Gip receptor agonist compounds

Abstract

To provide compounds and their pharmaceutically acceptable salts for the treatment of type II diabetes and obesity, and to provide pharmaceutical compositions containing the compounds.SOLUTION: A compound of the formula: SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to dihydroisoquinoline-amide compounds having agonist activity at the human glucose-dependent insulinotropic polypeptide (GIP) receptor, their pharmaceutically acceptable salts, pharmaceutical compositions, and therapeutic uses of the compounds. The compounds are useful for the treatment of type 2 diabetes mellitus (T2DM). These compounds are also useful for the treatment of obesity. [Background technology]

[0002] The prevalence of diabetes has continued to rise over the past few decades. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes cases. T2DM is characterized by high blood glucose levels, primarily related to insulin resistance. Current standard treatments for T2DM include diet and exercise, oral medications, and injectable hypoglycemic medications, including incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists. When oral medications and incretin-based therapies are insufficient, insulin therapy is considered. Despite advances in available treatments, many patients with T2DM still fail to achieve their glycemic control goals. Uncontrolled diabetes leads to a variety of conditions associated with increased patient morbidity and mortality. Alternative therapies are needed to enable more patients with T2DM to achieve their glycemic treatment goals.

[0003] Obesity is a complex medical disorder that leads to excessive accumulation of adipose tissue mass. Today, obesity is a global public health concern associated with unfavorable health outcomes and morbidity. In the desired treatment of obese patients, excess body weight should be reduced, obesity-related comorbidities should be improved, and long-term weight loss should be maintained. Alternative treatment options are needed to induce therapeutic weight loss in patients in need of such treatment.

[0004] Both GLP-1 and GIP are incretins, gastrointestinal hormones that regulate blood glucose by enhancing glucose-stimulated insulin secretion. Incretins are also involved in regulating gastric emptying and food intake. Incretin-based therapies have provided valuable treatment options for patients with T2DM and obesity. Tirzepatide, an agonist active at both the GLP-1 receptor (GLP-1R) and GIPR, is approved as an injectable for the treatment of T2DM (Mounjaro™) and for long-term weight management in obese adults (Zepbound™).

[0005] However, injectable peptide drugs can have many drawbacks, including inconvenience, pain, and the possibility of irritation at the injection site. Therefore, patients often prefer orally administered drugs. For example, although there are many GLP-1R agonists in clinical development, including orforglipron (Frias et al., Lancet 2023:402:472-83), there are currently no such GIPR non-peptide agonists.

[0006] There remains a need for alternative treatments for T2DM and obesity, particularly GIPR agonist compounds, especially those that can be administered orally. Summary of the Invention [Means for solving the problem]

[0007] In a first aspect, there is provided a compound of formula III,

[0008] [ka] During the ceremony, X is CH2, OCH2, or CH2CH2, and Y is CHR 18 and

[0009] [ka] is a single bond, or X is CH and Y is CR 18 and

[0010] [ka] is a double bond, or X is CHR 14 and Y is CHR 15 and

[0011] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH;

[0012] [ka] is a double bond, or X is CH and Y is N;

[0013] [ka] is a double bond, R 18 is H or CH3, A,

[0014] [ka] and R 1 is an 8-, 9-, or 10-membered N-containing bicyclic heterocycle, phenyl, or a 5- or 6-membered N-containing heterocycle, and the heterocycle or phenyl is CN, Hello, C1-C4 alkyl optionally substituted with OCH3; C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH; benzyl optionally substituted with OCH3; NHC(O)R 16 , and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 16 is NHC1-C4 alkyl, C3-C6 cycloalkyl, NHC3-C6 cycloalkyl, pyridyl optionally substituted with halo or CH3, or phenyl optionally substituted with halo; R 2 and R 2’ are independently H, halo, or OCH; R 3 but, i) a 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CH3, CD3, CHF2, OH, and CH2CN; or ii) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents selected from oxo, CH3, and halo; R 4 and R 5 are each CH3 or together form cyclopropyl, cyclobutyl, oxetane, tetrahydrofuran, pyrrolidine, or piperidine, wherein cyclopropyl or cyclobutyl is optionally substituted with one or two halo, and pyrrolidine or piperidine is optionally substituted with CH3; R 6 But H, D, OH, CH3, CO2R 10 , or

[0015] [ka] where R 10 is H or C-C alkyl optionally substituted with OC(O)C-C alkyl or morpholine, and R 6’ is H and R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 In or R 8 and R 9 optionally replaced by R 6 is D and R 6’ is D and R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 In or R 8 and R 9 optionally replaced by R 6 and R 7 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH, CF, and oxo; R 6’ is H, R 8 is CF3, CF2H, halo, cyclopropyl, CH3, or H; R 9 but, i) Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3 or oxo; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R13 OP(O)(OH)2 Oxo, C1-C4 haloalkoxy, C(O)NR 12 R 13 , (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, NR 12 R 13 , C(O)NR 12 R 13 a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from CN, a 4- to 6-membered heterocycle, or C-C alkyl optionally substituted with C-C cycloalkyl optionally substituted with halo; ii) a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents independently selected from CN, oxo, C(O)O(CH), OH, CH, and halo; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 However, OCH3, NR 12 R 13 or a 4- to 6-membered heterocycle), vii) 4- to 6-membered heterocycle, phenyl, NHS(O)2(CH3), or NR 12 R 13 C1-C4 alkyl optionally substituted with, wherein the heterocycle or phenyl is optionally substituted with CH3; viii) CN, ix) C(O)OH, (CH2) m P(O)(R 17 )2, NR 12 R 13and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; or x)(CH2) m P(O)(R 17 )2, R 12 and R 13 are independently H or CH3; Each R 17 are independently C1-C4 alkyl; Compounds of formula III, wherein m is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0016] In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula III, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0017] In a third aspect, there is provided a method of treating type II diabetes in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof.

[0018] In a fourth aspect, there is provided a method of treating obesity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof.

[0019] In a fifth aspect, there is provided a compound of formula III, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0020] In a sixth aspect, there is provided a compound of formula III, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

[0021] In a seventh aspect, there is provided a compound of formula III, or a pharmaceutically acceptable salt thereof, for use in treating obesity. DETAILED DESCRIPTION OF THE INVENTION

[0022] In one embodiment of Formula III, there is provided a compound of Formula IIIa:

[0023] [ka]

[0024] In one embodiment of Formula III, a compound is provided, wherein: X is CH2, OCH2, or CH2CH2, and Y is CH2;

[0025] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0026] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, X is N and Y is CH;

[0027] [ka] is a double bond, or X is CH and Y is N;

[0028] [ka] is a double bond, A,

[0029] [ka] and R 1 is an 8-, 9-, or 10-membered N-containing bicyclic heterocycle, phenyl, or a 5- or 6-membered N-containing heteroaryl, and the heterocycle, phenyl, or heteroaryl is CN, Hello, C1-C4 alkyl optionally substituted with OCH3; C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH; benzyl optionally substituted with OCH3; NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 2 and R 2’ are independently H, halo, or OCH; R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CH3, CD3, CHF2, OH, and CH2CN, or a 9-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents selected from oxo and CH3; R 4 and R 5 are each CH3 or together form cyclopropyl; R 6 But H, D, OH, CH3, CO2R 10 , or

[0030] [ka] and R 10is H or C-C alkyl optionally substituted with OC(O)C-C alkyl or morpholine, and R 6’ is H, or R 6 is D and R 6’ But D, R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 Or R 8 and R 9 or phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; R 8 is CF3, CF2H, halo, or cyclopropyl; R 9 but, i) Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, N(CH3)2, a 4- to 6-membered heterocycle, or a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with CN, oxo, C(O)O(CH3)3 or OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 However, OCH3, NR 12 R 13 or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle or phenyl, the heterocycle or phenyl optionally substituted with CH3; viii) CN, or ix) phenyl optionally substituted with C(O)OH; R 12 and R 13 are independently H or CH3.

[0031] In one embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 and R 9 is substituted with R 9 is CR 12 R 13 substituted with OP(O)(OH)2, and Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3 or oxo; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, Oxo, C1-C4 haloalkoxy, C(O)NR 12 R 13 , (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, NR12 R 13 , C(O)NR 12 R 13 , CN, a 4- to 6-membered heterocycle, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl optionally substituted with halo.

[0032] In one embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 and R 9 and optionally substituted with R 9 is CR 12 R 13 substituted with OP(O)(OH)2, and Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is a 5- or 6-membered heterocycle optionally further substituted with 1 or 2 substituents independently selected from OH, OCH3, N(CH3)2, a 4- to 6-membered heterocycle, or a C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl optionally substituted with halo.

[0033] In an alternative embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 or R 8 and R 9 and optionally substituted with R 9 teeth, i) Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3 or oxo; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, Oxo, C1-C4 haloalkoxy, C(O)NR 12 R 13 , (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, NR 12 R 13 , C(O)NR 12 R 13 a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from CN, a 4- to 6-membered heterocycle, or C-C alkyl optionally substituted with C-C cycloalkyl optionally substituted with halo; ii) a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents independently selected from CN, oxo, C(O)O(CH), OH, CH, and halo; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 However, OCH3, NR 12 R 13 or a 4- to 6-membered heterocycle), vii) 4- to 6-membered heterocycle, phenyl, NHS(O)2(CH3), or NR 12 R 13C1-C4 alkyl optionally substituted with, wherein the heterocycle or phenyl is optionally substituted with CH3; viii) CN, ix) C(O)OH, (CH2) m P(O)(R 17 )2, NR 12 R 13 and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; or x)(CH2) m P(O)(R 17 )2.

[0034] In an alternative embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 Or R 8 and R 9 or phenyl is optionally substituted with one or two substituents selected from halo, CF, and pyrazine optionally substituted with CFH or OCH; R 8 is CF, CFH, halo, or cyclopropyl; R 9 teeth, i) Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, N(CH3)2, a 4- to 6-membered heterocycle, or a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with CN, oxo, C(O)O(CH3)3, or OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 However, OCH3, NR 12 R 13 or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle or phenyl, the heterocycle or phenyl optionally substituted with CH3; viii) CN, or ix) phenyl optionally substituted with C(O)OH.

[0035] In one embodiment of Formula III, A is

[0036] [ka] is.

[0037] In one embodiment of Formula III, R 2 If present, F and R 2’ When present, R is H or F. In one embodiment of Formula III, R 2 is F if it exists.

[0038] In one embodiment of Formula III, X is CH2 or CH2CH2 and Y is CH2;

[0039] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0040] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH;

[0041] [ka] is a double bond, or

[0042] X is CH and Y is N;

[0043] [ka] is a double bond.

[0044] In one embodiment of Formula III, X is CH2 or CH2CH2 and Y is CH2;

[0045] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0046] [ka] is a single bond, and R 14 and R15 together with the carbon to which they are attached to form a fused cyclopropyl, or

[0047] X is N and Y is CH;

[0048] [ka] is a double bond.

[0049] In one embodiment of Formula III, R 4 and R 5 are CH3, respectively.

[0050] In one embodiment of Formula III, R 1 is an 8- or 9-membered N-containing bicyclic heterocycle, phenyl, or a 6-membered N-containing heterocycle, and the heterocycle or phenyl is CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and Optionally substituted with 1 to 3 substituents independently selected from: a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3.

[0051] In one embodiment of Formula III, R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CD, or CHF, or a 9-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents selected from oxo and CH.

[0052] In one embodiment of Formula III, R 6 are H, OH, CO2R 10 or

[0053] [ka] and R 6’ is H. In one embodiment of Formula III, R 6 is H, CO2R 10 or

[0054] [ka] and R 6’ is H. In an alternative embodiment of Formula III, R 6 is D and R 6’ is D.

[0055] In an alternative embodiment, R 6 and R 7 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH, CF, and oxo; R 6’ is H.

[0056] In an embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 or R 8 and R 9 and optionally substituted with R 8 is CF3, halo, cyclopropyl, CH3, or H; R 9 teeth, i) Hello, OH, C1-C4 alkoxy, 4- to 6-membered heterocycles, CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, NR 12 R 13 a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from: C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle; ii) a 9-membered N-containing bicyclic heterocycle; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 But NR 12 R 13 or a 4- to 6-membered heterocycle), vii) NHS(O)2(CH3), NR 12 R 13 or C1-C4 alkyl optionally substituted with phenyl, wherein the phenyl is optionally substituted with CH3; viii) CN, ix) C(O)OH, (CH2) m P(O)(R 17 )2, and NR 12 R 13 phenyl optionally substituted with 1 or 2 substituents independently selected from x)(CH2) m P(O)(R 17 )2, R 12 and R 13 are independently H or CH3; Each R 17 are independently C1-C4 alkyl; m is 0 or 1.

[0057] In one embodiment of Formula III, R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 In or R 8and R 9 and optionally substituted with R 8 is CF3, halo, or cyclopropyl; R 9 teeth, i) Hello, OH, C1-C4 alkoxy, 4- to 6-membered heterocycles, CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH, N(CH3)2, or a 4- to 6-membered heterocycle; ii) a 9-membered N-containing bicyclic heterocycle; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 But NR 12 R 13 or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl, or viii) CN; R 12 and R 13 are independently H or CH3.

[0058] In one embodiment, a compound of formula V,

[0059] [ka] During the ceremony, X is CH2 or CH2CH2 and Y is CH2;

[0060] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0061] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH;

[0062] [ka] is a double bond, or X is CH and Y is N;

[0063] [ka] is a double bond, A,

[0064] [ka] and R 1 is an 8- or 9-membered N-containing bicyclic heterocycle, phenyl, or a 6-membered N-containing heterocycle, and the heterocycle or phenyl is CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 2 But F, R 2 is H or F, R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with CH3, CD3, or CHF2, or a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents selected from oxo and CH3; R 6 But, H, OH, CO2R 10 , or

[0065] [ka] where R 10 is H or C-C alkyl optionally substituted with OC(O)C-C alkyl or morpholine, and R 6’ is H and R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 In or R 8 and R 9 optionally replaced by R 6 is D and R 6’ is D and R 7 is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R 8 In or R 8 and R 9 optionally replaced by Or R 6 and R 7together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH, CF, and oxo; R 6’ is H, R 8 is CF3, halo, cyclopropyl, CH3, or H; R 9 but, i) Hello, OH, C1-C4 alkoxy, 4- to 6-membered heterocycles, CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, NR 12 R 13 a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from: C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle; ii) a 9-membered N-containing bicyclic heterocycle; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 But NR 12 R 13 or a 4- to 6-membered heterocycle), vii) NHS(O)2(CH3), NR 12 R 13 or C1-C4 alkyl optionally substituted with phenyl, wherein the phenyl is optionally substituted with CH3; viii) CN, ix) C(O)OH, (CH2) mP(O)(R 17 )2, and NR 12 R 13 phenyl optionally substituted with one or two substituents independently selected from x)(CH2) m P(O)(R 17 )2, R 12 and R 13 are independently H or CH3; Each R 17 are independently C1-C4 alkyl; Compounds of formula V, wherein m is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment of Formula V, a compound of Formula Va is provided:

[0067] [ka]

[0068] In one embodiment, a compound of formula IV,

[0069] [ka] During the ceremony, X is CH2 or CH2CH2 and Y is CH2;

[0070] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0071] [ka] is a single bond, and R 14 and R 15together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH;

[0072] [ka] is a double bond, A,

[0073] [ka] and R 1 is an 8- or 9-membered N-containing bicyclic heterocycle, phenyl, or 6-membered N-containing heteroaryl, and the heterocycle, phenyl, or heteroaryl is CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 2 But F, R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with CH3, CD3, or CHF2, or a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents selected from oxo and CH3; R 6 But, H, CO2R 10 , or

[0074] [ka] and R 7is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 In or R 8 and R 9 and optionally substituted with R 8 is CF3, halo, or cyclopropyl; R 9 but, i) Hello, OH, C1-C4 alkoxy, 4- to 6-membered heterocycles, CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH, N(CH3)2, or a 4- to 6-membered heterocycle; ii) a 9-membered N-containing bicyclic heterocycle; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 But NR 12 R 13 or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl, or viii) CN; R 12 and R 13 are independently H or CH3.

[0075] In one embodiment of Formula IV, there is provided a compound of Formula IVa:

[0076] [ka]

[0077] In an alternative embodiment, the compound of formula I is

[0078] [ka] During the ceremony, X is -CH2-, -OCH2-, or -CH2CH2-; R 1 but, i) CN, Hello, C1-C4 alkyl optionally substituted with OCH3; C1-C4 haloalkyl, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH, and an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from benzyl optionally substituted with OCH; ii) CN, NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; or iii) pyrazolyl optionally substituted with 1 to 3 substituents selected from CN and CH3; R 2 is H, halo, or OCH3; R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with 1 or 2 substituents selected from CH, CHF, OH, and CHCN; R 4 and R5 are each CH3 or together form cyclopropyl; R 6 But H, OH, CH3, CO2R 10 , or

[0079] [ka] and R 7 but, i) Hello, CF3, and pyrazine optionally substituted with CF2H or OCH3; or ii)R 8 Or R 8 and R 9 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 8 is CF3, CF2H, halo, or cyclopropyl; R 9 but, i) Hello, OH, OCH3, SO2NH2, 4- to 6-membered heterocycles, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, a 4- to 6-membered heterocycle, or a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with CN, oxo, C(O)O(CH3)3 or OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, or vi) C(O)OCH3, R 10 is H or C1-C4 alkyl optionally substituted with OC(O)C1-C4 alkyl or morpholine; or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment of Formula I, there is provided a compound of Formula Ia:

[0081] [ka]

[0082] In one embodiment of Formula I, R 2 is F.

[0083] In one embodiment of Formula I, X is -CH2-.

[0084] In one embodiment of Formula I, R 4 and R 5 are CH3, respectively.

[0085] In one embodiment of Formula I, R 1 teeth, i) CN, Hello, C1-C4 alkyl, oxo, and a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from benzyl optionally substituted with OCH3; or ii) CN, and and phenyl optionally substituted with 1 or 2 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3.

[0086] In one embodiment of Formula I, R 3 is a 5-membered N-containing heteroaryl optionally substituted with CH3 or CHF2.

[0087] In one embodiment of Formula I, R6 is H, CO2R 10 or

[0088] [ka] is.

[0089] In one embodiment of Formula I, R 7 teeth, i) phenyl optionally substituted with halo or CF3, or ii)R 8 Or R 8 and R 9 is a 5- or 6-membered N-containing heteroaryl optionally substituted with During the ceremony, R 8 is CF3, halo, or cyclopropyl; R 9 teeth, Hello, OH, OCH3, oxo, and and C1-C4 alkyl.

[0090] In one embodiment, a compound of formula II,

[0091] [ka] During the ceremony, R 1 but, i) CN, Hello, C1-C4 alkyl, oxo, and a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from benzyl optionally substituted with OCH; ii) CN, and phenyl optionally substituted with 1 or 2 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 3 is a 5-membered N-containing heteroaryl optionally substituted with CH3 or CHF2; R 6 But, H, CO2R 10 , or

[0092] [ka] and R 7 but, i) phenyl optionally substituted with halo or CF3, or ii)R 8 Or R 8 and R 9 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 8 is CF3, halo, or cyclopropyl; R 9 but, Hello, OH, OCH3, oxo, and C1-C4 alkyl; R 10 is H or C1-C4 alkyl optionally substituted with OC(O)C1-C4 alkyl or morpholine; or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment of Formula II, there is provided a compound of Formula IIa:

[0094] [ka]

[0095] The following embodiments are embodiments of any or all of the applicable formulae above.

[0096] In one embodiment, A is

[0097] [ka] In certain embodiments, R 2 is F and R 2’ is H.

[0098] In one embodiment, X is CH2 or CH2CH2 and Y is CH2;

[0099] [ka] is a single bond. In certain embodiments, X is CH2 and Y is CH2;

[0100] [ka] is a single bond.

[0101] In one embodiment, R 1 teeth,

[0102] [ka] and CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and Optionally substituted with 1 to 3 substituents independently selected from: a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3.

[0103] In one embodiment, R 1 teeth,

[0104] [ka] and CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and Optionally substituted with 1 to 3 substituents independently selected from: a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3.

[0105] In one embodiment, R 1 teeth, i)

[0106] [ka] and CN, Hello, C1-C4 alkyl, oxo, and benzyl optionally substituted with OCH; ii) CN, and and phenyl optionally substituted with 1 or 2 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3.

[0107] In one embodiment, R 1 teeth,

[0108] [ka] and CN, F, Cl, CH3, CF3, OCH3, OCHF2, CD3, oxo, and benzyl substituted with OCH3, or Optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle substituted with CH3.

[0109] In one embodiment, R 1 teeth,

[0110] [ka] and CN, F, Cl, CH3, CF3, OCH3, OCHF2, CD3, oxo, and benzyl substituted with OCH3, or Optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle substituted with CH3.

[0111] In one embodiment, R 1 teeth, i)

[0112] [ka] and CN, F, CH3, oxo, and benzyl substituted with OCH3; or ii) phenyl substituted with CN and 9-membered N-containing bicyclic heterocycles substituted with CH3.

[0113] In one embodiment, R 1 teeth,

[0114] [ka] and CN, F, and Optionally substituted with 1 to 3 substituents independently selected from CH3.

[0115] In a further embodiment, R 1 teeth,

[0116] [ka] is selected from.

[0117] In a further embodiment, R 1 teeth,

[0118] [ka] is selected from.

[0119] In a further embodiment, R 3 is a CH, CHF, or CD substituted pyrazole, isothiazole, imidazopyrimidine, CH substituted imidazopyrazinone, or CH substituted pyridine. 3 teeth,

[0120] [ka] is.

[0121] In a further embodiment, R 3 is pyrazole substituted with CH or CHF. In certain embodiments, R3 teeth,

[0122] [ka] is.

[0123] In certain embodiments, R 3 teeth,

[0124] [ka] is.

[0125] In one embodiment, R 6 are H, OH, CO2R 10 , or

[0126] [ka] and R 10 is H, CH2CH3,

[0127] [ka] and R 6’ is H or R 6 is D and R 6 is D. In one embodiment, R 6 is H, CO2R 10 , or

[0128] [ka] and R 10 is H, CH2CH3,

[0129] [ka] In certain embodiments, R 6 is H and R 6’ is H.

[0130] In an alternative embodiment, R 6 and R 7 together optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo.

[0131] [ka] Form R 6’ is H.

[0132] In a further embodiment, R 7 teeth,

[0133] [ka] is.

[0134] In a further embodiment, R 7 teeth,

[0135] [ka] is.

[0136] In a further embodiment, R 7 teeth, i)

[0137] [ka] or ii)

[0138] [ka] is a 5- or 6-membered N-containing heteroaryl selected from:

[0139] In a further embodiment, R 7 teeth,

[0140] [ka] and R 8 is CF3, F, Cl, cyclopropyl, CH3, or H, and R 9 teeth, i)

[0141] [ka] a 5- or 6-membered heterocycle selected from ii)

[0142] [ka] a 9-membered N-containing bicyclic heterocycle which is iii) OCH3, iv) cyclopropyl, v)Br, vi)C(O)N(CH3)2, CH2C(O)NH(CH3),

[0143] [ka] vii) CH3,

[0144] [ka] CH2NHS(O)2CH3, CH2NH2, viii) CN, ix)

[0145] [ka] or x)P(O)(CH3)2.

