column: (R,R)Whelk-O1, 2.12*25 cm, 5 µm.

[0774] 8 EtOH is used for mobile phases A and B, 50% isocratic.

[0775] 9 Column:CHIRALPAK IH, 25*2 cm, 5 µm, mobile phase A is CO2, mobile phase B is IPA, isocratic 45%B.

[0776] 10 (R,R)-Whelk-01, 2*25 mm, 5 µm.

[0777] 11 Column: Chiralpak AD-H, 2*25 cm, 5 µm.

[0778] 12 Column: Chiralpak AD-H, 2*25 cm, 5 µm, gradient elution from 50% B to 0 B.

[0779] 13 Column: Chiralpak ADH, 2*25 cm, 5 µm, eluted with hexane (10 mM NH3MeOH) and 30% IPA.

[0780] 14The solvent system was 30% EtOH in hexanes (10 mM NH3-MeOH).

[0781] 15 Column: CHIRALPAK IG, 2 * 25 cm, 5 µm; eluted with 30% EtOH (10 mM NH3-MeOH) in hexanes, flow rate 20 mL / min, 234 / 274 nm.

[0782] 16 Column: CHIRAL ART Amylose-C NEO, 2.0 * 2 cm, 5 µm; eluted with 40% EtOH (10 mM NH3-MeOH) in hexanes, flow rate 20 mL / min, 245 / 254 nm.

[0783] Alternative Example 61

[0784] -Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, isomer 1

[0785] and

[0786] Alternative Example 62

[0787] 5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, isomer 2

[0788]

[0789] 5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (95 mg) was separated under the following conditions: Column: (R,R)-Whelk-01, 2.12 * 25 cm, 5 µm; eluted with 30% EtOH (10 mM - MeOH) in hexanes, flow rate 20 mL / min, UV 254 nm to give the title compound of isomer 1 as a white solid t (R) 11.5 min, (38.6 mg, 40.6%, 100% ee), ES / MS (m / z) 465.3 (M + H) and the title compound of isomer 2 as a white solid t (R)20 minutes (30.7 mg, 32.3%, 99.6% ee), ES / MS (m / z) 465.3 (M+H).

[0790] Example 79

[0791] 5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide, isomer 1

[0792] and

[0793] Example 80

[0794] 5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide, isomer 2

[0795]

[0796] 5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide (90 mg, 0.20 mmol) was separated by preparative chiral chromatography under the following conditions: column: CHIRALPAK IG-3, 4.6*50 mm, 3.0 µm, mobile phase A: hexane (0.1% DEA); mobile phase B: EtOH with a gradient elution from 70% to 30% B; flow rate 1 mL / min, UV 254 nm, t (R) Isomer 1 was at 2.1 minutes (25 mg, 21.8%) as a white solid, t (R) Isomer 2 was at 3.3 minutes (25 mg, 21.8%) as a white solid. ES / MS (m / z) 455.25 (M+H).

[0797] Example 81

[0798] 5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide, isomer 1

[0799] and

[0800] Example 82

[0801] 5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide, isomer 2

[0802]

[0803] 5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide (90 mg, 0.18 mmol) was separated by preparative chiral chromatography under the following conditions: column: CHIRALPAK IE, 2 * 25 cm, 5 µm; mobile phase A: ACN; mobile phase B: MtBE eluted with 25% B; 210 nm, 254 nm; t (R) Isomer 1 was at 5 minutes (39.3 mg, 43.6%, 100% ee), as a white solid. t (R) Isomer 2 was at 6 minutes (36.1 mg, 40.1%, 100% ee), as a white solid. ES / MS (m / z) 493.3 (M+H).

[0804] Example 83

[0805] 5-Amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide, isomer 1

[0806] and

[0807] Example 84

[0808] 5-Amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide, isomer 2

[0809]

[0810] 5-Amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridinyl]-1-isopropyl-pyrazole-4-carboxamide (68 mg, 0.18 mmol) was chiral separated under the following conditions: Column: Acquity UPLC CSH C18 (2.1×50 mm) 1.7 µm; Mobile phase A: H2O + 0.02% FA; Mobile phase B: ACN + 0.02% FA, eluted with a gradient of 2% B to 98% B over 4 minutes; Flow rate was 1 ml / min and the temperature was 55 °C.t (R) Isomer 1 was at 3.3 minutes (22 mg, 20%).t (R) Isomer 2 was at 4.7 minutes (23 mg, 21%). ES / MS (m / z) 454 (M+H).