[0146] In a further embodiment, R 7 teeth,

[0147] [ka] and R 8 is CF, F, or cyclopropyl, and R 9 teeth, i)

[0148] [ka] a 5- or 6-membered heterocycle selected from ii)

[0149] [ka] a 9-membered N-containing bicyclic heterocycle which is iii) OCH3, iv) cyclopropyl, v)Br, vi)C(O)N(CH3)2, CH2C(O)NH(CH3),

[0150] [ka] vii) CH3,

[0151] [ka] or viii) CN.

[0152] In a further embodiment, R 7 teeth,

[0153] i) [ka] or ii)

[0154] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 8is CF, F, or cyclopropyl, and R 9 teeth,

[0155] [ka] is a 5- or 6-membered heterocycle selected from

[0156] In a further embodiment, R 7 teeth,

[0157] [ka] and R 8 is CF3, F, Cl, cyclopropyl, CH3, or H, and R 9 teeth, i)

[0158] [ka] a 5- or 6-membered heterocycle selected from ii)

[0159] [ka] a 9-membered N-containing bicyclic heterocycle which is iii) OCH3, iv) cyclopropyl, v)Br, vi)C(O)N(CH3)2, CH3C(O)NH(CH3),

[0160] [ka] vii) CH3,

[0161] [ka] CH2NHS(O)2CH3, CH2NH2, viii) CN, or ix)

[0162] [ka] is.

[0163] In a further embodiment, R 7 teeth,

[0164] [ka] and R 8 is CF, F, or cyclopropyl, and R 9 teeth, i)

[0165] [ka] a 5- or 6-membered heterocycle selected from ii)

[0166] [ka] a 9-membered N-containing bicyclic heterocycle which is iii) OCH3, iv) cyclopropyl, v)Br, vi)C(O)N(CH3)2, CH3C(O)NH(CH3),

[0167] [ka] vii) CH3,

[0168] [ka] or viii) CN.

[0169] In a further embodiment, R 7 teeth,

[0170] [ka] and R 8 is CF, F, or cyclopropyl, and R 9 teeth, i)

[0171] [ka] a 5- or 6-membered heterocycle selected from ii)

[0172] [ka] a 9-membered N-containing bicyclic heterocycle which is iii) OCH3, iv) cyclopropyl, v)Br, vi)C(O)N(CH3)2, CH3C(O)NH(CH3),

[0173] [ka] vii) CH3,

[0174] [ka] or viii) CN.

[0175] In a further embodiment, R 7 teeth, i)

[0176] [ka] or ii)

[0177] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 8 is CF, F, or cyclopropyl, and R 9 teeth,

[0178] [ka] is a 5- or 6-membered heterocycle selected from

[0179] In certain embodiments, R 7 teeth,

[0180] [ka] and R 9 teeth,

[0181] [ka] is selected from.

[0182] In a further embodiment, R 7 teeth,

[0183] [ka] is selected from.

[0184] In a further embodiment, R 7 teeth,

[0185] [ka] is selected from.

[0186] In one embodiment, the compound is

[0187] [ka]

[0188]

change

[0189]

change

[0190]

change

[0191]

change

[0192]

change

[0193]

change

[0194]

change

[0195]

change

[0196]

change

[0197]

change

[0198]

change

[0199] [ka]

[0200] [ka]

[0201] [ka]

[0202] [ka]

[0203] [ka] Selected from or or a pharmaceutically acceptable salt thereof.

[0204] Embodiments: 1. A compound of the formula:

[0205] [ka] During the ceremony, X is CH2, OCH2, or CH2CH2, and Y is CH2;

[0206] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0207] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, X is N and Y is CH;

[0208] [ka] is a double bond, or X is CH and Y is N;

[0209] [ka] is a double bond, A,

[0210] [ka] and R 1 is an 8-, 9-, or 10-membered N-containing bicyclic heterocycle, phenyl, or a 5- or 6-membered N-containing heteroaryl, and the heterocycle, phenyl, or heteroaryl is CN, Hello, C1-C4 alkyl optionally substituted with OCH3; C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH; benzyl optionally substituted with OCH3; NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; R 2 and R 2’ are independently H, halo, or OCH; R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CH3, CD3, CHF2, OH, and CH2CN, or a 9-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents selected from oxo and CH3; R 4 and R 5 are each CH3 or together form cyclopropyl; R 6 But H, D, OH, CH3, CO2R 10 , or

[0211] [ka] and R 10 is H or C-C alkyl optionally substituted with OC(O)C-C alkyl or morpholine, and R 6’ is H, or R 6 is D and R 6’ But D, R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 Or R 8 and R 9 or phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; R 8 is CF3, CF2H, halo, or cyclopropyl; R 9 but, i) Hello, OH, C1-C4 alkoxy, SO2NH2, a 4-6 membered heterocycle optionally substituted with CH3; CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, N(CH3)2, a 4- to 6-membered heterocycle, or a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with CN, oxo, C(O)O(CH3)3 or OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 However, OCH3, NR 12 R 13 or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle or phenyl, the heterocycle or phenyl optionally substituted with CH3; viii) CN, or ix) phenyl optionally substituted with C(O)OH; R 12 and R 13 is independently H or CH3, or a pharmaceutically acceptable salt thereof. 2. A:

[0212] [ka] or a pharmaceutically acceptable salt thereof. 3. X is CH2 or CH2CH2 and Y is CH2;

[0213] [ka] is a single bond, or X is CHR 14 and Y is CHR 15 and

[0214] [ka] is a single bond, and R 14 and R 15 together with the carbon to which they are attached to form a fused cyclopropyl, or

[0215] X is N and Y is CH;

[0216] [ka] is a double bond, or a pharmaceutically acceptable salt thereof. 4. R 4 and R 5 and R are each CH3; or a pharmaceutically acceptable salt thereof. 5. R 1 but, an 8- or 9-membered N-containing bicyclic heterocycle, phenyl, or a 6-membered N-containing heteroaryl, wherein the heterocycle, phenyl, or heteroaryl is CN, Hello, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CD3, Oxo, benzyl optionally substituted with OCH3, and The compound of any one of embodiments 1-4, optionally substituted with 1-3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH3; or a pharmaceutically acceptable salt thereof. 6. R 1 but,

[0217] [ka] and CN, F, Cl, CH3, CF3, OCH3, OCHF2, CD3, Oxo, benzyl substituted with OCH3, and The compound of embodiment 5, optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle substituted with CH3; or a pharmaceutically acceptable salt thereof. 7. R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with CH3, CD3, or CHF2, or a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents selected from oxo and CH3, or a pharmaceutically acceptable salt thereof. 8. R 3 but,

[0218] [ka] or a pharmaceutically acceptable salt thereof. 9. R 6 But, H, CO2R 10 , or

[0219] [ka] and R 6’ The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein is H. 10. R 6 is H, or a pharmaceutically acceptable salt thereof. 11. R 7 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 8 Or R 8 and R 9 and optionally substituted with R 8 is CF3, halo, or cyclopropyl; R 9 but, i) Hello, OH, C1-C4 alkoxy, 4- to 6-membered heterocycles, CN, C3-C6 cycloalkyl, CD3, C1-C4 haloalkyl, CR 12 R 13 OP(O)(OH)2 oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH, N(CH3)2, or a 4- to 6-membered heterocycle; ii) a 9-membered N-containing bicyclic heterocycle; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 11 (wherein n is 0 or 1, and R 11 But NR 12 R 13or a 4- to 6-membered heterocycle), vii) C1-C4 alkyl, or viii) CN; A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof. 12. R 7 but,

[0220] [ka] or a pharmaceutically acceptable salt thereof. 13. A compound according to embodiment 1, having the following formula:

[0221] [ka] During the ceremony, X is -CH2-, -OCH2-, or -CH2CH2-; R 1 but, i) CN, Hello, C1-C4 alkyl optionally substituted with OCH3; C1-C4 haloalkyl, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH, and an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from benzyl optionally substituted with OCH; ii) CN, NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; or iii) pyrazolyl optionally substituted with 1 to 3 substituents selected from CN and CH3; R 2 is H, halo, or OCH3; R 3 is a 5- or 6-membered N-containing heteroaryl optionally substituted with 1 or 2 substituents selected from CH, CHF, OH, and CHCN; R 4 and R 5 are each CH3 or together form cyclopropyl; R 6 But H, OH, CH3, CO2R 10 , or

[0222] [ka] and R 7 but, i) Hello, CF3, and pyrazine optionally substituted with CF2H or OCH3; or ii)R 8 Or R 8 and R 9 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 8 is CF3, CF2H, halo, or cyclopropyl; R 9 but, i) Hello, OH, OCH3, SO2NH2, 4- to 6-membered heterocycles, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, a 4- to 6-membered heterocycle, or a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with CN, oxo, C(O)O(CH3)3 or OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, or vi) C(O)OCH3, R 10 is H or C1-C4 alkyl optionally substituted with OC(O)C1-C4 alkyl or morpholine; or a pharmaceutically acceptable salt thereof. 14. R 2 is F, or a pharmaceutically acceptable salt thereof. 15. The compound of embodiment 13 or embodiment 14, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-. 16. R 4 and R 5 and R are each CH3; or a pharmaceutically acceptable salt thereof. 17. R 1 but, i) CN, Hello, C1-C4 alkyl, oxo, and a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from benzyl optionally substituted with OCH3; or ii) CN, and The compound of any one of embodiments 13-16, wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with CH; or a pharmaceutically acceptable salt thereof. 18. R 1 but, i)

[0223] [ka] and CN, F, CH3, oxo, and benzyl substituted with OCH3; or ii) the compound of embodiment 17, which is a phenyl substituted with CN and a 9-membered N-containing bicyclic heterocycle substituted with CH; or a pharmaceutically acceptable salt thereof. 19. R 3 The compound of any one of embodiments 13-18, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered N-containing heteroaryl optionally substituted with CH3 or CHF2. 20. R 3 but,

[0224] [ka] 20. The compound of embodiment 19, wherein: 21. R 6 But, H, CO2R 10 , or

[0225] [ka] 21. The compound of any one of embodiments 13-20, wherein: 22. R6 However, CO2R 10 and R 10 But H, CH2CH3,

[0226] [ka] 22. The compound of embodiment 21, wherein: 23. R 6 is H, or a pharmaceutically acceptable salt thereof. 24. R 7 but, i) phenyl optionally substituted with halo or CF3, or ii)R 8 Or R 8 and R 9 is a 5- or 6-membered N-containing heteroaryl optionally substituted with A compound of the formula: R 8 is CF3, halo, or cyclopropyl; R 9 but, Hello, OH, OCH3, oxo, and The compound of any one of embodiments 13-23, wherein the heterocyclic ring is a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from: C1-C4 alkyl; or a pharmaceutically acceptable salt thereof. 25. R 7 but, i)

[0227] [ka] or ii)

[0228] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 8 is CF3, F, or cyclopropyl, and R 9 but,

[0229] [ka] or a pharmaceutically acceptable salt thereof.

[0230] In one embodiment, there is provided a pharmaceutical composition comprising a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient. In a preferred embodiment, the pharmaceutical composition is formulated for oral administration.

[0231] In one embodiment, a method for treating type II diabetes is provided, comprising administering to a patient in need thereof a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof. In another embodiment, a method for treating type II diabetes is provided, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0232] In one embodiment, there is provided a method for treating obesity, comprising administering to a patient in need thereof a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method for treating obesity, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0233] In a further embodiment, there is provided a method for long-term weight management, improved weight management, or providing therapeutic weight loss, comprising administering to a patient in need thereof a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method for long-term weight management, improved weight management, or providing therapeutic weight loss, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0234] In a further embodiment, a method is provided for treating overweight with at least one weight-related comorbidity, comprising administering to a patient in need thereof a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof. In another embodiment, a method is provided for treating overweight with at least one weight-related comorbidity, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the weight-related comorbidity is selected from cancer, depression, diabetes, dyslipidemia, hypertension, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0235] In a further embodiment, there is provided a method for treating a disorder selected from type 1 diabetes, metabolic syndrome, dyslipidemia, insulin resistance and diabetes-related fatty liver, chronic kidney disease (CKD), atherosclerosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), diabetic kidney disease, cognitive impairment, heart failure, hypertension, obstructive sleep apnea, and bone fragility, comprising administering to a patient in need thereof a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method for treating a disorder selected from metabolic syndrome, dyslipidemia, insulin resistance and diabetes-related fatty liver, chronic kidney disease (CKD), atherosclerosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), diabetic kidney disease, cognitive impairment, heart failure, hypertension, obstructive sleep apnea, and bone fragility, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0236] In one embodiment there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0237] In another embodiment, there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

[0238] In another embodiment, there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in treating obesity.

[0239] In a further embodiment, there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in providing long-term weight management, improved weight management, or therapeutic weight loss.

[0240] In a further embodiment, there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in treating overweight associated with at least one weight-related comorbidity. In certain embodiments, the weight-related comorbidity is selected from cancer, depression, diabetes, dyslipidemia, hypertension, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0241] In a further embodiment, there is provided a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for use in treating a disorder selected from type 1 diabetes, metabolic syndrome, dyslipidemia, insulin resistance and fatty liver associated with diabetes, CKD, atherosclerosis, NAFLD, NASH, diabetic kidney disease, cognitive impairment, heart failure, hypertension, obstructive sleep apnea, and bone fragility.

[0242] In one embodiment, there is provided the use of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes.

[0243] In one embodiment there is provided the use of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity.

[0244] In a further embodiment, there is provided the use of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for long-term weight management, improved weight management, or providing therapeutic weight loss.

[0245] In a further embodiment, there is provided the use of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of overweight with at least one weight-related comorbidity. In certain embodiments, the weight-related comorbidity is selected from cancer, depression, diabetes, dyslipidemia, hypertension, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0246] In a further embodiment, there is provided the use of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder selected from type 1 diabetes, metabolic syndrome, dyslipidemia, insulin resistance and fatty liver associated with diabetes, CKD, atherosclerosis, NAFLD, NASH, diabetic kidney disease, cognitive impairment, heart failure, hypertension, obstructive sleep apnea and bone fragility.

[0247] In one embodiment, there is provided a pharmaceutical composition for treating type II diabetes comprising an effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof.

[0248] In one embodiment, there is provided a pharmaceutical composition for treating obesity comprising an effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof.

[0249] In a further embodiment, there is provided a pharmaceutical composition for providing long-term weight management, improved weight management, or therapeutic weight loss, comprising an effective amount of a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof.

[0250] In a further embodiment, there is provided a pharmaceutical composition for treating overweight accompanied by at least one weight-related comorbidity, comprising an effective amount of a compound of any one of the above formulae, or a pharmaceutically acceptable salt thereof. In certain embodiments, the weight-related comorbidity is selected from cancer, depression, diabetes, dyslipidemia, hypertension, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0251] In a further embodiment, there is provided a pharmaceutical composition for treating a disorder selected from type 1 diabetes, metabolic syndrome, dyslipidemia, insulin resistance and fatty liver associated with diabetes, CKD, atherosclerosis, NAFLD, NASH, diabetic kidney disease, cognitive impairment, heart failure, hypertension, obstructive sleep apnea, and bone fragility, comprising an effective amount of a compound of any one of the above formulae, or a pharmaceutically acceptable salt thereof.

[0252] Any one compound of the above formula can be used in combination with one or more therapeutic agents simultaneously, separately, or sequentially. Examples of additional therapeutic agents include, but are not limited to, GLP-1 receptor agonists, glucagon receptor agonists, dual GLP-1-glucagon receptor agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, growth differentiation factor 15 modulators (GDF15), peptide tyrosine modulators (PYY), modified insulin, amylin receptor agonists, dual amylin-calcitonin receptor agonists, and modified urocortin-2 (UCN-2) agonists.

[0253] In a preferred embodiment, the compound of any one of the above formulas is administered orally. In a preferred embodiment, the compound of any one of the above formulas is administered once a day. In another preferred embodiment, the therapeutic use is in humans.

[0254] References to Formula III should be understood to refer to compounds of Formula III, along with any and all subformulas disclosed herein, including Formulas I, Ia, II, IIa, IIIa, IV, IVa, V, and Va.

[0255] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0256] "C1-C n The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl.

[0257] "C1-C n The term "haloalkyl" refers to a C-C alkyl group, as defined herein, substituted with one or more halogens. n refers to an alkyl group. Examples of C1-C4 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0258] "C1-C n The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0259] "C1-C n The term "haloalkoxy" refers to a C-C alkyl group, as defined herein, substituted with one or more halogens. n It refers to an alkoxy group. Examples of C1-C4 haloalkoxy groups include, but are not limited to, trifluoromethoxy and 2,2-difluoroethoxy.

[0260] "C3-C n The term "cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 3 to n carbon atoms.

[0261] The term "heterocycle" refers to an aromatic saturated or partially saturated ring containing one or more heteroatoms, preferably selected from N, S, and O. Examples of 4-membered heterocycles include, but are not limited to, oxetane. Examples of 5-membered heterocycles include, but are not limited to, pyrazole, imidazole, triazole, thiophene, oxadiazole, and thiadiazole. Examples of 6-membered heterocycles include, but are not limited to, pyridine and pyridazine.

[0262] The term "N-containing bicyclic heterocycle" refers to a bicyclic aromatic saturated or partially saturated ring containing at least one nitrogen atom and optionally one or more other heteroatoms. Examples of 8-membered N-containing bicyclic heterocycles include, but are not limited to, dihydropyrroloimidazole. Examples of 9-membered N-containing bicyclic heterocycles include, but are not limited to, pyrazolopyrimidine, imidazopyrimidine, dihydropyrazolopyrazine, dihydropyrrolotriazine, and tetrahydropyrazolopyrazine. Examples of 10-membered N-containing bicyclic heterocycles include, but are not limited to, naphthyridine and pyridopyridazine.

[0263] The term "heteroaryl" refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from N, S, and O. An "N-containing heteroaryl" contains at least one nitrogen atom and may optionally contain one or more other heteroatoms. Examples of 5-membered N-containing heteroaryls include, but are not limited to, pyrazole, imidazole, triazole, oxadiazole, and thiadiazole. Examples of 6-membered N-containing heteroaryls include, but are not limited to, pyridine and pyridazine.

[0264] In the compounds of Formula III provided herein, or pharmaceutically acceptable salts thereof, any or all hydrogens present in the compound or in specific groups or moieties within the compound may be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls where one to a maximum number of hydrogens present may be replaced with deuterium. For example, C2D x H5-x Ethyl refers to both C2H5 or C2H5 when one to five hydrogens in are replaced with deuterium, etc. Unless otherwise specified, when an atom is specifically designated as "D" or "deuterium," the atom is understood to have deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0265] As used herein, the term " pharmaceutically acceptable salt " refers to a salt of the compound of the present invention that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and the general methodology for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P.Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M.Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0266] The compounds herein, or pharmaceutically acceptable salts thereof, include all stereoisomers of the compounds, e.g., enantiomers, diastereomers (including cis and trans geometric isomers), racemic forms, and other mixtures of isomers. For example, the compounds herein, or pharmaceutically acceptable salts thereof, may have one or more asymmetric centers.

[0267] The term "therapeutically effective amount" refers to the amount or dosage of a compound of formula III, or its pharmaceutically acceptable salt, that provides the desired effect in a patient under diagnosis or treatment when administered in a single dose or multiple doses to the patient.As a skilled artisan, the attending physician can easily determine the effective amount by using conventional techniques and observing the results obtained under similar circumstances.Factors to be considered in determining the therapeutically effective amount or dosage of a compound include: whether the compound or its salt is administered; if used, co-administration of other drugs; the size, age, and general health of the patient; the degree of involvement or severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; and other relevant circumstances.

[0268] As used herein, the terms "treating," "treat," or "treatment" refer to slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition.

[0269] As used herein, the term "patient" includes mammals. The patient is preferably human.

[0270] The term "overweight with at least one weight-related comorbidity" refers to a disease or condition in which a subject is overweight and has at least one weight-related comorbidity. In certain embodiments, the comorbidity is selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease. In one embodiment, a subject who is overweight is defined as having a body mass index (BMI) of 25 or greater and less than 30.

[0271] The compound of formula III can be formulated as a pharmaceutical composition that can be administered by any route that makes the compound bioavailable. Preferably, such a composition is for oral administration. Preferably, the pharmaceutical composition is formulated as a tablet, capsule, or solution. The tablet, capsule, or solution can contain the compound of formula III in an amount effective to treat a patient in need of treatment. Such pharmaceutical compositions and processes for preparing them are well known in the art (see, for example, "Remington: The Science and Practice of Pharmacy," A. Adejare Editor, 23rd Ed., 2020, Elsevier Science). [Example]

[0272] The compounds of the present invention or salts thereof may be prepared by various procedures known to those skilled in the art, some of which are illustrated in the following schemes, preparations, and examples. The products of each step in the following schemes can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the following schemes, all substituents are as previously defined unless otherwise indicated. Reagents and starting materials are readily available to those skilled in the art. The following schemes, preparations, and examples are provided to further illustrate the present invention without limiting the scope of the present invention. In addition, those skilled in the art will understand that compounds of Formula I can be prepared by using starting materials or intermediates with the corresponding desired stereochemical configuration that can be prepared by those skilled in the art.

[0273] Abbreviation: "AIBN" refers to azobisisobutyronitrile "aq." refers to aqueous "BOC" or "Boc" refers to tert-butyloxycarbonyl "CDCl3" refers to deuterated chloroform "CD3OD" refers to deuterated methanol "ACN" refers to acetonitrile "AcOH" refers to acetic acid "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene "DCC" refers to N,N'-dicyclohexylcarbodiimide "DCE" refers to dichloroethane "DCM" refers to dichloromethane "DEA" refers to diethylamine "DEPBT" refers to diethyl(4-oxo-1,2,3-benzotriazin-3-yl)phosphate "DIEA" refers to N,N-diisopropylethylamine "DMA" stands for N,N-dimethylacetamide "DMEA" refers to N,N-dimethylethylamine "DMF" refers to N,N-dimethylformamide "DMSO" refers to dimethyl sulfoxide "DMSO-d6" refers to deuterated dimethyl sulfoxide "ee" refers to enantiomeric excess "ES-MS" refers to electrospray mass spectrometry "EtOAc" refers to ethyl acetate "EtOH" refers to ethanol "Et2O" refers to diethyl ether "Equiv" or "eq" refers to equivalent "FA" stands for formic acid "h" stands for hour "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate " 1 "H-NMR" refers to proton nuclear magnetic resonance "Prep-HPLC" refers to preparative high-performance liquid chromatography "Prep-TLC" refers to preparative thin-layer chromatography "HOAc" stands for acetic acid "IPA" refers to isopropanol "IPAm" refers to isopropylamine "KOAc" stands for potassium acetate "MeOH" refers to methanol "min" refers to minutes "MTBE" refers to methyl tert-butyl ether "m / z" refers to the mass-to-charge ratio "NaHMDS" refers to sodium bis(trimethylsilyl)amide "NBS" refers to N-bromosuccinimide "NCS" refers to N-chlorosuccinimide "NH4OAc" refers to ammonium acetate "NMP" refers to N-methyl pyrrolidine-2-one "PE" stands for petroleum ether "psi" stands for pounds per square inch "RBF" stands for round-bottom flask "RT" refers to room temperature "R f " refers to the retention factor "sat." means saturated "SFC" stands for supercritical fluid chromatography "tBu" refers to tert-butyl "TEA" refers to triethylamine "TFA" refers to trifluoroacetic acid "wt%" refers to percentage by weight

[0274] Catalyst abbreviation: "cataCXium® A Pd G3" refers to mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS number 1651823-59-4). "BrettPhos Pd G3" refers to [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1470372-59-8). "PCy3 Pd G4" refers to (methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC](tricyclohexylphosphine)-palladium (CAS number 2195390-53-3). "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium (CAS number 51364-51-3). "PdCl2(dtbpf)" refers to 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (CAS number 95408-45-0) "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium(0) (CAS number 14221-01-3). "Pd(dppf)Cl2" or "PdCl2(dppf)" refers to [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS number 72287-26-4). "Pd(dppf)Cl2·CH2Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with dichloromethane) (CAS number 95464-05-4). "Rh-COD-[(R)-MaxPhos]-BF4" refers to [((R)-tert-butylmethylphosphino)(di-tert-butylphosphino)amine](1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (CAS number 1263077-53-7). "SPhos Pd G3" refers to (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1445085-82-4). "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS number 161265-03-8). "XPhos Pd G3" refers to (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1445085-55-1). "XPhos Pd G4" refers to (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium (CAS number 1599466-81-5).