[0811] The following compounds in Table 21 were chiral separated substantially as described for 5-amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridinyl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2, with the conditions adjusted under appropriate conditions. The title compound can be triturated with isopropyl ether and dried under vacuum at about 45 °C for 14 hours to obtain a white solid.

[0812]

[0813]

[0814] Example 97

[0815] 5-Amino-3-[4-[2-[[3-(3-bicyclo[1.1.1]pentylmethyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, Isomer 1

[0816]

[0817] 2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-bicyclo[1.1.1]pentylmethyl)isoxazol-5-yl]propanamide, isomer 1 (10 mg, 0.023 mmol) and platinate(2-), tris(dimethylphosphine-P)hydro-, dihydrogen (Parkins catalyst, CAS# 173416-05-2) (10 mg, 0.023 mmol) were stirred in EtOH (0.2 mL) and H2O (0.2 mL) at 70 °C for 90 minutes. The reaction mixture was filtered through celite and concentrated. The residue was purified by C18 HPLC eluting with H2O:ACN (5-95%) containing 0.1% TFA. The free base of the desired product was formed by eluting the material through a cartridge of carbonate resin to give the title compound (4.3 mg, 39%). ES / MS (m / z) 463.2(M+H) 99% ee, chiral purity determination: YMA Chiral Cellulose-SB column, 4.6 x 100 mm, 3 µm eluted with 70 / 30 hexane (0.1% ethylenediamine) / IPA, 1 mL / min, t (R) 3.78.

[0818] The following compounds in Table 22 were prepared substantially as described for 5-amino-3-[4-[2-[[3-(3-bicyclo[1.1.1]pentylmethyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, isomer 1, using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and using appropriate chromatographic conditions for purification as needed. The temperature can be about 60 to 80 °C. Additionally, Parkin's catalyst can be used to drive the reaction to completion if desired.

[0819]

[0820] Although only certain representative compounds, materials, and method steps disclosed herein are explicitly described, other combinations of compounds, materials, and method steps are also intended to fall within the scope of the appended claims, even if not explicitly enumerated. Thus, combinations of steps, elements, components, or ingredients may be explicitly mentioned herein; however, other combinations of steps, elements, components, and ingredients are included even if not explicitly specified. The terms "comprising" and variations thereof used herein are used synonymously with the term "including" and variations thereof and are open-ended and non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" may be used in place of "comprising" and "including" to provide more specific embodiments of the invention and also to make a disclosure.

[0821] Biometric assay

[0822] The following assays demonstrate that the compounds described herein are RET kinase inhibitors.

[0823] Assay A: RET Enzyme Assay

[0824] The ability of compounds of Formula I, II or III to inhibit wild-type, V804M and G810S mutant RET kinases was screened using CisBio’s HTRF® KinEASE™-TK assay technology. The N-terminal GST-tagged recombinant human RET cytoplasmic domain (aa 658-end) (1.25 nM RET; Catalog No. 14-570M) from Eurofins or the N-terminal GST-tagged recombinant human V804M mutant RET cytoplasmic domain (aa 658-end) (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) from Millipore was incubated with 62.5 nM TK substrate biotin (part of CisBio, Catalog No. 62TK0PEC) and 1 mM ATP together with the test compound (0.4% final DMSO in the assay) in 1X Cisbio enzyme buffer consisting of 1 nM DTT, 5 mM MgCl2, 0.04% BSA and 0.05% Tween20 in a volume of 10 µL. Compounds were typically prepared as three-fold serial dilutions in DMSO and added to the assay to obtain appropriate final concentrations. After incubation at 22 °C for 40 - 60 minutes (40 minutes for V804M, 60 minutes for WT and G810S), the reaction was quenched by adding a quenching solution (10 µL) containing 7.8 nM streptavidin-XL665 and 0.5X TK-ab-Cryptate (both from CisBio, part of Cat. No. 62TK0PEC) in HTRF detection buffer. After incubation at 22 °C for 60 - 80 minutes (60 minutes for WT, 80 minutes for V804M and G810S), the extent of the reaction was measured by HTRF detection at excitation / emission 337 / 665 nm using a PHERastar plate reader. The percent inhibition was calculated, where 0% inhibition refers to the control condition without compound (only 0.4% DMSO) and 100% inhibition represents the condition without enzyme. The % inhibition values were fitted to a 4-parameter logistic curve and the determined IC 50The value is defined as the estimated concentration of the inhibitor at the inflection point of the fitted curve. The compounds of Examples 1, 15, 17, 35, 45, 52, 64, 66, 68, 70, 76, 80, 81, 84, 90, 94, and 98 all showed IC 50 values of less than 100 nM for wild-type, V804M, and G810S mutant RET kinases, respectively, in these assays. All compounds in Table A had IC 50 values of less than 700 nM in wild-type, V804M, and G810S mutant RET kinase assays.