[0275] In the following scheme, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 7 , R 8 , R 9 and X is as defined in formula III.

[0276] Scheme 1

[0277] [ka] Scheme 1 illustrates the preparation of intermediate 6, which is useful in the preparation of compounds of the present invention. Imidazole intermediate 1 is reacted with oxathiazolidine intermediate 2 using a carbonate base such as CsCO in a solvent such as DMA at elevated temperature to give intermediate 3. Intermediate 3 can then be converted to R using a palladium catalyst, a carbonate base, and an aqueous-organic solvent mixture at elevated temperature. 9 Boronate (R 9 -B(OH)2 or its ester) to give intermediate 4. Alternatively, intermediate 3 can be converted to the corresponding boronic acid using tetrahydroxydiboron, a palladium catalyst, a base such as potassium acetate, and a mixture of solvents such as MeOH and DCE at elevated temperature to give boronic acid 5, which can then be reacted with R under the conditions described above to give boronic acid 6. 9 Coupling with a boronate provides intermediate 4. The nitrogen protecting group of intermediate 4 (represented in the scheme above as protecting group, "PG") can then be removed under conditions known to those skilled in the art, for example, the Boc protecting group can be removed under acidic conditions (e.g., stirring the Boc-protected intermediate in HCl in 1,4-dioxane at room temperature) to provide 6.

[0278] Scheme 2

[0279] [ka] Scheme 2 illustrates the preparation of intermediate 10, which is useful in the preparation of compounds of the invention. Amine 7 is reacted with 2,4,6-triphenylpyrylium tetrafluoroborate in a chlorinated solvent such as DCM to give 8, which is then reacted with 2-nitropropane using an alkoxide base in a solvent such as DMSO at elevated temperature to give intermediate 9. The nitro group is then reduced using Raney® nickel and hydrogen gas to give amine 10.

[0280] Scheme 3

[0281] [ka] Scheme 3 illustrates the preparation of intermediates 15 and 20, which are useful in preparing compounds of the invention. Reaction of acid intermediate 11 with lithium diisopropylamide and chlorotitanium triisopropoxide at −70° C., followed by the addition of intermediate 12, provides intermediate 13. This acid is then converted to ester 14 (where “W” is an alkyl ester), for example, by adding (trimethylsilyl)diazomethane to 13 in an organic solvent to provide the methyl ester. Alternatively, the acid in intermediate 11 can be protected as an alkyl ester and then reacted with intermediate 12 to provide intermediate 14 directly. Reaction of intermediate 14 with HCl in a solvent such as 1,4-dioxane at 15° C. provides intermediate 15.

[0282] In a similar manner, intermediate 16 is reacted with lithium diisopropylamide and chlorotitanium triisopropoxide at −70° C., followed by the addition of intermediate 12, to give intermediate 17. The nitrile is then reacted with hydroxylamine hydrochloride and an organic base at elevated temperature to give intermediate 18, which is then cyclized to thiadiazolone 19 by the addition of di-1H-imidazol-1-ylmethanethione in an organic solvent such as THF at 15° C. Intermediate 19 is then converted to amine 20 under acidic conditions as described above.

[0283] Scheme 4

[0284] [ka] Scheme 4 illustrates the preparation of compound 54. Reaction of alkyl iodide 21 with aryl / heteroaryl iodide 22 (where "W" is an alkyl group, e.g., methyl or ethyl, and "PG" is a protecting group, e.g., Boc) using pyridine-2,6-bis(carboximidamide) dihydrochloride, nickel(II) chloride, and zinc in a solvent such as DMA provides 23. Aqueous LiOH in a solvent such as THF converts 23 to acid 24, which is then coupled with amine 25 under conditions known to those skilled in the art, for example, using an amide coupling reagent such as HATU, an organic base such as DIEA, and a polar aprotic solvent such as DMF, to provide 26. The protecting group of intermediate 26 is then removed using, for example, HCl in 1,4-dioxane and a solvent such as MeOH if "PG" is Boc, to provide intermediate 27. Intermediate 27 is then reacted with acid chloride 28 (where "Z" is a halogen) using an organic base such as DIEA in a solvent such as DCM to give 29, which is then cyclized with a carbonate base in a solvent such as ACN at elevated temperature to give intermediate 30. Compound 30 is then converted to the boronate ester 31 using bis(pinacolato)diboron, KOAc, and a palladium catalyst such as Pd(dppf)Cl.CHCl in a solvent such as 1,4-dioxane. Alternatively, bromide 30 is converted to the boronic acid using hypodiboric acid, KOAc, and a palladium catalyst such as XPhos Pd G at elevated temperature. Finally, boronate 31 is subjected to Suzuki cross-coupling with 32a (where "Z" is a halogen) under conditions known to those skilled in the art, for example, using a carbonate base and a palladium catalyst in an aqueous-organic mixture of a solvent such as EtOH / water at elevated temperature to give compound 54. Bromide 30 can also be converted to compound 54 in a one-pot procedure, in which 30 is first coupled with bis(neopentylglycolato)diboron using a palladium catalyst such as dichloro{bis[2-(diphenylphosphino)phenyl]ether}palladium(II) and a base such as potassium acetate in a solvent such as 1,4-dioxane at elevated temperature to give the boronic ester in situ.The boronate ester is then coupled with an aryl halide 32a using a second palladium catalyst such as XPhos Pd G4, a base such as K3PO4, and water at elevated temperature to give compound 54. Compound 30 can also be reacted with boronate 32b under Suzuki cross-coupling conditions as described above to give compound 54.

[0285] Scheme 5

[0286] [ka] Scheme 5 shows another approach to the preparation of compound 54. Protected amino acid derivative 23 (where "W" is an alkyl group, e.g., methyl or ethyl, and "PG" is a protecting group, e.g., Boc) is first deprotected, for example, using HCl in MeOH when "PG" is Boc, to give 33, which is then reacted with acid chloride 28 (where Z is a halogen) using an organic base such as TEA in a solvent such as THF to give 34. Intermediate 34 is then cyclized using a carbonate base in a solvent such as ACN to give intermediate 35, which is then converted to the boronic acid using hypodiboric acid, KOAc, and a palladium catalyst such as XPhos Pd G3 at elevated temperature to give boronic acid 36. Boronic acid 36 is then subjected to Suzuki cross-coupling with 32a (where "Z" is a halogen) under conditions known to those skilled in the art, for example, using a carbonate base and a palladium catalyst such as XPhos Pd G3 in an aqueous-organic mixture of a solvent such as 1,4-dioxane / water at elevated temperature to give 37. Alternatively, 35 is subjected to Suzuki cross-coupling with boronate 32b under the conditions described above to give 37. Aqueous LiOH in a solvent such as tert-butanol converts 37 to acid 38, which is then coupled with amine 25 under conditions known to those skilled in the art, for example, using an amide coupling reagent such as DEPBT, an organic base such as N-methylmorpholine, and a polar aprotic solvent such as DMA to give compound 54.

[0287] Scheme 6

[0288] [ka] Scheme 6 illustrates the preparation of compound 50 starting from acid 39, which is coupled to amine 40 using amide coupling conditions well known to those skilled in the art, for example, using an organic base such as HATU and TEA in a solvent such as DMF, to give 41. Compound 41 is then cyclized using a palladium catalyst such as bis(dibenzylideneacetone)palladium and bis(1,1-dimethylethyl)(methyl)phosphine tetrafluoroborate and a phosphate base such as KPO in a solvent such as toluene at elevated temperature to give 43. Subsequent deprotection using TFA and anisole at elevated temperature gives 44, which is then alkylated with ethyl bromoacetate using a carbonate base in a solvent such as DMF at elevated temperature to give 45. Compound 45 is treated with a base such as NaHMDS at −78° C. and then alkylated with alkyl bromide 46 to give 47, which then undergoes ester hydrolysis using aqueous LiOH to give 48. Acid 48 is then coupled with amine 49 to give 50 under coupling conditions well known to those skilled in the art, such as using HATU and TEA.

[0289] Scheme 7

[0290] [ka] Scheme 7 illustrates the preparation of alkyl phosphates, where "alkyl-OH" (51) represents the alkyl-hydroxyl substitution in compounds of the present invention. Reaction of alcohol 51 with diallyl n,n-diisopropylphosphoramidite in the presence of 1H-tetrazole in a solvent such as DCM, followed by addition of hydrogen peroxide at 0°C, affords 52. Removal of the allyl group using a palladium catalyst such as Pd(PPh3)4 and phenylsilane affords 53.

[0291] Preparation 1 6-chloro-5-iodo-3-nitropyridin-2-amine

[0292] [ka] To a mixture of 6-chloro-3-nitropyridin-2-amine (5 g, 28.2 mmol) and sulfuric acid (8.45 g, 5.17 mL, 84.7 mmol) in HO (15 mL), periodic acid (1.38 g, 5.9 mmol) was added, and the mixture was stirred at 100 °C under N for 0.5 h. Iodine (3.29 g, 12.7 mmol) was then added, and the reaction was stirred at 100 °C for an additional 2 h. The reaction mixture was diluted with saturated aqueous sodium thiosulfate (100 mL) and filtered to give the title compound (8 g, 90%) as a yellow solid. ES / MS m / z 299.9 (M+H).

[0293] Preparation 2 6-Chloro-5-iodo-N-methyl-3-nitropyridin-2-amine

[0294] [ka] To a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (3 g, 9.017 mmol) in THF (20 mL) was added NaH (757 mg, 19 mmol) at 0 °C under N. The reaction was stirred at 0 °C for 0.5 h, and methyl iodide (595 μL, 9.0 mmol) was added. The mixture was stirred for an additional 2 h and then quenched by the addition of saturated NH Cl (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over Na SO , and concentrated. The residue was purified on silica gel eluting with 0-20% EtOAc in PE to give the title compound (1.1 g, 34%) as a yellow solid. ES-MS m / z 314.0 (M+H).

[0295] Preparation 3 5-Amino-2-chloro-6-methylnicotinonitrile

[0296] [ka] To a solution of 2-chloro-6-methyl-5-nitronicotinonitrile (3.72 g, 18.5 mmol) in EtOH (160 mL) and HO (40 mL) at 25 °C was added NH Cl (5.19 g, 92.3 mmol) and iron (5.42 g, 92.3 mmol). The reaction was stirred at 80 °C for 2 h, filtered, and washed with hot EtOH (3 × 20 mL). The filtrate was concentrated under reduced pressure and then dissolved in EtOAc (100 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), dried over Na SO , filtered, and concentrated. The residue was purified on silica gel eluting with 0–5% MeOH in DCM to give the title compound (2.7 g, 87%) as a yellow solid. ES-MS m / z 168.2 (M+H).

[0297] The compounds in the following table were prepared in a similar manner as described in Preparation 3, using the appropriate nitropyridine. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to one skilled in the art.

[0298] [Table 1] a. The reaction was heated at 50° C. for 16 hours.

[0299] Preparation 5 6-Bromo-5-fluoro-2-metropyridin-3-amine

[0300] [ka] To a solution of 3-amino-5-fluoro-2-methylpyridine (1.0 g, 7.8 mmol) in DMF (20 mL) was added NBS (1.4 g, 7.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h, then quenched by the addition of HO (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified on silica gel eluting with 0-15% EtOAc in PE to give the title compound (1.6 g, 96%) as a brown solid. ES-MS m / z 207.0 (M+H).

[0301] Preparation 6 1-(5-bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one

[0302] [ka] To a mixture of 6-bromo-5-fluoro-2-methylpyridin-3-amine (600 mg, 2.84 mmol) and KOAc (338 mg, 3.41 mmol) in chloroform (12 mL) was added acetic anhydride (812 μL, 8.52 mmol) at 25° C. The reaction was stirred at 60° C. for 2 hours, and isoamyl nitrite (576 μL, 4.26 mmol) was added. The mixture was stirred at 60° C. for 16 hours, then filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-30% EtOAc in PE to give the title compound (130 mg, 15%) as a yellow solid. ES-MS m / z ( 79 B / 81 Br) 257.8, 259.8 (M+H).

[0303] The compounds in the following table were prepared in a similar manner as described in Preparation 6, using the appropriate aniline. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0304] [Table 2] a. Isolated as a mixture of the desired product and the deacetylated product. The mixture was used without further purification.

[0305] Preparation 8 5-Bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridine

[0306] [ka] To 1-(5-bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (106 mg, 390 μmol) in EtOH (3 mL) was added 1M aqueous LiOH (468 μL, 468 μmol) at 0° C. The reaction was stirred at 0° C. for 1 hour. The pH was adjusted to 7 with FA, the mixture was concentrated, then HO (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (107 mg, 98%, purity 77%) as a yellow solid. ES-MS m / z ( 79 B / 81 Br) 215.8, 217.8 (M+H).

[0307] The compounds in the following table were prepared in a similar manner as described in Preparation 8, using the appropriate N-acetylindazole. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0308] [Table 3]

[0309] Preparation 10 tert-Butyl (6-chloro-5-fluoropyridin-3-yl)carbamate

[0310] [ka] To a mixture of 5-bromo-2-chloro-3-fluoropyridine (5.00 g, 23.8 mmol) in 1,4-dioxane (150 mL) at 20 °C, Xantphos (550 mg, 950 μmol), tert-butyl carbamate (3.06 g, 26.1 mmol), CsCO (15.5 g, 47.5 mmol), and Pd(dba) (644 mg, 713 μmol) were added. The reaction was stirred at 85 °C under N for 12 h, then filtered, and the filter cake was washed with DCM (100 mL × 3). The filtrate was concentrated under reduced pressure. The residue was purified on silica gel eluting with 0–19% EtOAc in PE to give the title compound (3.9 g, 62%) as a yellow solid. ES-MS m / z 246.8 (M+H).

[0311] Preparation 11 tert-Butyl (6-chloro-5-fluoro-4-methylpyridin-3-yl)carbamate

[0312] [ka] To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (500 mg, 1.82 mmol) in THF (10 mL) was added n-butyllithium (2.5 M in hexanes, 1.82 mL, 4.56 mmol) dropwise at −78° C. under N. The reaction was stirred at −78° C. for 2 h, then iodomethane (183 μL, 2.92 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at −78° C. for an additional 3 h, then poured into ice-water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on silica gel eluting with 0–14% EtOAc in PE to give the title compound (405 mg, 77%) as a white solid. ES-MS m / z 260.9(M+H).

[0313] Preparation 12 6-chloro-5-fluoro-4-methylpyridin-3-amine hydrochloride

[0314] [ka] To a solution of tert-butyl (6-chloro-5-fluoro-4-methylpyridin-3-yl)carbamate (405 mg, 1.40 mmol) in MeOH (5 mL) was added 2 M HCl in dioxane (6.99 mL, 14.0 mmol). The mixture was stirred under N at 19 °C for 2 h and then concentrated to give the title compound (270 mg, 88%) as a white solid. ES-MS m / z 158.9 (M+H).

[0315] Preparation 13 5-Amino-2-bromo-4-methylbenzonitrile

[0316] [ka] To a solution of 3-amino-4-methylbenzonitrile (5 g, 0.04 mol) in ACN (75 mL) at 0° C. was added NBS (7 g, 0.04 mol) over 2 minutes. The reaction was allowed to stir for 15 minutes. The solid was filtered, washed with 30 mL of cold ACN, and then dried under vacuum to give the title compound (5.25 g, 70%) as an off-white solid. ES-MS m / z ( 79 Br / 81 Br)211.0 / 213.0.

[0317] Preparation 14 5-chloro-4-fluoro-1H-pyrazolo[3,4-c]pyridine

[0318] [ka] To a solution of 6-chloro-5-fluoro-4-methylpyridin-3-amine hydrochloride (170 mg, 777 μmol) in HOAc (2 mL) was added sodium nitrite (53.6 mg, 777 μmol). The reaction was stirred at room temperature for 12 hours, poured into aqueous NaHCO (50 mL), and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-30% EtOAc in PE to give the title compound (90 mg, 57%) as a white solid. ES-MS m / z 171.9 (M+H).

[0319] The compounds in the following table were prepared in a similar manner as described in Preparation 14, using the appropriate aniline. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0320] [Table 4] a. The reaction was stirred for 30 min instead of 12 h and the product was purified by trituration with Et2O.

[0321] Preparation 16 5-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

[0322] [ka] To a mixture of 5-bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridine (107 mg, 381 μmol) in THF (5 mL) was added dihydropyran (54.8 μL, 572 μmol) and p-toluenesulfonic acid (6.77 mg, 38.1 μmol) at 20° C. The reaction mixture was stirred at 50° C. for 16 h and concentrated under reduced pressure to give the crude product, which was identified by preparative TLC (PE: EtOAc = 5:1, R f=0.5) to give the title compound (87 mg, 73%) as a yellow oil. 79 B / 81 Br) 300.1, 302.1 (M+H).

[0323] The compounds in the following table were prepared from the appropriate NH indazole in a manner similar to that described in Preparation 16. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0324] [Table 5] a. Stir at 35℃

[0325] Preparation 20 6-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

[0326] [ka] Sodium hydride (3.966 g, 60 wt%, 99.14 mmol) was added to a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (12.27 g, 61.96 mmol) in DMF (206 mL) at 0 °C. The reaction was stirred for 20 minutes, then 1-chloromethyl-4-methoxy-benzene (10.1 mL, 74.4 mmol) was added, and the mixture was allowed to stir at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl at 0 °C and then diluted with water / saturated NH4Cl and Et2O. The aqueous layer was extracted twice with Et2O. The combined organics were extracted with water, saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel eluting with 5-30% EtOAc in cyclohexane to give the title compound (11.8 g, 60%) as a white solid. ES-MS m / z ( 79 B / 81 Br) 318.0, 320.0 (M+H).

[0327] Preparation 21 1-(4-Methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0328] [ka] Pd(PPh3)4 (2.9 g, 2.5 mmol) was added to a degassed solution of zinc cyanide (6.504 g, 55.39 mmol) and 6-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (11.8 g, 36.9 mmol) in DMF (148 mL). The reaction was purged with N2 and heated to 120 °C for 2 h. The reaction was diluted with EtOAc, filtered through diatomaceous earth, and concentrated. The residue was purified on silica gel eluting with 10-100% EtOAc in cyclohexane to give the title compound (9.0 g, 92%) as a white solid. ES-MS m / z 265.0 (M+H).

[0329] The compounds in the following table were prepared from the appropriate aryl halides in a manner similar to that described in Preparation 21. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0330] [Table 6] a. Synthesis from aryl iodides

[0331] Preparation 24 5-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[0332] [ka] To a mixture of 5-amino-2-chloro-6-(methylamino)nicotinonitrile (220 mg, 0.964 mmol) in DMA (5 mL) was added N,N'-carbonyldiimidazole (797 mg, 4.82 mmol). The reaction mixture was stirred under N at 80 °C for 3 days, then filtered and concentrated. The filtrate was purified by reverse-phase HPLC (with NHOAc as buffer) using a gradient of 18-58% ACN, followed by recrystallization from EtOH (10 mL) to afford the title compound (40 mg, 19%) as a yellow solid. ES-MS m / z 207.0 (MH).

[0333] Preparation 25 6-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0334] [ka] A mixture of 6-fluoro-1H-pyrazolo[4,3-b]pyridine (4.0 g, 29 mmol) and cesium carbonate (11.3 g, 34.7 mmol) was purged with N2. DMF (130 mL) and methyl iodide (2.4 mL, 37 mmol) were added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with water (2 x), then saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-90% EtOAc in cyclohexane to give the title compound as the first eluting isomer as a white solid (1.78 g, 40%). ES-MS m / z 152.0 (M+H)

[0335] Preparation 26 5-Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0336] [ka] To a mixture of 5-fluoro-1H-pyrazolo[3,4-b]pyridine (1.8 g, 13.13 mmol) in DMSO (100 mL) was added NaHMDS (1.0 M in THF, 19.7 mL, 19.7 mmol) and iodomethane (2.46 mL, 39.3 mmol). The reaction was allowed to stir at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (×3). The organic layers were combined, washed with water (×3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-40% EtOAc in cyclohexane to give the title compound as a white solid (1.3 g, 66%). 1 H-NMR(400MHz,DMSO-d6)δ 8.64-8.58(m,1H),8.19-8.11(,2H),4.07(s,3H).

[0337] Preparation 27 6-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

[0338] [ka] A mixture of 6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (1.22 g, 8.07 mmol) in DCM (33 mL) under a N atmosphere was treated with 3-chloroperoxybenzoic acid (3.78 g, 16.4 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction was cooled to 0 °C, forming a white precipitate, which was removed by vacuum filtration. The filter cake was washed with cold DCM. The filtrate was washed with 1 M NaOH (50 mL). The aqueous layer was extracted with DCM until no product remained in the aqueous layer. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give the title product as a white solid (1.23 g, 86%). ES / MS m / z 167.8 (M+H).

[0339] The compounds in the following table were prepared from the appropriate aza-indazole in a manner similar to that described in Preparation 27. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0340] [Table 7] a. The product was purified by 10-100% EtOAc / DCM on silica gel. b. The reaction solvent used was EtOAc and was heated to 45° C. for 18 hours.

[0341] Preparation 30 5-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0342] [ka] A mixture of 6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide (500.0 mg, 3.0 mmol) in DCM (54 mL) was purged with N2. The flask was cooled to 0 °C, and TEA (1.05 mL, 7.5 mmol) and oxalyl chloride (0.66 mL, 7.5 mmol) were added sequentially. The reaction was allowed to stir for 2 h while warming to room temperature. The reaction mixture was diluted with DCM and poured into saturated aqueous NaHCO3 (50 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-100% EtOAc in cyclohexane to give the title compound as a white solid (490 mg, 86%). ES-MS m / z 186.2 (M+H).

[0343] The compounds in the following table were prepared from the appropriate N-oxide in a manner similar to that described in Preparation 30. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0344] [Table 8] a. The compound was recrystallized from EtOAc and cyclohexane.

[0345] Preparation 33 2-Bromo-5-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)benzonitrile

[0346] [ka] To a mixture of (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (2.87 g, 16.2 mmol), 2-bromo-5-iodobenzonitrile (5.00 g, 16.2 mmol), cesium carbonate (21.2 g, 65.0 mmol), and Pd(dppf)Cl (1.07 g, 1.46 mmol) under a N atmosphere was added 1,4-dioxane / water (3:1) (81.2 mL). A long needle was inserted below the surface of the mixture, and N gas was bubbled through the mixture for 5 minutes. The mixture was heated to 55 °C for 1 hour, cooled to ambient temperature, and water (700 mL) was added with stirring. The mixture was filtered by vacuum filtration to give a brown solid cake, which was dissolved in DCM, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel eluting with 0-5% MeOH / DCM. The resulting residue was crystallized from cyclohexane / EtOAc to give the title compound (3.1 g, 61%) as a light yellow color. ES-MS m / z ( 79 Br / 81 Br)212.8 / 314.8

[0347] Preparation 34 5-chloro-1-methyl-1H-indazole-6-carbonitrile

[0348] [ka] and 5-chloro-2-methyl-2H-indazole-6-carbonitrile

[0349] [ka] To a mixture of 5-chloro-1H-indazole-6-carbonitrile (1.0 g, 5.6 mmol) and K2CO3 (2.33 g, 16.9 mmol) in DMF (28 mL) was added iodomethane (1.0 mL, 16.9 mmol). The reaction was allowed to stir at room temperature for 19 hours. The reaction was quenched with water (60 mL) and extracted with EtOAc (3 × 60 mL). The organic layers were combined, washed with water (2 ×), saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 20–40% EtOAc in cyclohexane to give 5-chloro-1-methyl-1H-indazole-6-carbonitrile (480 mg, 45%) and 5-chloro-2-methyl-2H-indazole-6-carbonitrile (210 mg, 20%) as white solids.

[0350] The compounds in the following table were prepared from the appropriate NH-indazole in a manner similar to that described in Preparation 34. The reactants could be added in a different order or in different equivalent amounts, and the purification method was adjusted to suit the compound. The two isomers were isolated and separated using common purification methods. Such variations would be apparent to one skilled in the art.

[0351] [Table 9] a. 1.2 equivalents of NaH was used instead of K2CO3

[0352] preparation 40 5-Bromo-1-methyl-1H-benzo[d][1,2,3]triazole-6-carbonitrile

[0353] [ka] and 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-5-carbonitrile

[0354] [ka] A mixture of 5,6-dibromo-1-methyl-1H-benzo[d][1,2,3]triazole (300 mg, 1.01 mmol) and cuprous cyanide (136 mg, 46.6 μL, 1.52 mmol) in NMP (5 mL) was heated in a sealed tube at 150 °C under microwave irradiation for 9 h and then combined with the second reaction mixture (170 μmol scale). NH H O (0.3 mL) was added to the reaction mixture, and the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated aqueous NaCl (3 × 30 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel eluting with 0–28% EtOAc / petrol to give a mixture of regioisomers. The mixture was separated by SFC [Column: Daicel Chiralpak® IG (250 mm × 30 mm, 10 μm); Mobile phase: 30% EtOH + 0.1% NH OH in CO ; Flow rate (mL / min): 80] to give 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-6-carbonitrile (40 mg, 15%), ES-MS m / z 237.0 (M+H); and the second eluting isomer 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-5-carbonitrile (30 mg, 12%), ES-MS m / z 237.0 (M+H).

[0355] Preparation 41 tert-Butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0356] [ka] A mixture of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (4.11 g, 19.1 mmol), tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.00 g, 15.9 mmol), and CsCO (10.4 g, 31.8 mmol) was purged with N. DMA (32 mL) was added, and the resulting mixture was stirred at 95 °C for 6 h. The reaction mixture was cooled and poured into water (350 mL) and EtOAc (75 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (4 × 40 mL). The organic layers were combined, washed with water (40 mL), then aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-10% MTBE in heptane to give the second eluting isomer as the title compound (4.11 g, 67%). ES-MS m / z ( 79 Br / 81 Br) 330.0 / 332.0(M-tBu+H).

[0357] Preparation 42 tert-Butyl (2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0358] [ka] A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (3.04 g, 12.9 mmol), tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (5.00 g, 12.9 mmol), CsCO (8.44 g, 25.9 mmol), and Pd(dppf)Cl (947 mg, 1.29 mmol), 1,4-dioxane (78.5 mL), and water (7.85 mL) was sparged with N for 5 minutes. The resulting mixture was stirred at 60 °C for 1 hour. An additional portion of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.3 g, 5.53 mmol) was added, and the mixture was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with water. The organic phase was dried over MgSO and concentrated under reduced pressure. The residue was purified on silica gel eluting with 30 to 100% EtOAc in cyclohexane. Crystallization from 20% EtOAc:80% cyclohexane, followed by high vacuum filtration, afforded the title compound (2.77 g, 52%) as a white solid. ES-MS m / z 359.0 (M-tBu+H).

[0359] Preparation 43 1-(5-Bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine hydrochloride

[0360] [ka] A solution of tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (5.00 g, 12.9 mmol) in MeOH (12.9 mL) was treated with 4 M HCl in dioxane (12.9 mL, 51.8 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated to give the title compound (4.145 g, 99%) as a white solid. ES-MS (m / z, 79 Br / 81Br) 286.0 / 288.0 (M+H).

[0361] The compounds in the following table were prepared from the appropriate tert-butyl carbamate in a manner similar to that described in Preparation 43. Different reaction times (2-43 hours), equivalents of HCl (4-18 equivalents), and co-solvents (MeOH, EtOH, EtOAc, dioxane) can be used. Such variations will be apparent to those skilled in the art.

[0362] [Table 10]

[0363] Preparation 45 N-(1-cyano-1-(4-fluorophenyl)-2-methylpropan-2-yl)-2-methylpropane-2-sulfinamide

[0364] [ka] To a solution of lithium diisopropylamide (5.7 g, 53 mmol) was added 2-(4-fluorophenyl)acetonitrile (3.0 g, 22 mmol) in THF (30 mL) at −70° C. The mixture was stirred under a N atmosphere for 30 minutes. Chlorotitanium triisopropoxide (14 mL, 55 mmol) was then added, and the reaction was stirred at −70° C. for 20 minutes. 2-Methyl-N-(propan-2-ylidene)propane-2-sulfinamide (8.0 g, 44 mmol) in THF (30 mL) was then added, and the mixture was stirred at −70° C. for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The organic layers were combined, washed with water (2×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-40% EtOAc in PE to give the title compound as a colorless oil (2.65 g, 36%). ES-MS m / z 296.9 (M+H).

[0365] Preparation 46 3-((tert-butylsulfinyl)amino)-2-(4-fluorophenyl)-N'-hydroxy-3-methylbutanimidamide

[0366] [ka] To a mixture of N-(1-cyano-1-(4-fluorophenyl)-2-methylpropan-2-yl)-2-methylpropane-2-sulfinamide (2.65 g, 8.05 mmol) and TEA (3.2 mL, 23 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.35 g, 19.4 mmol). The reaction was heated to 80 °C under a N atmosphere for 16 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified on silica eluting with 0-5% MeOH in DCM to give the title compound as a colorless oil (550 mg, 17.3%). ES-MS m / z 330.2 (M+H).

[0367] Preparation 47 N-(1-(4-fluorophenyl)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide

[0368] [ka] To a mixture of 3-((tert-butylsulfinyl)amino)-2-(4-fluorophenyl)-N'-hydroxy-3-methylbutanimidamide (550 mg, 1.39 mmol) in THF (8 mL) was added di-1H-imidazol-1-ylmethanethione (0.27 mL, 1.96 mmol). The reaction was stirred at 15 °C for 4 h. The reaction mixture was added to water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with saturated aqueous NaCl (2 x 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. To the residue was added THF (8 mL) and boron trifluoride etherate (1 mL, 8 mmol), and the reaction was stirred at 15 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified on silica eluting with 0-4% MeOH in DCM to give the title compound as a yellow solid (150 mg, 26%). ES-MS m / z 372.2 (M+H).

[0369] Preparation 48 3-((tert-butylsulfinyl)amino)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoic acid

[0370] [ka] To a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (5.80 g, 28.4 mmol) in THF (40 mL) at −70° C. was added lithium diisopropylamide solution (35.5 mL, 2 molar, 271.0 mmol), and the reaction was stirred at −70° C. for 30 minutes. Then, chlorotitanium triisopropoxide (31.1 g, 30.5 mL, 119 mmol) in THF (30 mL) was added at −70° C. and stirred for 30 minutes. After 30 minutes, 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (9.67 g, 90 wt%, 54.0 mmol) in THF (20 mL) was added. The mixture was stirred at −70° C. for 1 hour under N2. The reaction was quenched by adding water (50 mL), and the solid was removed by filtration and washed with EtOAc (3×30 mL). The filtrate was washed with EtOAc (3 x 50 mL). The aqueous layer was adjusted to pH 6 by the addition of 1 M HCl, and then the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-9% MeOH in DCM to give the title compound as a yellow oil (1.2 g, 80% purity, 9.2%) and a yellow oil (1.8 g, 50% purity, 8.7%). ES-MS m / z 366.0 (M+H).

[0371] Preparation 49 Methyl 3-((tert-butylsulfinyl)amino)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoate

[0372] [ka] To a solution of 3-((tert-butylsulfinyl)amino)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoic acid (3.7 g, 50 wt%, 5.1 mmol) in MeOH (20 mL) and DCM (20 mL) was added (trimethylsilyl)diazomethane solution (12 g, 15 mL, 2 molar, 30 mmol) at 25° C. The mixture was stirred under N at 25° C. for 12 h. The mixture was quenched with 0.2 mL of HOAc and then concentrated under reduced pressure to give the crude product, which was then combined with the second reaction crude (2.6 mmol scale). The residue was purified by silica gel eluting with a 0-6% DCM:MeOH gradient to give the compound methyl 3-((tert-butylsulfinyl)amino)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoate (1.87 g, 86% purity, 62% yield) as a yellow oil. ES-MS m / z 380.4 (M+H).

[0373] preparation 50 Ethyl 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetate

[0374] [ka] To a mixture of 4-(trifluoromethyl)-1H-pyrazole (5.00 g, 36.7 mmol) and potassium carbonate (10.2 g, 73.5 mmol) in DMF (50 mL) was added ethyl 2-bromoacetate (5.28 mL, 47.8 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over NaSO, and concentrated. The residue was purified by flash silica gel eluting with a gradient of 0% DCM / MeOH to give the title compound (6.8 g, 79%) as a colorless oil. ES-MS m / z M+H = 223.2.

[0375] Preparation 51 Ethyl 3-((tert-butylsulfinyl)amino)-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate

[0376] [ka] To a solution of ethyl 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (5.00 g, 21.38 mmol) in THF (50 mL) was added lithium diisopropylamide solution (25.66 mL, 2 molar, 51.31 mmol) at −70° C. and stirred for 30 minutes. Then, chlorotitanium triisopropoxide (15.25 g, 55.59 mmol) in THF (25 mL) was added at −70° C. and stirred for 30 minutes, followed by the addition of 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (prepared essentially as described in WO 2022170198 A1, 7.258 g, 42.76 mmol) in THF (25 mL). The mixture was stirred at −70° C. for 1 hour under N2. Water (100 mL) was added to the reaction mixture, the solid was filtered, and the filter cake was washed with EtOAc (100 mL × 3). The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC using a gradient of 25-65% ACN with NHOAc buffer. The eluate was concentrated to remove the organic solvent, and the remaining aqueous solution was lyophilized. The title compound (3.3 g, 31% yield, 77% purity) was obtained as a yellow oil. ES-MS m / z 384.3 (M+H).

[0377] The compounds in the following table were prepared from methyl 2-(4-fluorophenyl)acetate in a manner similar to that described in Preparation 51. Different reaction times (1-16 hours), equivalents of chlorotitanium triisopropoxide (2.6-4.2 equivalents), and equivalents of lithium diisopropylamide (2.4-3.3 equivalents) can be used. Such variations will be apparent to one skilled in the art.

[0378] [Table 11]

[0379] Preparation 53 3-(2-amino-1-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5(4H)-one hydrochloride

[0380] [ka] To a solution of N-(1-(4-fluorophenyl)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (150 mg, 0.37 mmol) in 1,4-dioxane (1 mL) was added hydrogen chloride (2.0 mL, 2.0 M in 1,4-dioxane, 4.0 mmol) at 15° C. The mixture was stirred at 15° C. for 3 hours. The reaction mixture was directly concentrated under reduced pressure to give the title compound (130 mg, 93% yield, 80% purity) as a yellow solid. ES-MS m / z 269.1 (M+H).

[0381] The compounds in the following table were prepared from the appropriate (tert-butylsulfinyl)amine in a manner similar to that described in Preparation 53. Different reaction times (1-2 hours), equivalents of HCl (4-10 equivalents), temperatures (0-25°C), and co-solvents (MeOH, EtOH, DCM, dioxane) can be used. Such variations will be apparent to those skilled in the art.

[0382] [Table 12] a. Compound isolated as the free base after extraction with EtOAc from aqueous NaHCO3.

[0383] Preparation 57 (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid

[0384] [ka] In a glovebox, a solution of tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (1.0 g, 2.5 mmol) in MeOH (30 mL) was treated with tetrahydroxydiboron (1.1 g, 13 mmol), a solution of XPhos Pd G3 (CAS number 1445085-55-1, 0.22 g, 0.25 mmol) in DCE (3 mL), and KOAc (1.0 g, 10 mmol). The resulting mixture was stirred under N at 40 °C for 16 h. The reaction was repeated on the same scale, and the reaction solutions were combined, adjusted to pH 6 with FA, and filtered. The filtrate was concentrated. The residue was purified on silica gel eluting with 0-4% (0.1% FA / MeOH) in DCM to give the title compound (1.45 g, 80%) as a brown solid. ES-MS m / z 352.3 (M+H).

[0385] Preparation 58 3-Bromo-5-methoxy-1,2,4-thiadiazole

[0386] [ka] To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (25.00 g, 122.8 mmol) in MeOH (80 mL) was added sodium methoxide (13.97 g, 245.7 mmol). The mixture was stirred at 25 °C under N for 16 h. An additional portion of sodium methoxide (6.985 g, 122.8 mmol) was added, and stirring was continued at 25 °C under N for 16 h. The mixture was concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-5% EtOAc in PE to give the title compound (9.7 g, 36% yield, 90% purity) as a white solid. ES-MS m / z 196.7 (M+H).

[0387] Preparation 59 tert-Butyl (1-(5-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0388] [ka] A solution of 2-bromo-5-methoxy-1,3,4-thiadiazole (526 mg, 2.56 mmol), (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (1.00 g, 2.56 mmol, approximately 90% pure), and Na2CO3 (543 mg, 5.13 mmol) in 1,4-dioxane (10 mL), EtOH (10 mL), and water (1 mL) was treated with XPhos Pd G3 (CAS number 1445085-55-1, 325 mg, 384 μmol). After stirring at 90 °C under N2 for 2 h, the reaction mixture was cooled and diluted with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL). The organic layers were combined, washed with saturated aqueous NaCl (3 x 15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-40% EtOAc in PE to give the title compound (170 mg, 14%) as a yellow solid. ES-MS m / z 422.0 (M+H).

[0389] The compounds in the following table were prepared in a similar manner as described in Preparation 59, using the appropriate boronic acid and heteroaryl bromide. Different catalysts and co-solvents may be used. Such variations will be apparent to those skilled in the art.

[0390] [Table 13] a. Reagents used: Pd(dppf)Cl2, Na2CO3, 1,4-dioxane / water; product was purified on silica gel eluting with 0-3% MeOH / DCM.

[0391] Preparation 61 5-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,4-thiadiazol-2-ol hydrochloride

[0392] [ka] A solution of tert-butyl (1-(5-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (70 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was treated with 2 M HCl in 1,4-dioxane (400 mL, 800 mmol). After stirring at room temperature for 16 h, the mixture was treated with additional 2 M HCl in 1,4-dioxane (300 mL, 600 mmol). After stirring at room temperature for another 16 h, the mixture was concentrated to give the title compound (60 mg, 68% purity, 82% yield) as a white solid. ES-MS m / z 307.9 (M+H).

[0393] The compounds in the following table were prepared in a similar manner as described in Preparation 61 using tert-butyl (1-(5-(5-methoxy-1,2,4-thiadiazol-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate and 2M HCl in 1,4-dioxane.

[0394] [Table 14]

[0395] Preparation 63 1-(5-(5-methoxy-1,2,4-thiadiazol-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine 2,2,2-trifluoroacetate

[0396] [ka] To a solution of tert-butyl (1-(5-(5-methoxy-1,2,4-thiadiazol-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (1.5 g, 80% purity, 2.8 mmol) in DCM (30 mL) was added TFA (3.3 mL, 43 mmol) at 15 °C. The mixture was then stirred at 15 °C for 1 h to give a solution of the title compound in DCM. This solution was used directly in the next step assuming quantitative yield. ES-MS m / z 322.2 (M+H).

[0397] Preparation 64 1-((5-fluoropyridin-2-yl)methyl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate

[0398] [ka] (5-Fluoropyridin-2-yl)methanamine (4.99 g, 39.5 mmol) was added to a mixture of 2,4,6-triphenylpyrylium tetrafluoroborate (14.5 g, 36.6 mmol) in DCM (100 mL) at room temperature, and the resulting mixture was stirred overnight before being concentrated to a foam. The foam was triturated with EtO, and the solvent was decanted off (repeated). The remaining residue was dried in vacuo overnight to give the title compound as a yellow foam, which was used directly in the next step assuming quantitative yield. ES-MS m / z 417.0 (M + ).

[0399] Preparation 65 5-Fluoro-2-(2-methyl-2-nitropropyl)pyridine

[0400] [ka] 2-Nitropropane (12.9 mL, 144 mmol) was added over 10 minutes to an ice-water bath-cooled solution of sodium methoxide (22.2 mL, 120 mmol) in MeOH (240 mL). The resulting mixture was stirred at room temperature for 30 minutes and then concentrated to give a white solid, which was dried overnight in vacuo. In a 250 mL three-neck flask equipped with a mechanical stirrer under N2, 1-((5-fluoropyridin-2-yl)methyl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate (19 g, 38 mmol) and DMSO (50 mL) were added to the white solid. The resulting mixture was stirred at 70 °C for 2 hours. The mixture was cooled to room temperature and then diluted with Et2O (200 mL), giving a precipitate. The solid was removed by filtration through diatomaceous earth and rinsed with Et2O. The filtrate (800 mL) was washed with water (200 mL). The layers were separated and the aqueous layer was extracted with EtO (3 x 50 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over MgSO, filtered, and concentrated. The residue was purified on silica gel eluting with 5-100% EtOAc in DCM to give the title compound (5.63 g, 75%) as a yellow oil. ES-MS m / z 198.8 (M+H).

[0401] Preparation 66 1-(5-fluoropyridin-2-yl)-2-methylpropan-2-amine hydrochloride

[0402] [ka] In a pressure vessel under a stream of N2, a solution of 5-fluoro-2-(2-methyl-2-nitropropyl)pyridine (4.62 g, 23.3 mmol) in MeOH (100 mL) was added to a mixture of Raney® nickel (19.28 g, 328.5 mmol) in MeOH (100 mL). The vessel was sealed, purged five times with N2, purged five times with H2, and pressurized to 60 psi with H2. After shaking at room temperature for 5 hours, the suspension was filtered through diatomaceous earth, and the solids were rinsed with MeOH to give a clear, pale yellow filtrate, which was combined with the filtrate from a second reaction carried out in a similar manner with 996 mg of 5-fluoro-2-(2-methyl-2-nitropropyl)pyridine. The combined filtrate was concentrated. The residue was dissolved in Et2O (200 mL) and filtered through fluted filter paper to remove the solids. The filtrate was concentrated to give 1-(5-fluoropyridin-2-yl)-2-methylpropan-2-amine (4.19 g) as a pale orange oil. This oil was dissolved in ether (200 mL) and treated with 4 M HCl in dioxane (7.0 mL, 28 mmol) to give a precipitate. The solvent was removed under reduced pressure to give a quantitative yield of the title compound (6.55 g) as a yellow solid. ES / MS m / z 169.0 (M+H).

[0403] Preparation 67 tert-Butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)hydrazine-1-carboxylate

[0404] [ka] To a solution of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate (9.0 g, 48 mmol) in MeOH (100 mL) was added tert-butyl hydrazine carboxylate (6.4 g, 48 mmol) and HOAc (8.3 mL, 140 mmol). The mixture was stirred at room temperature for 2 h, and then NaBHCN (4.5 g, 72 mmol) was added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure and diluted with water (100 mL). NaCO was added to adjust the pH to 8, and the mixture was extracted with EtOAc (2 × 100 mL). The organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0–10% EtOAc in PE to give the title compound (13.2 g, 86%) as a white solid. ES-MS m / z 304.2(M+H).

[0405] Preparation 68 1-Hydraziner-2-methylpropan-2-amine trihydrochloride

[0406] [ka] To a solution of tert-butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)hydrazine-1-carboxylate (15.2 g, 47.6 mmol) in MeOH (100 mL) was added hydrogen chloride (100 mL, 4 M in MeOH, 400 mmol). The mixture was stirred at 25° C. for 16 h and then concentrated under reduced pressure to give the title compound (8.8 g, 83%) as a white solid. 1 H-NMR(400MHz,CD3OD)δ 3.10(s,2H),1.38(s,6H).

[0407] Preparation 69 1-(5-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-amine

[0408] [ka] To a mixture of 1-hydraziner-2-methylpropan-2-amine trihydrochloride (2.5 g, 11 mmol) and 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (1.6 g, 11 mmol) in EtOH (10 mL) was added TEA (1.6 mL, 11 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was then concentrated under reduced pressure to give the title compound (3.2 g, 96% yield, 60% purity) as a yellow solid. ES-MS m / z 180.3 (M+H).

[0409] Preparation 70 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoate

[0410] [ka] A mixture of 4-iodo-1-methyl-1H-pyrazole (20.0 g, 96.2 mmol), pyridine-2,6-bis(carboximidamide) dihydrochloride (5.05 g, 19.2 mmol), nickel(II) chloride, dimethoxyethane adduct (CAS number 29046-78-4, 4.23 g, 19.2 mmol), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (47.5 g, 144 mmol), and zinc (8.46 g, 129 mmol) in DMA (300 mL) was purged with N and stirred under N at 40 °C for 16 h. The reaction mixture was slowly quenched at 0 °C with saturated aqueous NH Cl (300 mL) and then filtered. The filtrate was diluted with water (200 mL) and extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with water (2 × 300 mL), then saturated aqueous NaCl (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0–33% EtOAc in PE to give the title compound (12.16 g, 42%) as a colorless oil. ES-MS m / z 284.1 (M+H). >99% ee. [Chiral SFC-column: Chiralcel® OJ-3, 4.6 × 150 mm, 3 μm; column temperature 35 °C; mobile phase: gradient of 5–50% EtOH (0.05% DMEA) in CO; flow rate: 3 mL / min].