[0825] Assay B: RET Cell Assay

[0826] The ability of the compounds of Formulas (I), (II), and (III) to inhibit the intracellular autophosphorylation of RET at tyrosine 1062 was screened by In-Cell Western. HEK293 cells containing doxycycline-inducible plasmids for the inducible expression of KIF5B-RET WT and RET mutant forms V804M and G810S were seeded at 25,000 cells / well into black poly-D-lysine pre-coated 384-well plates (Corning, Catalog No. 356697). Expression of KIF5B-RET was induced with 1 μg / mL doxycycline and the cells were cultured overnight at 37 °C. Compounds were prepared as three-fold serial dilutions in DMSO and then further diluted 1:100 in medium and then added to the cells (0.1% final DMSO concentration). Compound treatment was carried out at 37 °C for 1 h, then the cells were fixed with 4% formaldehyde for 20 min at room temperature, and the cells were permeabilized with ice-cold MeOH for 10 min at room temperature. The cells were incubated with blocking buffer (Li-COR, Catalogue No. 927-70010) for 1 h at room temperature. Incubation with a primary antibody 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) was carried out overnight at 4 °C. Incubation with secondary antibodies 800CW goat anti-rabbit IgG (Li-COR, Catalogue No. 926-32211, 1 / 1000 dilution) and 680CW goat anti-mouse IgG (Li-COR, Catalogue No. 926-68070, 1 / 1000 dilution) was carried out for 1 h at room temperature. All antibodies were diluted in Performed in a closed buffer. After washing the cells with PBS-T (Cell Signaling technology, Catalogue No. 9809), images were acquired on a Li-COR Odyssey LCx at 700 and 800 nm. Calculate the percentage of the DMSO control, where 100% signal refers to the control condition without the compound (only 0.4% DMSO), and 0% signal represents the condition with the control compound. Fit the % values of the DMSO control to a 4-parameter logistic curve, and the determined EC 50 value was defined as the estimated concentration of the inhibitor at the inflection point of the fitted curve. The compounds of Examples 1, 15, 17, 31, 33, 35, 45, 52, 64, 66, 68, 70, 76, 80, 81, 84, 90, 94, and 98 all inhibited the intracellular autophosphorylation of RET at tyrosine 1062 in wild-type, V804M, and G810S RET mutant cells respectively with an EC 50 value less than 100 nM. All compounds in Table A had an IC 50 value less than 700 nM in wild-type, V804M, and G810S mutant RET kinase assays. Sequence Listing <110> Eli Lilly and Company <120> Compounds Useful for Inhibiting RET Kinase <130> X22660 <150> 63 / 015,933 <151> 2020-04-27 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 1114 <212> PRT <213> Homo sapiens <400> 1 Met Ala Lys Ala Thr Ser Gly Ala Ala Gly Leu Arg Leu Leu Leu Leu 1 5 10 15 Leu Leu Leu Pro Leu Leu Gly Lys Val Ala Leu Gly Leu Tyr Phe Ser 20 25 30 Arg Asp Ala Tyr Trp Glu Lys Leu Tyr Val Asp Gln Ala Ala Gly Thr 35 40 45 Pro Leu Leu Tyr Val His Ala Leu Arg Asp Ala Pro Glu Glu Val Pro 50 55 60 Ser Phe Arg Leu Gly Gln His Leu Tyr Gly Thr Tyr Arg Thr Arg Leu 65 70 75 80 His Glu Asn Asn Trp Ile Cys Ile Gln Glu Asp Thr Gly Leu Leu Tyr 85 90 95 Leu Asn Arg Ser Leu Asp His Ser Ser Trp Glu Lys Leu Ser Val Arg 100 105 110 Asn Arg Gly Phe Pro Leu Leu Thr Val Tyr Leu Lys Val Phe Leu Ser 115 120 125 Pro Thr Ser Leu Arg Glu Gly Glu Cys Gln Trp Pro Gly Cys Ala Arg 130 135 140 Val Tyr Phe Ser Phe Phe Asn Thr Ser Phe Pro Ala Cys Ser Ser Leu 145 150 155 160 Lys Pro Arg Glu Leu Cys Phe Pro Glu Thr Arg Pro Ser Phe Arg Ile 165 170 175 Arg Glu Asn Arg Pro Pro Gly Thr Phe His Gln Phe Arg Leu Leu Pro 180 185 190 Val Gln Phe Leu Cys Pro Asn Ile Ser Val Ala Tyr Arg Leu Leu Glu 195 200 205 Gly Glu Gly Leu Pro Phe Arg Cys Ala Pro Asp Ser Leu Glu Val Ser 210 215 220 Thr Arg Trp Ala Leu Asp Arg Glu Gln Arg Glu Lys Tyr Glu Leu Val 225 230 235 240 Ala Val Cys Thr Val His Ala Gly Ala Arg Glu Glu Val Val Met Val 245 250 255 Pro Phe Pro Val Thr Val Tyr Asp Glu Asp Asp Ser Ala Pro Thr Phe 260 265 270 Pro Ala Gly Val Asp Thr Ala Ser Ala Val Val Glu Phe Lys Arg Lys 275 280 285 Glu Asp Thr Val Val Ala Thr Leu