[0411] Preparation 71 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0412] [ka] To a solution of 1-difluoromethyl-4-iodo-1H-pyrazole (15.0 g, 59.6 mmol) in DMA (50 mL) under N was added pyridine-2,6-bis(carboximidamide) dihydrochloride (2.83 g, 12.0 mmol), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (29.5 g, 89.7 mmol), zinc (7.79 g, 119 mmol), and nickel(II) chloride, dimethoxyethane adduct (CAS number 29046-78-4, 2.60 g, 11.8 mmol). The resulting mixture was stirred at 60 °C (internal) for 12 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) and then filtered through diatomaceous earth, rinsing with EtOAc (2 × 50 mL). The filtrate was diluted with water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-10% EtOAc in PE to give the title compound (13.0 g, 67%) as a colorless oil. ES-MS m / z 264.1 (M-tBu+H). >99% ee. [Chiral SFC-column: Chiralpak® AD-3, 4.6 × 150 mm, 3 μm; column temperature 35 °C; mobile phase: gradient of 10-50% EtOH in CO (containing 0.2% 7 M NH in MeOH); flow rate: 2.5 mL / min].

[0413] Preparation 72 (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid

[0414] [ka] A solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (12.0 g, 36.8 mmol) in THF (120 mL) was treated with 1 M aqueous LiOH·HO (110 mL, 110 mmol) and stirred at 25 °C under N for 1 h. The mixture was extracted with DCM (3 × 30 mL). The aqueous phase was adjusted to pH 2–3 with 1 N aqueous HCl, and the resulting white solid was collected by filtration, suspended in PE (100 mL), and stirred for 12 h. Filtration and drying in vacuo afforded the title compound (10.5 g, 94%) as a white solid. ES-MS m / z 250.1 (M-tBu+H). >99% ee, [SFC-column: Chiralpak® AD-3, 4.6 × 150 mm, 3 μm; column temperature 35 °C; mobile phase: 15% IPA (containing 0.5% IPAm): 85% CO2; flow rate: 2.5 mL / min].

[0415] The compounds in the following table were prepared in a manner similar to that described in Preparation 72. Alternatively, the product can be extracted with EtOAc after acidifying the reaction mixture. The compounds can also be isolated as their corresponding lithium carboxylate salts by concentrating the basic reaction mixture, as would be apparent to one skilled in the art.

[0416] [Table 15]

[0417] Preparation 74 tert-Butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0418] [ka] A stirred mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (8.3 g, 27 mmol), 1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine hydrochloride (8.4 g, 26 mmol), DIEA (16 mL, 91 mmol), and DMF (50 mL) was cooled at 0 °C and treated dropwise with HATU (12 g, 31 mmol). After 4 h at room temperature, the reaction mixture was partitioned between EtOAc (400 mL) and water (400 mL). The aqueous layer was extracted with EtOAc (300 mL). The organic layers were combined, washed with water (500 mL), then saturated aqueous NaCl (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 50-65% MTBE in heptane to give the title compound (14.4 g, 96%) as a white foam. ES-MS m / z ( 79 Br / 81 Br)517.2 / 519.2(M-tBu+H).

[0419] The compounds in the following table were prepared in a similar manner as described in Preparation 74, using the appropriate carboxylic acid and the appropriate amine. The reactants may be added in a different order or in different equivalent amounts. DMA and DMSO are suitable substitutes for DMF. Reaction times (30 minutes to overnight) and temperatures (0°C to room temperature) may be varied, and different methods may be used to work up or purify the compounds (normal phase, or reverse phase at high pH, ​​neutral pH, or low pH). Such variations will be apparent to those skilled in the art.

[0420] [Table 16-1]

[0421] [Table 16-2]

[0422] Preparation 83 tert-Butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0423] [ka] To a mixture of tert-butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (2.05 g, 3.58 mmol), 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (900 mg, 3.56 mmol), KCO (1.47 g, 10.6 mmol), and Pd(dppf)Cl·CHCl (581 mg, 711 μmol) was added 4:1 dioxane / water (20 mL) sparged with N under N. The resulting reaction mixture was stirred at 90°C for 3.5 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on silica gel eluting with 0-100% EtOAc / cyclohexane to give the title compound (1.25 g, 57%) as a yellow solid. ES-MS m / z 520.2 (M-BOC+H), 642.2 (M+Na).

[0424] Preparation 84 tert-Butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0425] [ka] To a 1 L RBF equipped with a stir bar was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (30.8 g, 131 mmol), tert-butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (50.0 g, 87.2 mmol), Pd(dppf)Cl (5.5 g, 6.7 mmol), and KCO (36.2 g, 262 mmol), followed by 1,4-dioxane (279 mL) and water (69.8 mL). The mixture was degassed in vacuo, purged with N2 (3x), and heated to 90 °C for 1 h. The mixture was diluted with DCM (500 mL) and washed with water (1 L). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give a dark oil. The material was purified by silica gel column eluting with 0-5% MeOH in EtOAc to give the title compound (42 g, 80%) as a light tan foamy solid. ES-MS m / z 602.4 (M+H)

[0426] The compounds in the following table were prepared in a similar manner as described in Preparations 83 and 84, using the appropriate aryl bromide and the appropriate boronic ester or boronic acid. The reactants may be added in a different order or in different equivalent amounts, the reaction time (5-32 hours) and temperature (90-100°C) may be varied, and the compounds may be worked up or purified using different methods that will be apparent to those skilled in the art.

[0427] [Table 17]

[0428] Preparation 87 (R)-2-Amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)propanamide hydrochloride

[0429] [ka] A solution of tert-butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.25 g, 2.02 mmol) in MeOH (10 mL) was added to 4 M HCl in 1,4-dioxane (7.6 mL, 30 mmol). After stirring at room temperature for 18 h, the mixture was concentrated under a stream of N to give the title compound (1.1 g, 98%) as a yellow solid. ES-MS (m / z) 520.0 (M+H).

[0430] Preparation 88 (R)-2-Amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide hydrochloride

[0431] [ka] To a 1 L RBF equipped with a stir bar was added tert-butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (67.4 g, 112 mmol) and 1,4-dioxane (280 mL). The mixture was heated to 40° C. and monitored with an internal temperature probe. HCl (4 M in 1,4-dioxane, 140 mL, 560 mmol) was added over 15 minutes and the mixture was stirred overnight. The mixture was cooled to ambient temperature and 100 mL of MeOH was added. The solution was concentrated under reduced pressure at 40° C. The residue was then dissolved in MeOH (100 mL) and DCM (200 mL) and concentrated to give the title compound (68.3 g, quantitative yield) as a light tan foamy solid: ES-MS (m / z) 502.2 (M+H).

[0432] The compounds in the following table were prepared from the appropriate tert-butyl carbamate in a manner similar to that described in Preparations 87 and 88. Different reaction times (15 min-24 h), equivalents of HCl (3-25 equivalents), and co-solvents (such as EtOAc) can be used. Such variations will be apparent to those skilled in the art. Alternative conditions, TFA in DCM, gave the TFA salt. The deprotected amine was isolated as the corresponding salt.

[0433] [Table 18] a. Deprotection was carried out with TFA in DCM

[0434] Preparation 96 (R)-N-(1-(5-(2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanamide hydrochloride

[0435] [ka] A solution of tert-butyl ((2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (150 mg, 204 μmol, approximately 88% purity) in MeOH (3 mL) was treated with 2 M HCl in MeOH (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 25° C. for 12 hours and then concentrated under reduced pressure to give a quantitative yield of the title compound (140 mg, approximately 70% purity) as a yellow solid. ES-MS m / z 462.2 (M+H).

[0436] Preparation 97 (2R)-2-amino-N-(2-methyl-1-(5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride and (R)-N-(1-(5-(2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-2-amino-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride (mixture)

[0437] [ka] To a solution of tert-butyl ((2R)-1-((2-methyl-1-(5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (4.14 g, 90% pure, 6.11 mmol) in MeOH (15 mL) was added 2 M HCl in 1,4-dioxane (20 mL, 2 molar, 40 mmol). The mixture was stirred at 30° C. for 1 h and then directly concentrated to give the title compound as a 3:1 mixture of THP-protected and THP-deprotected products (3.6 g, assuming quantitative yield) as a yellow solid. (2R)-2-amino-N-(2-methyl-1-(5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride: ES-MS m / z 510.3 (M+H). For (R)—N-(1-(5-(2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-2-amino-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride: ES-MS m / z 426.2 (M+H).

[0438] Preparation 98 Methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)acrylate

[0439] [ka] To a cooled mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (300 g, 2.72 mol) and methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (966 g, 2.92 mol) in DCM (1.5 L) was added DBU (435 mL, 2.89 mol) in one portion at 0–5 °C under N. The mixture was warmed to 15–20 °C and stirred for 2 h. The reaction mixture was diluted with water (2 L) and extracted with DCM (2 × 0.5 L). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (3 L) by stirring for 1 h, then the solid was collected by filtration. The reaction was repeated 10 times. The collected material from all 11 reactions was combined to give the title compound (7.00 kg, 74%) as a yellow solid. ES-MS m / z 316.1(M+H).

[0440] Preparation 99 Methyl 2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoate

[0441] [ka] To a solution of methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (700 g, 2.22 mol) in MeOH (7 L), diacetato[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) (Ru(OAc)2[(R)-binap], CAS number 325146-81-4, 46.8 g, 55.5 mmol) and HOAc (127 mL, 2.22 mol) were added under Ar. The resulting mixture was degassed in vacuo and purged with H2 several times. After stirring under H2 (435 psi) at 60 °C for 16 h, the reaction mixture was concentrated under reduced pressure. The reaction was repeated nine times on the same scale. The residues from all ten reactions were combined to give the title compound (6.80 kg, 97%) as a yellow oil that was enantiomerically enriched in the (R)-enantiomer (approximately 3:1). ES-MS m / z 318.1 (M+H).

[0442] preparation 100 (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid

[0443] [ka] A solution of enantiomerically (R)-enantiomer-enriched methyl 2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoate (3.40 kg, 10.7 mol) in MeOH (10.2 L) at 0 °C was treated with a mixture of LiOH·HO (1.80 kg, 42.9 mol) and HO (13.6 L). After stirring at 20 °C for 16 h, the mixture was partially concentrated under reduced pressure, adjusted to pH 3–4 with 1 M aqueous HSO, and the solid was collected by filtration. The reaction was repeated on the same scale, and the resulting solids were combined and dried under vacuum at 45 °C to give enantiomerically enriched (R)-enantiomer of 2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (5.00 kg, 77% yield) as a black solid. ES-MS m / z 304.1 (M+H).

[0444] The material was divided into five equal portions. Each portion (1.00 kg, 3.30 mol) was dissolved in acetone (20 L) and stirred at 25 °C for 10 minutes, after which (1S,2R)-2-amino-1,2-diphenylethan-1-ol (633 g, 2.97 mol) was added. After stirring at 25 °C for 12 hours, the mixture was filtered, and the solids isolated from the five reactions were combined to give the (1S,2R)-2-amino-1,2-diphenylethan-1-ol salt of the title compound (5.40 kg, 63%) as a white solid. A solution of the salt (1.01 kg, 1.96 mol) in water (15 L) at 0 °C was adjusted to pH 9 with 20% aqueous NaCO and extracted with EtOAc (3 × 4 L) to remove neutral impurities. The aqueous phase was cooled to 0 °C, adjusted to pH 2 with HSO, and extracted with EtOAc (3 × 4 L). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (10.0 L) by mixing at 20 °C for 2 h, and then the solid was collected by filtration. This reaction was repeated five times on the same scale, and the material isolated from all six reactions was combined to give the title compound (2.00 kg, 56% yield) as a white solid. ES-MS m / z 304.1 (M+H).[a] D 20 = -4.98° (C = 1.0, ACN:HO, 5:1). >98% ee. [Chiral SFC-column: Chiralpak® AD-3, 150 × 4.6 mm, 3 μm; column temperature: 35 °C; mobile phase: gradient 10–50% IPA in CO (containing 0.1% IPAm); flow rate: 2.5 mL / min].

[0445] Preparation 101 Benzyl (R)-(1-((1-(4-fluorophenyl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0446] [ka] To a solution of (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (6.5 g, 21 mmol), 1-(4-fluorophenyl)-2-methylpropan-2-amine (3.6 g, 21 mmol), and HATU (9.8 g, 26 mmol) in DMA (50 mL) was added DIEA (8.3 g, 11 mL, 64 mmol). The mixture was stirred at 25 °C for 16 h, then poured into water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water (50 mL × 5), dried over Na SO , and concentrated. The crude product was purified on silica eluting with 0 to 60% EtOAc in PE to give the title compound (9.09 g, 88%) as a brown oil. ES-MS m / z 453.3(M+H).

[0447] Preparation 102 (R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide

[0448] [ka] To a slurry of 5% Pd / C (wet) (1 g, 0.5 mmol) in EtOAc (25 mL) was added a solution of benzyl (R)-(1-((1-(4-fluorophenyl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (22 g, 49 mmol) in MeOH (200 mL). The reaction was stirred overnight at room temperature under 45 psi of H. An additional portion of 5% Pd / C (1 g, 0.5 mmol) was added and the reaction was stirred for 3 h. The mixture was filtered, and the filtrate was concentrated to give the title compound (14.7 g, 95%) as a colorless oil. ES-MS m / z 319.2 (M+H).

[0449] Preparation 103 ((R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide dihydrochloride

[0450] [ka] (R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide (14.7 g, 46.2 mmol) was dissolved in MTBE (150 mL). 4N HCl / dioxane (3.5 g, 24 mL, 96 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The solid was filtered, washed with EtO, and dried in vacuo to give the title compound (17.5 g, 44.7 mmol, 97%) as a white solid.

[0451] Preparation 104 Methyl (R)-2-amino-3-(1-methyl-1H-pyrazol-4-yl)propanoate hydrochloride

[0452] [ka] A solution of (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (180 g, 593 mmol) in MeOH (1.26 L) was treated with SOCl (141 g, 1.19 mol), and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (1.0 L), and Pd / C (50 wt%, 100 g) was added. The suspension was degassed and purged with H (3x), and stirred under H (20 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (130 g, 87%) as a white solid. ES-MS m / z 184.1 (M+H).

[0453] Preparation 105 5-Bromo-8-fluorobethochroman

[0454] [ka] To a solution of 2-(2-bromo-5-fluorophenyl)ethan-1-ol (2.40 kg, 10.9 mol) and 1,3,5-trioxane (1.15 kg, 12.8 mol) in DCM (16.8 L) was added TiCl (4.04 kg, 21.3 mol) dropwise at 0 °C over 1 h and then stirred at 25 °C for 12 h. The reaction was quenched by the dropwise addition of water (6.00 L). The aqueous phase was then extracted with DCM (5.00 L). The mixture was concentrated under reduced pressure. The mixture was then diluted with EtOAc (10.0 L) and water (3.00 L), the phases were separated, and the combined organics were washed with saturated aqueous NaCl (3.00 L), dried over NaSO, filtered, and concentrated to give the title compound (2400 g) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6)δ 7.54(dd,J=8.4,5.2Hz,1H),7.05(t,J=9.2Hz,1H),4.69(s,1H),3.90(t,J=5.6Hz,2H),2.67(t,J=5.6Hz,2H).

[0455] Preparation 106 5-Bromo-8-fluoroisochroman-1-one

[0456] [ka] To a solution of 5-bromo-8-fluoroisochroman (2300 g, 2.16 mol) in ACN / water = 3 / 1 (23.0 L) was added tetrabutylammonium iodide (718 g, 2.13 mol) and tert-butyl hydroperoxide (3.43 kg, 26.6 mol, 380 mL, 70% purity) dropwise at 25 °C over 1 h, then stirred at 80 °C for 12 h. The reaction was cooled to 25 °C, quenched with saturated Na2SO3 (9.20 L), and extracted with DCM (9.20 L). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by trituration with MeOH (6000 mL) at 60-25° C. for 120 min, then triturated again with MTBE (7500 mL) at 25° C. for 60 min to give the title compound (1030 g, 39%) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ 7.95(d,J=9.2Hz,1H),7.28(dd,J=10.4Hz,1H),4.49(t,J=6.0Hz,2H),3.08(t,J=6Hz,2H).

[0457] Preparation 107 3-Bromo-2-(2-chloroethyl)-6-fluorobenzoyl chloride

[0458] [ka] To a solution of 5-bromo-8-fluoroisochroman-1-one (10.0 g, 40.8 mmol) in DCE (100 mL) was added benzyl(triethyl)ammonium chloride (18.7 g, 82.1 mmol) and thionyl chloride (15.0 mL, 204 mmol), followed by boron trifluoride etherate (10.2 mL, 81.4 mmol). The mixture was sealed in a glass pressure vessel and heated at 110 °C with stirring for 2 days. The mixture was cooled, opened, diluted with toluene (50 mL), and then concentrated under reduced pressure at 45 °C to produce a pale yellow solid. Toluene (50 mL) was added, and the mixture was concentrated (3x) to give the title compound as a light yellow solid, with residual benzyl(triethyl)ammonium chloride contributing to the mass. The yield was estimated to be 100% (40.8 mmol), and this material was used directly without further purification.

[0459] Preparation 108 (R)-3-Bromo-2-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide

[0460] [ka] To a solution of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide hydrochloride (34.0 g, 59.2 mmol) in DCM (296 mL) was added DIEA (41 mL, 0.24 mol). To this solution was added 3-bromo-2-(2-chloroethyl)-6-fluorobenzoyl chloride (60 mmol as crude mixture prepared in Preparation 107) in portions over 20 minutes. The solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give a thick oil, diluted with EtOAc (700 mL), and diluted with water, 0.1 N HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (46.0 g, 97%) as a light tan foamy solid. ES-MS m / z ( 79 Br / 81 Br, 35 Cl / 37 Cl)764.0 / 766.0(M+H).

[0461] The compounds in the following table were prepared in a similar manner as described in Preparation 108, using the appropriate primary amine and either TEA or DIEA as the base in a suitable solvent such as DCM, THF, or DMA. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0462] [Table 19-1]

[0463] [Table 19-2]

[0464] [Table 19-3]

[0465] Preparation 123 (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0466] [ka] To a solution of (R)-3-bromo-2-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (46.0 g, 57.1 mmol) in ACN (350 mL) was added cesium carbonate (56.0 g, 172 mmol) and stirred at 40° C. for 18 h, then diluted with EtOAc (500 mL) and washed with water (1.5 L). The aqueous phase was then extracted with EtOAc (300 mL), and the two organic phases were combined and then washed sequentially with water (500 mL) and saturated aqueous NaCl (500 mL). 1N HCl (100 mL) was added to the organics, and the mixture was shaken in a separatory funnel for 2 minutes. The organics were separated, washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel eluting with 50-100% EtOAc in cyclohexane followed by 5% MeOH in EtOAc to give the title compound (33.0 g, 79%) as a white foamy solid. ES-MS m / z ( 79 Br / 81 Br)728.2 / 730.2(M+H).

[0467] The compounds in the following table were prepared in a manner similar to that described in Preparation 123, using the appropriate secondary amide and either potassium carbonate or cesium carbonate in a suitable solvent such as NMP, ACN, DMF, DMA, or THF. Reactions were carried out at temperatures ranging from ambient to 70°C for durations ranging from 1 to 18 hours. Aqueous 1N HCl washing of the organics can reduce certain impurities but is not necessary for the preparation. Reactants can be added in different orders or in different equivalent amounts, and purification methods were adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0468] [Table 20-1]

[0469] [Table 20-2]

[0470] [Table 20-3]

[0471] Preparation 138 (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(8-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0472] [ka] To a mixture of (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide (1.5 g, 2.1 mmol), bis(pinacolato)diboron (1.0 g, 4.1 mmol), KOAc (0.61 g, 6.2 mmol), and Pd(dppf)Cl.CH.sub.2Cl.sub.2 (0.17 g, 0.21 mmol) under a N.sub.2 atmosphere, 1,4-dioxane (10 mL) was added. A long needle was inserted below the surface of the mixture, and N2 gas was bubbled through the mixture for 5 minutes. The mixture was then heated to 100 °C for 1 hour, diluted with DCM, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel (80-100% EtOAc in cyclohexane). The residue was triturated with EtOAc and cyclohexane to give an oily solid, which was diluted with DCM (20 mL) and concentrated under reduced pressure to give a tan foamy solid. ES-MS m / z 776.6 (M+H).

[0473] The compounds in the following table were prepared in a similar manner as described in Preparation 138, using the appropriate aryl halide. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0474] [Table 21-1]

[0475] [Table 21-2]

[0476] Preparation 144 (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid

[0477] [ka] To a mixture of (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide (1.4 g, 1.6 mmol) in MeOH (24 mL) was added hypodiboric acid (1.4 g, 16 mmol), a solution of XPhos Pd G3 (0.26 g, 0.31 mmol) in DCE (2.4 mL), and KOAc (0.61 g, 6.2 mmol). The reaction was stirred at 40° C. under a N atmosphere for 16 hours. The reaction was cooled to room temperature and filtered. The filtrate was adjusted to approximately pH 7 with FA and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-5% MeOH in DCM (containing 0.5% FA) to give the title compound as a yellow solid (830 mg, 72%). ES-MS m / z 694.2 (M+H).

[0478] The compounds in the following table were prepared in a manner similar to that described in Preparation 144, using the appropriate aryl halide. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0479] [Table 22-1]

[0480] [Table 22-2] a. Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.1 equiv.) was used as a catalyst along with ethylene glycol (4 equiv.); KOAc (3.5 equiv.) was used as a base. MeOH was used as a solvent, and the reaction was heated to 40° C. for 16 h.

[0481] Preparation 155 (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid

[0482] [ka] A 20 mL vial containing a stir bar was sequentially charged with (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)propanamide (280 mg, 375 μmol), bis(pinacolato)diborane (191 mg, 752 μmol), KOAc (110 mg, 1.12 mmol), and Pd(dppf)Cl₂·CHCl₂ (31 mg, 0.10 equiv., 38 μmol). The reaction mixture was evacuated and backfilled with N2 three times, then 1,4-dioxane (5 mL) was added. The reaction mixture was stirred at 100 °C for 1 h, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (100 g C18 column, Solvent A = 10 mM ammonium bicarbonate with 5% MeOH in HO, Solvent B = ACN, gradient 50-70% B) to afford the title compound (75.1 mg, 81% purity, 23% yield) as a light brown solid. ES-MS m / z 712.4 (M+H).

[0483] Preparation 156 (2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(8-fluoro-5-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0484] [ka] (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl in 1,4-dioxane (5 mL), EtOH (5 mL) and water (0.5 mL). To a solution of (2H-methyl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (135 mg, 183 μmol) at 20 °C was added 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (68.7 mg, 220 μmol), sodium carbonate (58.2 mg, 39.5 μL, 549 μmol), and XPhos Pd G3 (31.0 mg, 36.6 μmol). The mixture was purged with N2 three times and then stirred at 90 °C under N2 for 16 h. The reaction mixture was then filtered and concentrated. The residue was purified on silica gel eluting with 0–5% MeOH in DCM to give the title compound (138 mg, 0.14 mmol, 77% yield, 89% purity) as a brown solid. ES-MS m / z 869.9(M+H).

[0485] The compounds in the following table were prepared in a manner similar to that described in Preparation 156, using the appropriate aryl halide and boronic acid. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0486] [Table 23-1]

[0487] [Table 23-2]

[0488] [Table 23-3]

[0489] [Table 23-4]

[0490] [Table 23-5] a. Pd(dppf)Cl2, potassium carbonate, 1,4-dioxane / water, 80°C, 16 hours b. From the appropriate boronic acid ester, mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II), potassium carbonate, dioxane / water, 100°C, 12 hours

[0491] Preparation 172 (2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid

[0492] [ka] To a solution of (R)-(8-fluoro-2-(1-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (500 mg, 87 wt%, 1.16 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 5-chloro-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazole-6-carbonitrile (455 mg, 80% pure, 1.39 mmol), potassium carbonate (481 mg, 204 μL, 3.48 mmol), and mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (169 mg, 0.2 equiv., 232 μmol) were added. The solution was stirred at 100° C. under N for 12 h. The solution was then cooled to 25° C. and treated with LiOH (2 mL, 1 M aqueous, 2 mmol). After stirring at 25° C. for 4 h, the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (15 mL×3). The aqueous layer was separated and acidified to pH 4 with 1 N HCl, and the mixture was then extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The reaction mixture was purified on silica gel (0-7% MeOH in DCM gradient) to give the title compound (440 mg, 64% yield, 91% purity) as a yellow solid. ES-MS m / z 543.2 (M+H).

[0493] Preparation 173 (R)-2-(5-(6-cyano-1-methyl-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid

[0494] [ka] To a solution of methyl (R)-2-(5-(6-cyano-1-methyl-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoate (100 mg, 93% purity, 191 μmol) in THF (2 mL) was added 1N LiOH (382 μL, 1M aqueous, 382 μmol). The reaction mixture was stirred at 25 °C for 1 h, then adjusted to pH 4 by adding 1M HCl (aqueous), diluted with HO (4 mL), and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (90 mg, 88% purity, 88% yield) as a pale yellow solid. ES-MS m / z 473.0 (M+H).

[0495] Preparation 174 (2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(1-(4-fluorophenyl)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide

[0496] [ka] To a mixture of (2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (200 mg, 91% purity, 335 μmol), diethyl (4-oxo-1,2,3-benzotriazin-3-yl)phosphate (200 mg, 668 μmol) and NaHCO (200 mg, 2.38 mmol) in DMF (5 mL) was added 3-(2-amino-1-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5(4H)-one hydrochloride (130 mg, 70% purity, 300 μmol) at 0 °C. The reaction mixture was stirred at 15° C. for 2 hours under N. Then, 3-(2-amino-1-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5(4H)-one hydrochloride (130 mg, 80% purity, 342 μmol) and diethyl (4-oxo-1,2,3-benzotriazin-3-yl)phosphate (150 mg, 501 μmol) were added, and the reaction mixture was stirred at 15° C. for 16 hours under N. The reaction mixture was then adjusted to pH 7 with 1 N HCl (aq), diluted with HO (10 mL), and extracted with EtOAc (15 mL×2). The combined organic layers were washed with saturated aqueous NaCl (15 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel (0-80% EtOAc in DCM gradient) to give the title compound (180 mg, 52% yield, 76% purity) as a colorless solid. ES-MS m / z 792.1 (M+H).

[0497] Preparation 175 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoic acid

[0498] [ka] To a solution of methyl 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoate (660 mg, 91 wt%, 801 μmol) in ACN (20 mL) and water (2 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (563 mg, 4.00 mmol). The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was then diluted with HO (20 mL) and acidified to pH 5 with 1 N HCl (aq), and the mixture was then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (599 mg, 94% yield, 92% purity) as a brown solid. ES-MS m / z 736.4 (M+H).

[0499] The compounds with carboxylic acids in the table below were prepared from the appropriate carboxylic acid esters in a manner similar to that described in Preparation 175. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0500] [Table 24]

[0501] Example 162 Methyl 3-((R)-2-(5-(6-cyano-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoate hydrochloride

[0502] [ka] To a solution of methyl 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-3-methyl-2-(3-(trifluoromethyl)phenyl)butanoate (320 mg, 92 wt%, 368 μmol) in MeOH (5 mL) was added 2 M hydrogen chloride in MeOH (3.67 g, 4.00 mL, 8.00 mmol) at 25° C. The mixture was stirred at 25° C. for 12 hours. The mixture was then concentrated under reduced pressure to provide the title compound (292 mg, 95%, 90% pure) as a yellow solid. ES-MS m / z 738.2 (M+Na).

[0503] The compounds in the following table were prepared from THP-protected compounds in a manner similar to that described in Example 162. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to one skilled in the art.

[0504] [Table 25]

[0505] The compounds with carboxylic acids in the table below were prepared from the appropriate carboxylic acid esters in a manner similar to that described in Preparation 175. Reactants may be added in a different order or in different equivalent amounts, and purification methods adjusted to suit the compound. Such variations will be apparent to those skilled in the art.

[0506] [Table 26]

[0507] Preparation 183 2-Morpholinoethyl 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoate

[0508] [ka] A mixture of 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoic acid (150.0 mg, 187.6 μmol, 92% purity), DCC (78.2 mg, 375 μmol), and 1H-benzo[d][1,2,3]triazol-1-ol (51.2 mg, 375 μmol) in THF (5 mL) was stirred at 20° C. for 30 minutes. 2-Morpholinoethan-1-ol (62.1 mg, 469 μmol) was then added, and the mixture was stirred at 20° C. for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-5% MeOH in DCM to give the title compound (96.3 mg, 57%) as a white solid. ES-MS m / z 849.5 (M+H).

[0509] Preparation 184 1-(Propionyloxy)ethyl 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoate

[0510] [ka] To a solution of 1-chloroethyl propionate (200 mg, 1.24 mmol) and 3-((2R)-2-(5-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-(4-fluorophenyl)-3-methylbutanoic acid (100 mg, 125 μmol) in acetone (2 mL) was added KCO (50 mg, 0.36 mmol) and potassium iodide (50 mg, 0.30 mmol). The mixture was stirred at 40° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with 10:1 DCM / MeOH to give (R f =0.6), the title compound (68 mg, 61% yield, 93% purity) was obtained as a yellow solid. ES-MS m / z 858.3 (M+Na).

[0511] Preparation 185 6-Bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0512] [ka] The following procedure was carried out in 14 reactions run in parallel at the scale described herein. A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (500 g, 2.52 mol) and K2CO3 (523 g, 3.79 mol) in DMF (3.50 L) was degassed and purged with N2 three times. To the mixture was slowly added iodomethane (430 g, 3.03 mol) at 25-35 °C. The mixture was stirred under a N2 atmosphere at 25 °C for 6 h.

[0513] The two reactions were combined for workup. The reaction mixture was quenched with HO (21.0 L) at 0-5°C and extracted with EtOAc (1.00 L x 6). The combined organic layer was washed with saturated aqueous NaCl (6.00 L x 2), and then the organic layer was concentrated under reduced pressure.

[0514] All 14 reactions were combined for purification. The product from the aqueous workup was purified on silica gel eluting with 5-11% EtOAc in petroleum ether and then triturated with MTBE (3.50 L) at 25° C. for 1 h. The solid was collected by filtration and dried under reduced pressure to give the title compound (3.51 kg, 47%) as a yellow solid. ES-MS m / z 212 (M+H).

[0515] Preparation 186 1-Methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0516] [ka] The following procedure was carried out in four reactions run in parallel at the scale described herein. A mixture of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (104 g, 490 mmol), Pd(PPh) (113 g, 98.0 mmol), and Zn(CN) (85.5 g, 728 mmol) in DMF (1.04 L) was degassed and purged with N three times. The mixture was stirred at 120 °C under N for 12 h.

[0517] The four reactions were combined for workup. The combined reaction mixture was filtered, water (12.0 L) was added to the filtrate, and the mixture was extracted with EtOAc (3.20 L x 5). The combined organic layers were washed with saturated aqueous NaCl (1.00 L), and the organic layer was concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-100% EtOAc in petroleum ether to give the title compound (300 g, 89% yield) as a white solid. ES-MS m / z 159 (M+H).

[0518] Preparation 187 6-cyano-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

[0519] [ka] The following procedure was carried out in three reactions run in parallel at the scale described herein. A mixture of 1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (100 g, 632 mmol), methyltrioxorhenium (15.8 g, 63.2 mmol), and HO (30 wt% aqueous solution, 361 g, 3.19 mol, 306 mL) in DCM (1.00 L) was degassed and purged with N three times. The mixture was stirred under N at 45 °C for 48 h.

[0520] The three reactions were combined for workup. MnO (10 wt%, 30 g) and H O (900 mL) were added to the combined reaction mixture at 45 °C under N, and the resulting mixture was stirred at 40-45 °C for 30 min. The mixture was filtered, and the filter cake was washed with DCM (600 mL) to give a mixture of the title compound and MnO as a gray solid (300 g). TLC (EtOAc) R f= 0.3 The mixture was used without further purification.

[0521] Preparation 188 5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0522] [ka] Three reactions were carried out in parallel at the scale described herein. To a solution of 6-cyano-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide (100 g, 574 mmol) and DIEA (111 g, 861 mmol, 150 mL) in DCM (1.00 L) was added oxalyl chloride (87.4 g, 689 mmol) dropwise over 1 h at 0 °C. The resulting mixture was stirred at 0–20 °C for 6 h.

[0523] The three reactions were combined for workup. The combined reaction mixture was quenched with water (900 mL) and extracted with DCM (600 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (900 mL), and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified on silica gel eluting with 25-100% EtOAc in petroleum ether to give the title compound (200 g, 60% yield) as an off-white solid. ES-MS m / z 193 (M+H).

[0524] Preparation 189 3,5-Dichloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0525] [ka] A mixture of 5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (1.0 g, 5.2 mmol), NCS (0.83 g, 6.2 mmol), and DMF (10 mL) was heated to 50° C. under a nitrogen atmosphere for 25 hours. Additional NCS (350 mg, 2.6 mmol) was added, and the mixture was heated to 50° C. for 23 hours. The mixture was then diluted with water (20 mL), heated to reflux for 1 minute, then cooled to room temperature, and filtered. The resulting solid was dissolved in MeOH (40 mL) under reflux and then cooled to room temperature. High vacuum filtration afforded the title compound (800 mg, 68% yield) as a white solid. ES-MS m / z 227 (M+H).

[0526] Preparation 190 5-chloro-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0527] [ka] A mixture of 5-chloro-1-methyl-1H-pyrazole[4,3-b]pyridine-6-nitrile (7.70 g, 40.0 mmol), ACN (72.0 mL), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (28.3 g, 79.9 mmol) was heated to 100 °C for 20 h in a 500 mL pressure vessel. The mixture was diluted with water (500 mL) and saturated aqueous K2CO3 to a pH of approximately 8, forming a precipitate. The solid was collected by vacuum filtration, and the solid and filtrate were then combined and diluted with EtOAc. The resulting solution was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse-phase HPLC using a gradient of 18-45% ACN in aqueous NH4HCO3, and the product was triturated with DCM and cyclohexane to give the title compound (2.24 g, 27% yield) as a pale yellow solid. ES-MS m / z 211 (M+H).

[0528] Preparation 191 5-Bromo-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0529] [ka] A mixture of 5-bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridine (1.95 g, 80 wt%, 7.22 mmol) in DMF (20 mL) was purged with N three times, and then 60% NaH in mineral oil (347 mg, 60 wt%, 8.67 mmol) was added to the mixture at 0 °C. The mixture was stirred under N at 0 °C for 30 min, and then iodomethane (1.55 g, 708 μL, 10.8 mmol) was added. The mixture was stirred under N at 0 °C for 1 h, then poured into H O (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with saturated aqueous NaCl (60 mL × 3), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 6-7% EtOAc in 4:1 hexanes:DCM to give the title compound (746 mg, 44% yield) as a yellow solid. ES-MS m / z 230, 232 (M+H).

[0530] Preparation 192 5-Bromo-3-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0531] [ka] To a solution of 5-bromo-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg, 426 μmol) in ACN (1 mL) was added NCS (60 mg, 1.1 equiv., 0.45 mmol). The reaction mixture was stirred at 50° C. for 3 h, then diluted with water (5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by preparative TLC (1:3 EtOAc / hexane, R f =0.6) to give the title compound (104 mg, 90% yield) as a white solid. ES-MS m / z 264,266 (M+H).

[0532] Preparation 193 5-Bromo-3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0533] [ka] Three reactions were carried out in parallel at the scale described herein. A mixture of 5-bromo-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (900 mg, 3.87 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (4.16 g, 11.6 mmol) in ACN (12 mL) was degassed with N. The mixture was stirred at 100 °C for 16 h. The mixture was diluted with HO (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure.

[0534] The residues from the three reactions were combined and purified on silica gel eluting with 0-3% EtOAc in 4:1 hexane / DCM, then repurified by reverse-phase preparative HPLC [Column: Welch Xtimate C18; Mobile phase: Gradient of 20%-60% ACN in water (containing 0.225% FA)] to give the title compound (1.41 g, 49% yield) as a white solid. ES-MS m / z 248 (M+H).

[0535] Preparation 194 5-chloro-3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0536] [ka] A mixture of 5-chloro-6-fluoro-1-methyl-1H-pyrazole[4,3-b]pyridine (1.60 g, 8.62 mmol), ACN (7.18 mL), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15.3 g, 43.2 mmol) was heated to 70 °C for 20 h under N. The mixture was then heated to 90 °C for an additional 6 h. The mixture was diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure. The residue was purified on silica gel eluting with 10-20% EtOAc in cyclohexane to give a white solid. Further purification was performed by reverse-phase flash chromatography on a C-18 column using an ammonium bicarbonate-modified water / ACN solvent system (30-45%) to give a suspension. The solid was collected by vacuum filtration to give the title compound (600 mg, 34% yield) as a white solid. ES-MS m / z 204(M+H).

[0537] Preparation 195 tert-Butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0538] [ka] tert-Butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl) in nitrogen-sparged 1,4-dioxane (314 mL) and nitrogen-sparged water (78.5 mL). A mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (45.0 g, 78.5 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (24.2 g, 110 mmol), K2CO3 (32.5 g, 235 mmol), and Pd(dppf)Cl2 (5.74 g, 7.84 mmol) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The mixture was then partially concentrated under reduced pressure to a volume of 150 mL and partitioned between EtOAc (500 mL) and water (500 mL). Saturated aqueous NaCl (50 mL) was added, and the organic layer was then removed, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-10% MeOH in DCM to give the title compound (48.0 g, 90% purity, 94% yield) as a dark foamy solid. ES-MS m / z 531 (M+H-tBu).

[0539] Preparation 196 (R)-2-Amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide dihydrochloride

[0540] [ka] A solution of tert-butyl (R)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (48.0 g, 73.6 mmol, 90% purity) in 1,4-dioxane (245 mL) was treated with HCl (125 mL of a 4 M solution in 1,4-dioxane, 500 mmol) and stirred at 35 °C under a nitrogen atmosphere for 3 h. The mixture was then concentrated to dryness under reduced pressure to give the title compound (44.0 g, 95% purity, 100% yield) as a red powder. ES-MS m / z 487 (M+H).

[0541] Preparation 197 Methyl (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate hydrochloride

[0542] [ka] A solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (39.9 g, 131 mmol) in 2 M HCl in MeOH (392 mL, 784 mmol) was stirred at 25° C. for 16 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was redissolved in a mixture of THF (100 mL) and 1,4-dioxane (100 mL) and concentrated under reduced pressure to give the title compound (35.7 g, 90% purity, 96% yield) as a white solid. ES-MS m / z 220 (M+H).

[0543] Preparation 198 (R)-3-Bromo-2-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide

[0544] [ka] A mixture of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide dihydrochloride (44.0 g, 78.7 mmol) in DCM (393 mL) was cooled in an ice-water bath under nitrogen, and DIEA (54.2 mL, 315 mmol) was added, followed by the dropwise addition of a solution of 3-bromo-2-(2-chloroethyl)-6-fluorobenzoyl chloride (26.0 g, 86.7 mmol) in DCM (100 mL). The ice bath was removed, and the resulting mixture was stirred at room temperature for 30 minutes, then diluted with water (500 mL) and adjusted to pH 3 with 1 N aqueous HCl. Acidification was performed. The layers were separated, and the organic layer was washed with 300 mL of water and 300 mL of saturated aqueous NaHCO, dried over NaSO, and concentrated under reduced pressure to give the title compound as an oil (64.9 g, 99% yield, 90% purity). ES-MS m / z 749,751 (M+H).

[0545] Preparation 199 (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0546] [ka] A mixture of (R)-3-bromo-2-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (64.9 g, 7.9 mmol, 90% pure), ACN (195 mL), and CsCO (63.4 g, 195 mmol) was stirred under nitrogen at 30 °C for 21 h, concentrated under reduced pressure to a total volume of 50 mL, diluted with EtOAc (700 mL), and washed with water (1 L). The organics were then shaken with 1 N aqueous HCl (1 L) in a separatory funnel for 2 min, and the aqueous layer was removed. The organic layer was washed with half-saturated aqueous NaHCO, dried over NaSO, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 40-80% EtOAc in cyclohexane to give the title compound as a tan foam (49.9 g, 90%). ES-MS m / z 713,715 (M+H).

[0547] Preparation 200 (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(8-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0548] [ka] In an N2-filled glovebox, (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide (600 mg, 799 μmol, 95% purity), 4,4,4′,4′ ,5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.62 g, 6.39 mmol), potassium acetate (235 mg, 2.40 mmol), and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (69.9 mg, 79.9 μmol) were added to a dry reaction vial, followed by DMF (20 mL). The vial was sealed, removed from the glove box, and stirred at 100 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with water (30 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica using a gradient of 0-100% EtOAc in hexanes to give the title compound (486 mg, 76%, 95% purity) as a brown oil. ES-MS m / z 761 (M+H).

[0549] Preparation 201 Methyl (R)-2-(3-bromo-2-(2-chloroethyl)-6-fluorobenzamido)-3-(1-difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0550] [ka] To a mixture of methyl (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate hydrochloride (29 g, 0.10 mol, 90% purity) and TEA (0.14 L, 1.0 mol) in THF (260 mL) was added a solution of 3-bromo-2-(2-chloroethyl)-6-fluorobenzoyl chloride (53 g, 0.14 mol, 81% purity) in THF (150 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h, diluted with water (400 mL), and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (200 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel with a gradient of 0 to 25% EtOAc in hexane to give the title compound (47.48 g, 92%, 96% purity) as a yellow solid. ES-MS m / z 482(M+H).

[0551] Preparation 202 Methyl (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0552] [ka] A mixture of methyl (R)-2-(3-bromo-2-(2-chloroethyl)-6-fluorobenzamido)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (47.48 g, 94.43 mmol, 96% purity), water (0.20 mL, 11 mmol), and cesium carbonate (36.5 g, 112 mmol) in ACN (500 mL) was stirred at 25 °C for 2 hours, filtered, and the filter cake was washed with EtOAc (25 mL × 3). The filtrate was concentrated to remove most of the solvent, diluted with HO (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel with a gradient of 0-40% EtOAc in hexanes to give the title compound (42.45 g, 96%, 95% purity) as a yellow oil. ES-MS m / z 446,448 (M+H).

[0553] Preparation 203 (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methoxy-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid

[0554] [ka] In a N2-filled glovebox, a solution of methyl (R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (11.8 g, 25.1 mmol, 95% purity) in MeOH (210 mL) was treated with hypoboric acid (11.3 g, 126 mmol), a solution of XPhos Pd G3 (2.13 g, 2.51 mmol) in DCE (30 mL), and potassium acetate (7.40 g, 75.4 mmol). The reaction mixture was removed from the glovebox, stirred under N2 at 40 °C for 16 h, filtered, adjusted to pH 7 with formic acid, and concentrated. The residue was purified on silica gel with a gradient of 0-4% MeOH + 0.5% formic acid in DCM to give the title compound (11.9 g, 98%, 85% purity) as a brown oil. ES-MS m / z 412 (M+H).

[0555] Preparation 204 Methyl (R)-2-(5-(3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0556] [ka] A N2-degassed mixture of (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methoxy-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (2.4 g, 5.0 mmol, 85% purity), 5-bromo-3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (1.41 g, 5.63 mmol, 99% purity), sodium carbonate (1.6 g, 15 mmol), and XPhos Pd G3 (0.84 g, 0.99 mmol) in 1,4-dioxane (80 mL) and water (8 mL) was stirred at 90 °C under N2 for 1 h, filtered, and concentrated. The residue was purified on silica gel eluting with a gradient of 0-5% MeOH in DCM to give the title compound (1.83 g, 68%, 98% purity) as a yellow solid. ES-MS m / z 535 (M+H).

[0557] Preparation 205 (R)-2-(5-(3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid

[0558] [ka] To a mixture of methyl (R)-2-(5-(3,6-difluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (1.83 g, 3.36 mmol, 98% purity) in tert-butanol (50 mL) and water (25 mL) was added 1N aqueous LiOH (10.5 mL, 10.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, adjusted to pH 3 with 1N aqueous HCl, diluted with HO (50 mL), and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.9 g, 98%, 90% pure) as a pale yellow solid. ES-MS m / z 521 (M+H).

[0559] Preparation 206 Methyl 3-(2-(diphenylmethylene)hydraziner)-5-fluoropicolinate

[0560] [ka] (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (1.23 g, 2.13 mmol) and toluene (100 mL) were placed in a 250 mL three-neck RBF equipped with a thermocouple, nitrogen inlet, and reflux condenser. The solution was sparged with N for 5 minutes, and diacetoxypalladium (581 mg, 2.59 mmol) was added, with continued sparging. After 5 minutes, methyl-3-bromo-5-fluoropyridine-2-carboxylate (10.0 g, 42.7 mmol) was added, followed by the portionwise addition of (diphenylmethylene)hydrazine (8.33 g, 42.4 mmol) and cesium carbonate (27.8 g, 85.3 mmol). The reaction mixture was stirred at 70 °C under N for 70 min, cooled to room temperature, and filtered through a pad of SiO (120 g), rinsing the pad with EtOAc (800 mL). The filtrate was concentrated, and the resulting yellow solid was suspended in 4:1 heptane:water. It was quenched with EtOAc (100 mL) and stirred at room temperature overnight. The solid was collected by filtration, rinsed with heptane (50 mL), and dried under reduced pressure at 40 °C to give the title compound (14.01 g, 93%) as a light yellow solid. ES-MS m / z 350 (M+H).

[0561] Preparation 207 Methyl 3-(2-(diphenylmethylene)-1-methylhydrazineyl)-5-fluoropicolinate

[0562] [ka] A 500 mL three-neck RBF equipped with a nitrogen inlet, thermocouple, and dropping funnel was charged with a suspension of methyl 3-(2-(diphenylmethylene)hydraziner)-5-fluoropicolinate (14.0 g, 40.1 mmol) in ACN (150 mL). Cesium carbonate (20.01 g, 61.41 mmol) was added in one portion, followed by the dropwise addition of iodomethane (2.75 mL, 44.0 mmol) over 3 minutes. The reaction mixture was stirred at room temperature for 2 hours, then at 35°C overnight, and then at 65°C for 7 hours. A second portion of iodomethane (2.50 mL, 40.0 mmol) was added, and the reaction mixture was stirred at 65°C for 10 hours, cooled to room temperature, and stirred at room temperature overnight. The reaction mixture was then stirred at 65°C for an additional 10 hours, cooled to room temperature, and stirred at room temperature for 2 days. A third portion of iodomethane (650 μL, 10.0 mmol) was added, and the reaction mixture was stirred at 65° C. for 2 h. Cesium carbonate (6.55 g, 20.1 mmol) was added, and the reaction mixture was stirred at room temperature for 80 min, filtered, and rinsed with ACN (50 mL). The filtrate was concentrated, and the residue was diluted with EtOH (100 mL) and stirred at 40° C. for 1 h, then at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography (SiO, gradient 5–20% EtOAc in cyclohexane) to afford the title compound (10.4 g, 71%) as a light orange solid. ES-MS m / z 364 (M+H).