Arg Val Phe Asp Ala Asp Val Val 290 295 300 Pro Ala Ser Gly Glu Leu Val Arg Arg Tyr Thr Ser Thr Leu Leu Pro 305 310 315 320 Gly Asp Thr Trp Ala Gln Gln Thr Phe Arg Val Glu His Trp Pro Asn 325 330 335 Glu Thr Ser Val Gln Ala Asn Gly Ser Phe Val Arg Ala Thr Val His 340 345 350 Asp Tyr Arg Leu Val Leu Asn Arg Asn Leu Ser Ile Ser Glu Asn Arg 355 360 365 Thr Met Gln Leu Ala Val Leu Val Asn Asp Ser Asp Phe Gln Gly Pro 370 375 380 Gly Ala Gly Val Leu Leu Leu His Phe Asn Val Ser Val Leu Pro Val 385 390 395 400 Ser Leu His Leu Pro Ser Thr Tyr Ser Leu Ser Val Ser Arg Arg Ala 405 410 415 Arg Arg Phe Ala Gln Ile Gly Lys Val Cys Val Glu Asn Cys Gln Ala 420 425 430 Phe Ser Gly Ile Asn Val Gln Tyr Lys Leu His Ser Ser Gly Ala Asn 435 440 445 Cys Ser Thr Leu Gly Val Val Thr Ser Ala Glu Asp Thr Ser Gly Ile 450 455 460 Leu Phe Val Asn Asp Thr Lys Ala Leu Arg Arg Pro Lys Cys Ala Glu 465 470 475 480 Leu His Tyr Met Val Val Ala Thr Asp Gln Gln Thr Ser Arg Gln Ala 485 490 495 Gln Ala Gln Leu Leu Val Thr Val Glu Gly Ser Tyr Val Ala Glu Glu 500 505 510 Ala Gly Cys Pro Leu Ser Cys Ala Val Ser Lys Arg Arg Leu Glu Cys 515 520 525 Glu Glu Cys Gly Gly Leu Gly Ser Pro Thr Gly Arg Cys Glu Trp Arg 530 535 540 Gln Gly Asp Gly Lys Gly Ile Thr Arg Asn Phe Ser Thr Cys Ser Pro 545 550 555 560 Ser Thr Lys Thr Cys Pro Asp Gly His Cys Asp Val Val Glu Thr Gln 565 570 575 Asp Ile Asn Ile Cys Pro Gln Asp Cys Leu Arg Gly Ser Ile Val Gly 580 585 590 Gly His Glu Pro Gly Glu Pro Arg Gly Ile Lys Ala Gly Tyr Gly Thr 595 600 605 Cys Asn Cys Phe Pro Glu Glu Glu Lys Cys Phe Cys Glu Pro Glu Asp 610 615 620 Ile Gln Asp Pro Leu Cys Asp Glu Leu Cys Arg Thr Val Ile Ala Ala 625 630 635 640 Ala Val Leu Phe Ser Phe Ile Val Ser Val Leu Leu Ser Ala Phe Cys 645 650 655 Ile His Cys Tyr His Lys Phe Ala His Lys Pro Pro Ile Ser Ser Ala 660 665 670 Glu Met Thr Phe Arg Arg Pro Ala Gln Ala Phe Pro Val Ser Tyr Ser 675 680 685 Ser Ser Gly Ala Arg Arg Pro Ser Leu Asp Ser Met Glu Asn Gln Val 690 695 700 Ser Val Asp Ala Phe Lys Ile Leu Glu Asp Pro Lys Trp Glu Phe Pro 705 710 715 720 Arg Lys Asn Leu Val Leu Gly Lys Thr Leu Gly Glu Gly Glu Phe Gly 725 730 735 Lys Val Val Lys Ala Thr Ala Phe His Leu Lys Gly Arg Ala Gly Tyr 740 745 750 Thr Thr Val Ala Val Lys Met Leu Lys Glu Asn Ala Ser Pro Ser Glu 755 760 765 Leu Arg Asp Leu Leu Ser Glu Phe Asn Val Leu Lys Gln Val Asn His 770 775 780 Pro His Val Ile Lys Leu Tyr Gly Ala Cys Ser Gln Asp Gly Pro Leu 785 790 795 800 Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly Ser Leu Arg Gly Phe Leu 805 810 815 Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr Leu Gly Ser Gly Gly Ser 820 825 830 Arg Asn Ser Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr Met 835 840 845 Gly Asp Leu Ile Ser Phe Ala Trp Gln Ile Ser Gln Gly Met Gln Tyr 850 855 860 Leu Ala Glu Met Lys Leu Val His Arg Asp Leu Ala Ala Arg Asn Ile 865 870 875 880 Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser Asp Phe Gly Leu Ser 885 890 895 Arg Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg 900 905 910 Ile Pro Val Lys Trp Met Ala Ile Glu Ser Leu Phe Asp His Ile Tyr 915 920 925 Thr Thr Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile 930 935 940 Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly Ile Pro Pro Glu Arg Leu 945 950 955 960 Phe Asn Leu Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys 965 970 975 Ser Glu Glu Met Tyr Arg Leu Met Leu Gln Cys Trp Lys Gln Glu Pro 980 985 990 Asp Lys Arg Pro Val Phe Ala Asp Ile Ser Lys Asp Leu Glu Lys Met 995 1000 1005 Met Val Lys Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr Pro 1010 1015 1020 Ser Asp Ser Leu Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr 1025 1030 1035 Pro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg Ala Leu Pro 1040 1045 1050 Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Met Ser Asp Pro Asn 1055 1060 1065 Trp Pro Gly Glu Ser Pro Val Pro Leu Thr Arg Ala Asp Gly Thr 1070 1075 1080 Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp Ser Val Tyr Ala Asn 1085 1090 1095 Trp Met Leu Ser Pro Ser Ala Ala Lys Leu Met Asp Thr Phe Asp 1100 1105 1110 Ser