[0563] Preparation 208 6-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-ol 4-methylbenzenesulfonate

[0564] [ka] In a 100 mL three-neck RBF equipped with a nitrogen inlet, reflux condenser, and thermocouple, a suspension of methyl 3-(2-(diphenylmethylene)-1-methylhydrazinel)-5-fluoropicolinate (3.01 g, 93% purity, 7.70 mmol) in EtOH (30 mL) was treated with p-toluenesulfonic acid monohydrate (3.02 g, 15.9 mmol). The reaction mixture was stirred at 80 °C for 12 h and then at room temperature for 2 days. The reaction mixture was filtered, and the solid was rinsed with EtOH (5 mL) and dried under reduced pressure at 40 °C. The filtrate was stirred overnight in an ice-water bath, refiltered, and rinsed with EtOH (5 mL). The solid was dried under reduced pressure at 40 °C and then combined with the first crop to give the title compound (1.31 g, 50%) as a white solid. ES-MS m / z 168.0 (M+H).

[0565] Preparation 209 6-Fluoro-3-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0566] [ka] To a dry 40 mL sealed tube containing a magnetic stir bar and a mixture of 6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-ol 4-methylbenzenesulfonate (600 mg, 1.77 mmol) and K2CO3 (515 mg, 3.73 mmol) in DMA (6 mL) was added MeI (120 μL, 1.92 mmol). The reaction mixture was stirred at 40 °C for 16 h, then diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, 0-40% EtOAc in hexanes gradient) afforded the compound (184 mg, 53%) as a white solid. ES-MS m / z 181.9 (M+H).

[0567] Preparation 210 5-Fluoro-2-methylnicotinonitrile

[0568] [ka] A mixture of 2-chloro-5-fluoronicotinonitrile (1.00 g, 6.39 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 2.20 mL, 7.70 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (472 mg, 645 μmol), and KCO (2.69 g, 19.5 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was evacuated and backfilled with N three times in a dry 100 mL RBF containing a magnetic stir bar. The mixture was stirred under N at 120 °C for 16 h, filtered, and the filtrate was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organics were washed with saturated aqueous NaCl (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, 0-15% EtOAc in hexanes gradient) afforded the compound (481 mg, 47%) as a white solid. ES-MS m / z 137.0 (M+H).

[0569] Preparation 211 6-Methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0570] [ka] To a solution of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (700 mg, 3.30 mmol), cesium carbonate (1.61 g, 4.95 mmol), and tBuXPhos Pd G3 (348 mg, 330 μmol) in toluene (10 mL) was added methanol (1.34 mL, 33.0 mmol). The mixture was evacuated and backfilled with N2 three times, then the mixture was stirred under N2 at 80 °C for 16 h. A separate reaction was set up in the same manner using 300 mg (1.41 mmol) of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine and proportional amounts of the remaining reagents. Upon completion, the reaction mixture was combined and poured into water (20 mL). The aqueous mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-80% EtOAc in hexanes) afforded the compound (755 mg, 94%) as a white solid. ES-MS m / z 164.2 (M+H).

[0571] Preparation 212 6-Methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

[0572] [ka] To a solution of 6-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine (755 mg, 4.44 mmol) in EtOAc (10 mL) was added meta-chloroperoxybenzoic acid (1.15 g, 85 wt%, 5.66 mmol). The mixture was evacuated and backfilled with N three times, then the mixture was stirred under N at 25 °C for 16 h. The reaction mixture was diluted with EtOAc (20 mL), then a solution of saturated aqueous NaHCO (10 mL) and a solution of saturated aqueous NaSO (10 mL) were added, and the mixture was stirred at 25 °C for 30 min. The layers were separated, and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (543 mg, 55%) as a yellow solid. ES-MS m / z 180.1 (M+H).

[0573] The compounds in the following table were prepared in a manner similar to that described in Preparation 212, using the appropriate pyridine or pyridine derivative. Different reaction temperatures, reaction times, charges of meta-chloroperoxybenzoic acid, and purifications can be used. Such variations will be apparent to those skilled in the art.

[0574] [Table 27] a: Column chromatography (SiO2, gradient of 0-60% EtOAc in hexanes) b: DCM used as solvent and for workup. Column chromatography (SiO2, gradient of 0-45% EtOAc in hexanes)

[0575] Preparation 215 5-chloro-6-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0576] [ka] To a mixture of 6-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide (1.21 g, 90 wt%, 6.08 mmol) in ACN (13 mL) was slowly added POCl (2.3 mL, 25 mmol) at 0 °C. The mixture was evacuated and backfilled with N three times, then the mixture was stirred under N at 25 °C for 2 h. The reaction mixture was slowly added to a solution of saturated aqueous NaCO (40 mL), and then the mixture was extracted with EtOAc (70 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, 0–50% EtOAc in hexanes gradient) afforded the compound (772 mg, 61%) as a white solid. ES-MS m / z 198.0 (M+H).

[0577] The compounds in the following table were prepared in a manner similar to that described in Preparation 215, using the appropriate pyridine-N-oxide. Different reaction temperatures, reaction solvents, POCl3 charges, and reaction workups may be used. Such variations will be apparent to those skilled in the art.

[0578] [Table 28] a: DCE used as reaction solvent, DCM used as work-up solvent.

[0579] Preparation 218 3,5-Dichloro-6-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0580] [ka] In a dry 8 mL sealed tube, 5-chloro-6-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg, 95 wt%, 482 μmol) was suspended in ACN (2 mL). NCS (65.2 mg, 483 μmol) was added, and the reaction mixture was stirred at 50 °C for 3 h. An additional portion of NCS (20.3 mg, 151 μmol) was added, and the reaction mixture was stirred at 50 °C for 1 h. The reaction was cooled to room temperature, and then the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, 0–2% methanol in DCM gradient) afforded the compound (106 mg, 85%) as a white solid. ES-MS m / z 231.9 (M+H).

[0581] Preparation 219 5-Bromo-6-fluoro-1-(methyl-d3)-1H-pyrazolo[4,3-b]pyridine

[0582] [ka] To a solution of 5-bromo-6-fluoro-1H-pyrazolo[4,3-b]pyridine (334 mg, 81 wt%, 1.25 mmol) in DMF (3 mL) was added NaH (60.1 mg, 60 wt%, 1.50 mmol) in mineral oil at 0 °C. The reaction mixture was evacuated and backfilled with N2 three times, then stirred at 0 °C for 30 min. To the resulting mixture was added iodomethane-d3 (150 μmol, 2.41 mmol), and the reaction mixture was stirred at 0 °C for 1.5 h to give a white suspension. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, 0–60% EtOAc in hexanes gradient) afforded the compound (207 mg, 64%) as a white solid. ES-MS m / z 232.9 / 234.9 (M+H).

[0583] Preparation 220 6-Bromo-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0584] [ka] To a mixture of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (4.01 g, 18.9 mmol) in ACN (80 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (8.73 g, 24.6 mmol). The mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into water (120 mL) and extracted with EtOAc (120 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified on silica gel eluting with 0-30% EtOAc / hexane to give the title compound (1.9 g, 39%) as an off-white solid. ES-MS m / z 230.0 (M+H).

[0585] The compounds in the following table were prepared in a manner similar to that described in Preparation 220, using the appropriate azaindazole. Different reagent charges, reaction temperatures and times, the presence of acetic acid as an additive, and purification methods can be used. Such variations will be apparent to those skilled in the art.

[0586] [Table 29] a: 9:1 ACN / acetic acid used as solvent. Purified by preparative HPLC: YMC Triart C18 150 * 25mm * 5 μm, Mobile phase: A: H2O (10 mM NH4HCO3); B: ACN, Gradient: 28.00% to 58.00% B in 10.00 min b: Purified by preparative HPLC as above using a gradient B from 34.00% to 64.00%

[0587] Preparation 223 3-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol

[0588] [ka] To a mixture of 6-bromo-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (1.8 g, 88% wt, 6.9 mmol) and KOH (2.37 g, 82% wt, 34.6 mmol) in 1,4-dioxane (18 mL) and water (18 mL) was added tBuXPhos Pd G3 (0.26 g, 0.32 mmol). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL). The pH of the aqueous phase was adjusted to 3 with 1 N HCl (aq), and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (951 mg, 75%) as an off-white solid. ES-MS m / z 168.0(M+H).

[0589] Preparation 224 6-(Difluoromethoxy)-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0590] [ka] To a mixture of 3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol (403 mg, 91% wt, 2.19 mmol) in DMF (10 mL) was added K2CO3 (1.51 g, 10.9 mmol) and sodium chloro(difluoro)acetate (2.03 g, 13.3 mmol). The mixture was stirred at 100 °C for 16 h. K2CO3 (919 mg, 6.65 mmol) and sodium chloro(difluoro)acetate (1.06 g, 6.95 mmol) were added to the mixture at 15 °C, and the mixture was then stirred at 100 °C for 2 h. Additional K2CO3 (912 mg, 6.60 mmol) and sodium chloro(difluoro)acetate (1.01 g, 6.62 mmol) were added to the above mixture at 15 °C, and the mixture was then stirred at 95 °C for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified on silica gel eluting with 0-60% EtOAc / hexane to give the title compound (131 mg, 25%) as a purple solid. ES-MS m / z 218.0 (M+H).

[0591] Preparation 225 6-(Difluoromethoxy)-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

[0592] [ka] To a mixture of 6-(difluoromethoxy)-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine (130 mg, 90% wt, 539 μmol) in EtOAc (3 mL) was added meta-chloroperoxybenzoic acid (133 mg, 85% wt, 655 μmol) at 15° C. The mixture was degassed and refilled with N three times, then the mixture was stirred under a N atmosphere at 15° C. for 16 h. Additional meta-chloroperoxybenzoic acid (216 mg, 85% wt, 1.06 mmol) was added to the mixture, and the mixture was stirred under a N atmosphere at 30° C. for 16 h. Additional meta-chloroperoxybenzoic acid (105 mg, 85% wt, 517 μmol) was added to the mixture, and the mixture was stirred under a N atmosphere at 30° C. for 16 h. The mixture was directly purified without workup by flash silica gel chromatography eluting with 0-80% EtOAc / hexanes to give the title compound (92 mg, 66%) as a pale pink solid. ES-MS m / z 234.0 (M+H).

[0593] Preparation 226 5-chloro-6-(difluoromethoxy)-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine

[0594] [ka] To a mixture of 6-(difluoromethoxy)-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide (92 mg, 90% wt, 0.36 mmol) in ACN (2 mL) was added phosphorus oxychloride (266 mg, 160 μL, 1.74 mmol) at 0 °C. The mixture was degassed and refilled with N three times, and then the mixture was stirred at room temperature for 3 days. The reaction mixture was slowly added to saturated aqueous NaHCO (10 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO and concentrated in vacuo. The resulting residue was purified by SFC [column: Princeton SFC 4-ETH (250 mm × 30 mm, 10 μm); mobile phase: 20% IPA in CO + 0.1% NH OH; flow rate (mL / min): 60] to give the title compound (80 mg, 90%) as a pale yellow solid. ES-MS m / z 252.0(M+H).

[0595] Preparation 227 1-Methyl-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

[0596] [ka] A mixture of 5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (196.5 mg, 1.02 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (71.8 mg, 101 μmol) was placed under an argon atmosphere, and then 1,4-dioxane (10.0 mL) was added, followed by 1,1,1,2,2,2-hexabutyldistannane (770 μL, 1.53 mmol). Stirring was started, and the reaction was heated to 105 °C for 18.1 h. The reaction was then cooled to room temperature and quenched by the addition of 6 mL of 1 M aqueous KF and diluted with saturated aqueous NaCl and EtOAc. The organic layer was removed, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography using a gradient of 0-50% EtOAc in heptane to give the title compound (132.2 mg, 26%) as a yellow oil. ES-MS m / z 449.2 (M+H).

[0597] The compounds in the following table were prepared in a manner similar to that described in Preparation 227, using the appropriate 5-haloazaindazole, but changing the 5-halogen from chloride to bromide. Different reaction times, concentrations, workup, and purifications can be used. Such variations will be apparent to those skilled in the art.

[0598] [Table 30] a. 0.3 M reaction, 16 h reaction time. The crude reaction mixture was concentrated under reduced pressure and directly purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexanes.

[0599] Preparation 229 6-chloro-5-methoxy-2-methylpyridazin-3(2H)-one

[0600] [ka] To a mixture of 5,6-dichloro-2-methylpyridazin-3(2H)-one (9.98 g, 55.8 mmol) in anhydrous MeOH (110 mL) under a N atmosphere was added a solution of sodium methanolate (12.7 mL, 25 wt% in MeOH, 55.5 mmol). The reaction vessel was fitted with a reflux condenser and stirred at 50° C. for 90 minutes, after which it was cooled to room temperature and concentrated under reduced pressure. The resulting residue was washed with water, and the solid was collected by filtration. The filter cake was washed with hexane, then collected and lyophilized to give the title compound (8.65 g, 89%) as a white solid. ES-MS m / z 174.8 (M+H).

[0601] Preparation 230 5,6-Dichloro-2-methoxynicotinonitrile

[0602] [ka] To a solution of 6-chloro-2-methoxypyridine-3-carbonitrile (498 mg, 2.95 mmol) in ethyl acetate (10 mL) was added NCS (1.6 g, 12 mmol) at 25 °C. The mixture was then heated to 120 °C and stirred for 16 h, after which it was cooled to room temperature and quenched by the addition of saturated aqueous Na2CO3 (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0–13% EtOAc in hexanes, followed by preparative HPLC (F-Welch Xtimate C18 40 * Purification by 200 mm 7 μm; mobile phase: [A: HO (0.225% HCOH); B: MeOH]; 28-68% B, 20.00 min; flow rate: 60.00 ml / min) and lyophilization gave the title compound (162 mg, 27%) as a white solid. NMR: 1 H NMR(DMSO-d6)δ 8.71(s,1H),4.00(s,3H).

[0603] Preparation 231 2-Chloro-6-methylpyridine-3,5-dicarbonitrile

[0604] [ka] To a solution of 5-bromo-2-chloro-6-methylnicotinonitrile (200 mg, 864 μmol), trimethylsilyl cyanide (0.23 mL, 1.73 mmol), and zinc fluoride (53.6 mg, 518 μmol) in DMA (10 mL) was added XantPhos-Pd-G2 (154 mg, 173 μmol). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C under a N2 atmosphere for 16 h. The reaction mixture was then diluted with H2O (30 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0–20% EtOAc in hexanes to give the title compound (112 mg, 69%) as a yellow solid. NMR: 1 H NMR(DMSO-d6)δ 9.18(s,1H),2.61(s,3H).

[0605] Preparation 232 1-(Bromodifluoromethyl)-5-chloro-4-methoxypyridin-2(1H)-one

[0606] [ka] To a solution of 5-chloro-4-methoxypyridin-2(1H)-one (250 mg, 1.57 mmol) in DMF (4 mL) in a sealed tube cooled to 0 °C was added sodium hydride (125 mg, 3.13 mmol of a 60 wt% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h. Dibromodifluoromethane (1.41 mL, 15.7 mmol) was then added, and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with EtOAc (30 mL) and washed with water (3 × 30 mL). The organic layer was dried over NaSO, filtered, concentrated under reduced pressure, and then purified by silica gel chromatography using a gradient of 0 to 25% EtOAc in hexanes to give the title compound (47 mg, 10%). ES-MS m / z 287.9, 289.9, 291.9 (M+H).

[0607] Preparation 233 5-chloro-4-methoxy-1-(trifluoromethyl)pyridin-2(1H)-one

[0608] [ka] To a solution of 1-(bromodifluoromethyl)-5-chloro-4-methoxypyridin-2(1H)-one (47 mg, 96% wt, 0.16 mmol) in DCM (1.5 mL) was added silver(I) tetrafluoroborate (33 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then diluted with DCM (5 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (1:1 hexane / EtOAc, rf=0.5) to give the title compound (20 mg, 52%) as a white solid. ES / MS m / z 228.0 / 230.0 (M+H)

[0609] Preparation 234 Methyl 2-bromo-6-methylimidazo[2,1-b]thiazole-3-carboxylate

[0610] [ka] A mixture of 2-amino-5-bromo-thiazole-4-carboxylic acid methyl ester (1.00 g, 4.23 mmol), ethanol (20 mL), and bromoacetone (588 mg, 360 μL, 4.29 mmol) was heated to 100° C. overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in EtOAc and poured into saturated aqueous NaHCO. The layers were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 0-100% EtOAc / heptane) to afford the title compound (81.8 mg, 6.5%) as a yellow solid. ES / MS m / z 273.2 / 275.0 (M+H)

[0611] Preparation 235 2-Bromo-6-methylimidazo[2,1-b]thiazole-3-carboxamide

[0612] [ka] A mixture of methyl 2-bromo-6-methylimidazo[2,1-b]thiazole-3-carboxylate (81.8 mg, 297 μmol) and ammonia in methanol (7 M, 1 mL) was heated to 50° C. for 15 hours. After 15 hours, the heat was removed and the reaction was stirred at room temperature for approximately 48 hours. A mixture of DCM and MeOH was added and the reaction was concentrated under reduced pressure to give the title compound (64.5 mg, 75%). ES / MS m / z 260.0 / 262.0 (M+H).

[0613] Preparation 236 2-Bromo-6-methylimidazo[2,1-b]thiazole-3-carbonitrile

[0614] [ka] To a mixture of 2-bromo-6-methylimidazo[2,1-b]thiazole-3-carboxamide (64.5 mg, 248 μmol) in DCM (3 mL) was added TEA (65 mg, 90 μL, 0.65 mmol). The reaction was cooled to 0 °C, and then trifluoroacetic anhydride (75 mg, 50 μL, 0.36 mmol) was added. After 5 min, the ice bath was removed, and the reaction was stirred at room temperature for 30 min. The reaction was quenched by the addition of MeOH and concentrated under reduced pressure. The crude mixture was redissolved in EtOAc and washed with saturated aqueous NH 4 Cl, followed by saturated aqueous NaHCO 3 . The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The solid residue was triturated with MeOH and filtered. The MeOH filtrate was removed, and then the solid was dissolved in EtOAc. The EtOAc filtrate was concentrated under reduced pressure to give the title compound (33.7 mg, 53%) as a white solid. ES / MS m / z 242.0 / 244.0(M+H)

[0615] Preparation 237 1-Cyclopropyl-4-iodopyridin-2(1H)-one

[0616] [ka] A mixture of 4-iodopyridin-2(1H)-one (8.0 g, 36 mmol), copper diacetate (6.98 g, 1.6 mL, 38.4 mmol), 2,2'-bipyridine (6.0 g, 5.1 mL, 38 mmol), cyclopropylboronic acid (7.0 g, 2.81 mmol), and sodium carbonate (8.7 g, 5.9 mL, 82 mmol) in 1,2-DCE (240 mL) was heated to 70 °C under air for 15 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl, and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient 0-100% EtOAc / CHX, followed by gradient 0-50% MeOH / DCM) to give the title compound (1.05 g, 9.4%) as a yellow oil. ES / MS m / z 261.6(M+H)

[0617] Preparation 238 5-Bromo-1-(methyl-d3)pyridin-2(1H)-one

[0618] [ka] To a solution of 5-bromo-1H-pyridin-2-one (2.0 g, 11 mmol) in DMF (20 mL) at 0 °C was added 60% NaH in mineral oil (673 mg, 60 wt%, 16.8 mmol). The reaction mixture was degassed and refilled with N2 three times. After stirring at 0 °C for 0.5 h, iodomethane-d3 (4.4 g, 1.9 mL, 2.7 equiv, 31 mmol) was added in one portion, and the reaction mixture was then stirred at 0 °C for 1.5 h to give a white suspension. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0-4% methanol / dichloromethane gradient elution) to give the title compound (1.68 g, 69%) as a yellow oil. ES / MS m / z: ( 79 Br / 81 Br) 190.9, 192.9 (M+H).

[0619] Preparation 239 1-(5-Bromopyrimidin-2-yl)-N,N-dimethylmethanamine

[0620] [ka] To a mixture of 5-bromo-2-(bromomethyl)pyrimidine (500 mg, 1.98 mmol) in THF (5 mL) was added 40% dimethylamine in water (1.12 g, 2.00 mmol). The reaction mixture was stirred at 24° C. for 12 hours, then quenched by adding 2M NaOH (aqueous) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with saturated aqueous NaCl (20 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (334 mg, 74%) was obtained as a yellow solid. ES / MS m / z:(79 Br / 81 Br) 215.8, 217.8 (M+H).

[0621] Preparation 240 4-Bromo-1-(difluoromethyl)pyridin-2(1H)-one

[0622] [ka] To a mixture of 4-bromopyridin-2(1H)-one (2.10 g, 12.1 mmol) in DMF (50 mL) was added sodium chloro(difluoro)acetate (3.8 g, 25 mmol) and CsCO (7.6 g, 23 mmol). The reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (200 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-12% EtOAc / hexane gradient elution) to give the title compound (385 mg, 14%) as a colorless oil. ES / MS m / z: ( 79 Br / 81 Br) 223.8, 225.9 (M+H).

[0623] Preparation 241 3-Benzoyl-1-cyclopropylpyrimidine-2,4(1H,3H)-dione

[0624] [ka] To a solution of 3-benzoylpyrimidine-2,4(1H,3H)-dione (24.1 g, 90% wt, 100 mmol) and cyclopropylboronic acid (21.1 g, 246 mmol) in 1,2-dichloroethane (450 mL) was added copper(II) acetate (17.9 g, 98.6 mmol), 2,2′-bipyridine (16.1 g, 103 mmol), and sodium carbonate (22 g, 0.21 mol) at 20° C. The reaction mixture was degassed and refilled with O 3 three times at 20° C. The mixture was then stirred under O 2 (15 psi) at 75° C. for 16 h. The mixture was cooled to room temperature, and EtOAc (500 mL) was added, followed by filtration through a pad of diatomaceous earth, washing with EtOAc (400 mL). The filtrate was concentrated under reduced pressure to give a residue as a green oil. The residue was triturated with EtOAc / MeOH / hexane (v:v:v=1:1:1, 150 mL) at 20° C. for 0.5 h. The mixture was filtered to obtain a cake, and the filter cake was then dried under reduced pressure to give the title compound (4.5 g, 9.1%) as a light green solid. ES / MS m / z: 257.0 (M+H).