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: wherein A-(R1) n is each R1 is independently halogen, C1-C6 alkyl, -(C0-C4 alkyl)(C3-C7 cycloalkyl), -(C0-C4 alkyl)(C4-C 10 bicyclic) or -(C0-C4 alkyl)(C5-C6 aryl), wherein each R1 is optionally substituted by one or more groups independently selected from halogen, methyl or tri-halomethyl, and n is 1 or 2; X1 and X3 are CH, and X2 and X4 are each independently N or CH; and R2 is C1-C4 alkyl or -(C0-C4 alkyl)(C3-C7 cycloalkyl), each optionally substituted by one or more groups independently selected from deuterium or methyl.

2. The compound or its pharmaceutically acceptable salt according to claim 1, wherein X1, X2, X3 and X4 are each CH.

3. The compound or its pharmaceutically acceptable salt according to claim 1, wherein X2 is N, and X1, X3 and X4 are each CH.

4. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein A-(R1) n is 5. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R1 is 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]pent-1-yl; 3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl; (3,3-dimethylcyclobutyl)methyl.

6. The compound or its pharmaceutically acceptable salt according to claim 5, wherein R1 is 2,2-dimethylpropyl.

7. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein at least one R1 is halogen, -CH2C(CH3)3, 8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R2 is 9. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R2 is -CH(CH3)2 or 10. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, said compound having the following formula:

11. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, said compound having the following formula:

12. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, said compound having the following formula: wherein φ indicates a stereocenter.

13. The compound according to claim 12, wherein the formula has R-enantiomeric chirality at the φ position.

14. The compound according to claim 12, wherein the formula has S-enantiomeric chirality at the φ position.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

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