[0625] Preparation 242 4-chloro-1-cyclopropylpyrimidin-2(1H)-one

[0626] [ka] A suspension of 3-benzoyl-1-cyclopropylpyrimidine-2,4(1H,3H)-dione (1.49 g, 90% wt, 5.23 mmol) in phosphoryl trichloride (20 g, 12 mL, 0.13 mol) was degassed and purged with nitrogen three times at 20° C. The reaction mixture was stirred at 70° C. under a nitrogen atmosphere for 16 hours. After completion, the mixture was cooled to room temperature and concentrated under reduced pressure to give a dark oil. The crude residue was then diluted with DCM (30 mL) and slowly added to ice-cold saturated aqueous sodium bicarbonate solution (40 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown solid. The resulting solid was triturated with a DCM / hexane mixture (1:10 v / v, 20 mL) at 20° C. for 30 minutes. The mixture was then filtered to give a solid cake which was then dried under reduced pressure to give the title compound as a yellow solid (465 mg, 42%). ES / MS m / z: 79 Br / 81 Br 170.9 / 172.9(M+H).

[0627] Preparation 243 4-Bromo-1-cyclopropylpyridin-2(1H)-one

[0628] [ka] To a solution of 4-bromopyridin-2(1H)-one (10.0 g, 56.5 mmol) in DCE (150 mL) was added cyclopropylboronic acid (9.81 mg, 113 mmol), 4A molecular sieves (5 g), and Na2CO3 (12.3 g, 114 mmol). The reaction mixture was stirred at 25 °C for 5 min. A suspension of copper diacetate (10.4 g, 56.6 mmol) and 2,2'-bipyridine (8.93 g, 56.6 mmol) in DCE (100 mL) was heated to 50 °C, and the hot suspension was added to the above reaction mixture. The reaction mixture was evacuated and backfilled with O2 three times, then stirred at 70 °C under O2 (15 psi) for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (50 mL × 3). The filtrate was concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-35% EtOAc in hexanes) afforded the compound (9.17 g, 64%) as a white solid. ES-MS m / z 213.9 / 215.9 (M+H).

[0629] Preparation 244 (1-Cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid

[0630] [ka] To a mixture of 4-bromo-1-cyclopropylpyridin-2(1H)-one (1.98 g, 85% purity, 7.86 mmol) and bis(pinacolato)diborane (2.64 g, 10.3 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (2.36 g, 23.8 mmol) and PdCl(dppf) (602.3 mg, 814.9 μmol). The mixture was degassed and purged with N (3×). The resulting mixture was gradually heated to 100° C. and stirred at 100° C. under N for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×20 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (Welch Xtimate® C18, 40 × 200 mm, 7 μm, gradient 0 to 20% ACN in 0.225% aqueous FA) to give the title compound (515 mg, 35%) as a pink solid. ES-MS m / z 180.0 (M+H).

[0631] Preparation 245 3-Acetyl-1-methylpyrrolidin-2-one (racemic mixture)

[0632] [ka] A solution of 1-methylpyrrolidin-2-one (50.0 g, 504 mmol) in THF (400 mL) was degassed and purged with N (3x). The solution was cooled to -78 °C, and lithium diisopropylamide (2.0 M in THF, 280 mL, 560 mmol) was added dropwise over 60 min. The reaction mixture was stirred at -78 °C for 2 h, then methyl acetate (80 mL, 1000 mmol) was added dropwise at -78 °C. The resulting mixture was allowed to warm to 20 °C and stirred for 16 h. The reaction mixture was treated with 1 N aqueous HCl (1000 mL) and extracted with 10:1 DCM:MeOH (3 x 500 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-4% MeOH in DCM to give the title compound (44.3 g, 59%) as a yellow solid. ES-MS m / z 142.1(M+H).

[0633] Preparation 246 4,4,4-trifluoro-1-(1-methyl-2-oxopyrrolidin-3-yl)butane-1,3-dione (racemic mixture)

[0634] [ka] A solution of 3-acetyl-1-methylpyrrolidin-2-one (racemic mixture) (20.3 g, 95% purity, 137 mmol) in THF (300 mL) was degassed and purged with N (3x). The solution was cooled to 0 °C, and lithium diisopropylamide (2.0 M in THF, 200 mL, 400 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. The mixture was then cooled to -78 °C, and ethyl 2,2,2-trifluoroacetate (21 mL, 180 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 1 h. The mixture was diluted with MeOH (300 mL) and concentrated under reduced pressure. The residue was purified on silica eluting with 0-4% MeOH in DCM to give the title compound (27.1 g, 79%) as a yellow solid. ES-MS m / z 238.2 (M+H).

[0635] Preparation 247 3-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1-methylpyrrolidin-2-one (racemic mixture)

[0636] [ka] A mixture of 4,4,4-trifluoro-1-(1-methyl-2-oxopyrrolidin-3-yl)butane-1,3-dione (racemic mixture) (900 mg, 95% purity, 3.60 mmol), 1-hydraziner-2-methylpropan-2-amine trihydrochloride (965 mg, 90% purity, 4.09 mmol), and TEA (2.1 mL, 15 mmol) in EtOH (15 mL) was stirred at 80 °C for a total of 32 h. The reaction mixture was directly purified by reverse-phase preparative HPLC (Welch Xtimate® C18, 40 × 200 mm, 7 μm, gradient 10–50% ACN in 10 mM aqueous NH4HCO3 containing 0.05% NH4OH) to give the title compound (160 mg, 15%) as a yellow oil. ES-MS m / z 305.1 (M+H).

[0637] Preparation 248 tert-Butyl (2-methyl-1-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0638] [ka] To a solution of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.80 kg, 15.1 mol) in DMF (26.6 L) was added CsCO (8.21 kg, 25.2 mol) and 3-(trifluoromethyl)-1H-pyrazole (1.71 kg, 12.6 mol). The mixture was stirred at 75 °C for 4 h. The residue was diluted with HO (38 L) and extracted with EtOAc (3 × 19 L). The combined organic layers were washed with saturated aqueous NaCl (3 × 19 L), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was treated with n-heptane (11.4 L) and then concentrated under reduced pressure (2 ×). The residue was resuspended in n-heptane (11.4 L), filtered, and the filter cake was dried to give the title compound (2.50 kg, 64.5%) as a white solid. ES-MS m / z 208.1 (M+H-Boc), 252.0 (M+H-tBu).

[0639] The compounds in the following table were prepared in a manner similar to that described in Preparation 248, using the appropriate pyrazole. Different reaction temperatures and times may be used. Such variations will be apparent to those skilled in the art.

[0640] [Table 31] a: The crude product was purified by preparative HPLC (column: YMC Triart C18 250 * 30mm * 5 μm; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN] and lyophilized. b: Dimethylacetamide solvent was used instead of DMF solvent.

[0641] Preparation 251 tert-Butyl (1-(5-(1,3,6,2-dioxazaborocan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0642] [ka] Using a deoxygenated solvent under a nitrogen atmosphere, a solution of bis(pinacolato)diboron (2.18 kg, 8.59 mol) in 2-methyltetrahydrofuran (11.0 L) was treated with 4,4'-di-tert-butyl-2,2'-dipyridyl (37.5 g, 0.14 mol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (CAS 12148-71-9, 46.3 g, 0.07 mol) at 25° C. The mixture was stirred at 25° C. for 0.5 h, followed by the addition of a solution of tert-butyl (2-methyl-1-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (2.20 kg, 7.16 mol) in 2-methyltetrahydrofuran (4.40 L). The resulting mixture was stirred at 70°C for 16 hours, then cooled to 0-5°C and treated dropwise with a solution of diethanolamine (1.50 kg, 14.3 mol) in IPA (2.20 L) at 0-5°C over 2 hours. The mixture was stirred at 25°C for 16 hours, and then filtered. The filter cake was washed with MTBE (4.40 L), and the remaining solid was stirred with MTBE:IPA (1:1, 11.0 L) at 25°C for 16 hours. The mixture was filtered, and the filter cake was dried in vacuo to give the title compound (2.10 kg, 67%) as a white solid. ES-MS m / z 252.0 (M+H-Boc-diethanolamine, DEA), 296.0 (M+H-tBu-DEA).

[0643] Preparation 252 tert-Butyl (2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0644] [ka] In a glovebox filled with N2, bis(pinacolato)diboron (5.5 g, 22 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.36 g, 0.55 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (0.29 g, 1.1 mmol) were added to a dry reaction vial. 2-Methyltetrahydrofuran (40 mL) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. A solution of tert-butyl (2-methyl-1-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (5.7 g, 98% purity, 18 mmol) in 2-methyltetrahydrofuran (60 mL) was added, and the resulting reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica eluting with 0-1% MeOH in DCM to give the title compound (7.3 g, 88%) as a white solid. ES-MS m / z 434.0 (M+H).

[0645] Preparation 253 tert-Butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate

[0646] [ka] To a solution of tert-butyl-(2-methyl-4-oxobutan-2-yl)carbamate (12.02 g, 59.72 mmol) in EtOH (180 mL) was added NH4OH (65.0 mL, 28 wt%, 470 mmol). The reaction mixture was cooled to 0 °C, and 1,1,1-trifluoro-3,3-dibromoacetone (120 mL, 881 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h, poured into water (300 mL), and extracted with EtOAc (300 mL × 2). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Two rounds of column chromatography (1st round: SiO2, 0–4% MeOH gradient in CHCl2; 2nd round: SiO2, 0–2% MeOH gradient in CHCl2) afforded the title compound (9.4 g, 50%) as a white solid.

[0647] Preparation 254 tert-Butyl (1-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0648] [ka] A 2 L RBF equipped with a magnetic stir bar was charged with 4-bromo-1-cyclopropylpyridin-2(1H)-one (15.5 g, 72.4 mmol), Na2CO3 (22.3 g, 210 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl2 (5.91 g, 7.24 mmol), 1,4-dioxane (280 mL), IPA (64 mL), and water (210 mL). The resulting mixture was purged with nitrogen for 3 min, and then tert-butyl (1-(5-(1,3,6,2-dioxazaborocan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (32.4 g, 77.1 mmol) was added. The reaction mixture was purged with nitrogen for 10 minutes, sealed with a septum equipped with a nitrogen balloon, and heated at 65°C for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (2 x 150 mL). Water (300 mL) was added to the filtrate, and the aqueous phase was separated and extracted with EtOAc (2 x 150 mL). The combined organics were washed with saturated aqueous NaCl (300 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was suspended in 30% EtOAc in hexanes (50 mL) and sonicated. A light brown solid slowly precipitated. The solid was filtered, and the precipitate was resuspended in MTBE (568 mL) and stirred at 50°C for 1 hour. The suspension was filtered, and the filtrate was evaporated to give the title compound (24.1 g, 74%) as a pale yellow solid. ES-MS m / z 441.2 (M+H).

[0649] The compounds in the following table were prepared in a manner similar to that described in Preparation 254, using the appropriate (hetero)aryl halide. Different reaction temperatures and times can be used. Such variations will be apparent to those skilled in the art. The catalyst can be replaced with (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate or [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. The base can optionally be replaced with KPO. Purification can be achieved by column chromatography on silica gel.

[0650] [Table 32-1]

[0651] [Table 32-2] a XPhos Pd G3 as catalyst, 10:1 dioxane:water as solvent, purified by column chromatography (SiO2, gradient of 0-3% MeOH in DCM) b BrettPhos Pd G3 as catalyst, purified by column chromatography (SiO2, gradient of 0–5% MeOH in DCM) c BrettPhos Pd G3 as catalyst, K3PO4 as base, purified by column chromatography (SiO2, gradient of 0-100% EtOAc in heptane) d BrettPhos Pd G3 as catalyst, purified by column chromatography (SiO2, gradient of 0–24% EtOAc in hexanes) eBrettPhos Pd G3 as catalyst, purified by column chromatography [SiO2, gradient of 0–50% solvent B (3:1 EtOAc:EtOH) in heptane] f 10:1 dioxane:water as solvent, purification by column chromatography (SiO2, gradient of 10-30% EtOAc in cyclohexane) g 5:1 dioxane:water as solvent, purification by column chromatography (SiO2, gradient of 0-5% MeOH in DCM) h 5:1 dioxane:water as solvent, purification by column chromatography (SiO2, gradient of 0-30% EtOAc in cyclohexane) i BrettPhos Pd G3 as catalyst, purified by column chromatography [SiO2, gradient of 0–100% solvent B (3:1 EtOAc:EtOH) in heptane]

[0652] Preparation 264 tert-Butyl (1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0653] [ka] To a mixture of 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (33.0 g, 95% purity, 124 mmol), tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (45.4 g, 118 mmol), and NaCO (39.4 g, 372 mmol) in 1,4-dioxane (700 mL) and water (70 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (18.1 g, 24.8 mmol). The flask was evacuated and backfilled with N three times. The mixture was stirred at 90°C under N2 for 12 hours, filtered, and the filter cake was washed with EtOAc (300 mL x 2). The filtrate was concentrated under reduced pressure. Column chromatography (SiO2, 0-40% EtOAc gradient in petroleum ether) afforded the title compound (7.3 g, 12%) as a yellow solid, which, along with 33 g of impure title compound, was repurified by column chromatography (SiO2, 0-45% EtOAc gradient in CHCl2) to afford additional title compound (23.5 g, 42%) as a white solid. ES-MS m / z 433.0 (M+H).

[0654] The compounds in the following table were prepared in a manner similar to that described in Preparation 264, using the appropriate boronic ester or acid. Different reaction temperatures and times may be used. Such variations will be apparent to one skilled in the art.

[0655] [Table 33] * K2CO3 as base, PdCl2(dtbpf) as catalyst

[0656] Preparation 267 tert-Butyl (2-methyl-1-(1-(1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate

[0657] [ka] To a 20 mL microwave vial equipped with a magnetic stir bar was added tert-butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate (1.06 g, 3.45 mmol) and K2CO3 (1.40 g, 10.1 mmol). The vial was capped, evacuated, and backfilled with N2 three times, then DMF (9 mL) was added, followed by rac-3-bromo-1-methylpyrrolidin-2-one (760 μL, 6.87 mmol). The reaction mixture was stirred at 60 °C overnight, cooled to room temperature, and partitioned between ethyl acetate and HO. The layers were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) afforded the compound (885.7 mg, 64%) as an off-white solid. ES-MS m / z 405.0 (M+H).

[0658] The compounds in the following table were prepared in a manner similar to that described in Preparation 267, using the appropriate alkyl halide. Different reaction temperatures and times may be used. Such variations will be apparent to those skilled in the art.

[0659] [Table 34]

[0660] Preparation 272 tert-Butyl (2-methyl-1-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate

[0661] [ka] A mixture of tert-butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate (300.3 mg, 977.2 μmol), (1-methyl-1H-pyrazol-3-yl)methanol (134.5 mg, 98% purity, 1.176 mmol), and triphenylphosphine (513.5 mg, 1.958 mmol) in toluene (10 mL) was degassed and purged with N three times in a dry 50.0 mL RBF containing a magnetic stir bar, then diisopropyldiazene-1,2-dicarboxylate (390 μL, 1.98 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 10 min, heated to 100 °C, and stirred for 2 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (70 mL × 2). The combined organics were washed with saturated aqueous NaCl (70 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. Reverse-phase preparative HPLC (F-Welch Xtimate C18, 40 × 200 mm, 7 μm, gradient 30–70% ACN in 0.225% aqueous formic acid) afforded the title compound (90.2 mg, 22%) as a yellow oil. ES-MS m / z 402.6 (M+H).

[0662] Preparation 273 tert-Butyl (1-(1-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methylpropan-2-yl)carbamate

[0663] [ka] To a dry 50 mL RBF containing a magnetic stir bar and a solution of tert-butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate (331 mg, 97.2% purity, 1.05 mmol), (1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid (390 mg, 95% purity, 2.07 mmol), 4-dimethylaminopyridine (129 mg, 1.06 mmol), sodium 2-methylpropan-2-olate (306 mg, 3.18 mmol), and 4 Å molecular sieves (517 mg) in DCE (15 mL), copper diacetate (193 mg, 1.06 mmol) was added. The mixture was evacuated and backfilled with O2 three times, then stirred under O2 (15 psi) at 45 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. Column chromatography (SiO2, 0-80% EtOAc in hexanes gradient) afforded the compound (141 mg, 24%) as a yellow solid. ES-MS m / z 441.2 (M+H).

[0664] Preparation 274 tert-Butyl (1-(1-(6-cyanopyridazin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methylpropan-2-yl)carbamate

[0665] [ka] tert-Butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate (254 mg, 825 μmol), K2CO3 (78.1 mg, 565 μmol), and 6-chloropyridazine-3-carbonitrile (105 mg, 753 μmol) were added to a microwave vial. The vial was evacuated and backfilled with N2 three times. DMF (1.72 mL) was then added, and the mixture was heated to 80 °C in an aluminum heating block. The reaction was cooled to room temperature, and the mixture was diluted with EtOAc and then poured into water. The layers were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) afforded the title compound (231 mg, 65%) as a yellow oil. ES-MS m / z 411.2 (M+H).

[0666] Preparation 275 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0667] [ka] To a solution of ethyl-1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (500 mg, 1.25 mmol) in a mixture of THF (5 mL) and EtOH (5 mL) was added a solution of lithium hydroxide in water (1.0 M, 6.26 mL, 6.26 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH 2 with aqueous 1 M HCl and then extracted with EtOAc (20 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound (460 mg, 94%) as a colorless oil. ES-MS m / z 251.8 (M+H-Boc).

[0668] Preparation 276 tert-Butyl (1-(5-(dimethylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0669] [ka] To a solution of 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (200 mg, 90 wt%, 512 μmol), dimethylamine hydrochloride (85 mg, 1.0 mmol), and HATU (266 mg, 700 μmol) in DMA (3 mL) was added diisopropylethylamine (500 μL, 2.91 mmol). The reaction mixture was stirred at 25 °C for 12 h. The mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, 0–50% EtOAc gradient in hexane) afforded the compound (191 mg, 89%) as a white solid. ES-MS m / z 379.0 (M+H).

[0670] Preparation 277 tert-Butyl (1-(5-([1,2,4]triazolo[4,3-a]pyrimidin-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0671] [ka] A mixture of tert-butyl (2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (458 mg, 1.00 mmol), 6-bromo-[1,2,4]triazolo[4,3-a]pyrimidine (200 mg, 1.00 mmol), NaCO (213 mg, 2.01 mmol), and Pd(dppf)Cl (73.5 mg, 100 μmol) in 1,4-dioxane (5 mL) and water (0.5 mL) in a dry 10 mL RBF was evacuated and backfilled with N three times. The mixture was stirred at 70 °C under N for 12 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient of 0-50% EtOAc in petroleum ether) afforded the product in 89% purity. The material was further purified by preparative HPLC (column: YMC Triart C18 250 * 30mm * 5 μm; mobile phase: [A: HO (10 mM NHHCO); B: ACN]; B%: 36.00% to 66.00%, 10.00 min; flow rate: 25.00 mL / min) to give the title compound (140 mg, 31%) as a white solid. ES-MS m / z 425.9 (M+H).

[0672] Preparation 278 tert-Butyl (1-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0673] [ka] In a dry 50 mL RBF, a solution of 4-chloro-1-cyclopropylpyrimidin-2(1H)-one (452 ​​mg, 80 wt%, 2.12 mmol) in 1,4-dioxane (20 mL) was treated with tert-butyl (2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (1.15 g, 2.52 mmol), NaCO (443 mg, 4.18 mmol), bis(tri-tert-butylphosphine)palladium(0) (226 mg, 442 μmol), and water (2 mL) at 20 °C. The reaction mixture was evacuated and backfilled with N three times, and the mixture was stirred under N at 60 °C for 30 min. The reaction mixture was cooled to room temperature, and then Na2SO4 (approximately 5 g) was added to the mixture. The suspension was filtered through a short pad of silica gel and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. Column chromatography (SiO2, 0-90% EtOAc in hexanes gradient) afforded the compound (373 mg, 38%) as a light yellow solid. ES-MS m / z 442.1 (M+H).

[0674] Preparation 279 tert-Butyl (1-(2-bromo-4-fluorophenyl)-2-methylpropan-2-yl)carbamate

[0675] [ka] To a solution of 1-(2-bromo-4-fluorophenyl)-2-methylpropan-2-amine (5.01 g, 20.4 mmol) in 1,4-dioxane (50 mL) was added N,N-diisopropylethylamine (7.1 mL, 41 mmol), followed by di-tert-butyl dicarbonate (5.8 g, 6.1 mL, 27 mmol). The reaction mixture was stirred at 17 °C for 16 h, then diluted with HO (100 mL) and extracted with EtOAc (2 × 70 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 50 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0–8% EtOAc in hexanes to give the title compound (7.00 g, 93%) as a white solid. ES-MS m / z 289.8, 291.7 (M-isobutene + H).

[0676] Preparation 280 Butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorobenzoate

[0677] [ka] To a solution of tert-butyl 1-(2-bromo-4-fluorophenyl)-2-methylpropan-2-yl)carbamate (6.00 g, 94 wt%, 16.3 mmol) in DMF (60 mL) was added 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (2.00 g, 3.27 mmol), KCO (5.62 g, 40.7 mmol), Pd(OAc) (357 mg, 1.59 mmol), and n-butanol (100 mL). The reaction mixture was degassed and refilled with CO three times, then placed under an atmosphere of CO at 30 psi and stirred at 80 °C for 16 h. Additional Pd(OAc) (390 mg, 1.74 mmol) was then added, and the reaction was placed under an atmosphere of CO at 50 psi and stirred at 80 °C for an additional 16 h. The reaction was then cooled to room temperature, diluted with EtOAc (300 mL), filtered, and additional EtOAc (3 × 30 mL) was used to rinse the filter cake. The filtrate was then washed with saturated aqueous NaCl (3 × 150 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0 to 4% EtOAc in hexanes to give the title compound (2.35 g, 38%) as a colorless oil. ES-MS m / z 268.5 (M-Boc+H).

[0678] Preparation 281 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorobenzoic acid

[0679] [ka] To a solution of butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorobenzoate (2.35 g, 97 wt%, 6.20 mmol) in THF (30 mL) was added LiOH (32.0 mL of a 2 M aqueous solution, 64.0 mmol). The reaction mixture was then heated to 50 °C and stirred for 16 h. After cooling to room temperature, the reaction was acidified to pH ∼3 using aqueous 1 M HCl and extracted with EtOAc (2 × 60 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound (1.75 g, 86%) as a white solid. ES-MS m / z 212.1 (M-Boc+H).

[0680] Preparation 282 tert-Butyl (1-(2-amino-4-fluorophenyl)-2-methylpropan-2-yl)carbamate

[0681] [ka] To a solution of 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorobenzoic acid (201 mg, 95 wt%, 613 μmol) in DMF (2 mL) was added TEA (215 μL, 1.54 mmol), followed by diphenylphosphoryl azide (197 μL, 913 μmol). Stirring was started and the reaction was heated to 90° C. for 2 h. HO (0.5 mL) was then added and the mixture was stirred at 90° C. for 16 h, then at 100° C. for 3 h, then at 130° C. for 4 h, after which the reaction was cooled to room temperature, diluted with HO (10 mL), and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 15 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-12% EtOAc in hexanes to give the title compound (136 mg, 71%) as a colorless oil. ES-MS m / z 227.2 (M-isobutene + H).

[0682] Preparation 283 tert-Butyl (1-(2-(3-(2-chloroacetyl)ureido)-4-fluorophenyl)-2-methylpropan-2-yl)carbamate

[0683] [ka] A solution of tert-butyl 1-(2-amino-4-fluorophenyl)-2-methylpropan-2-yl)carbamate (136 mg, 91 wt%, 438 μmol) in THF (3 mL) was degassed and refilled with N three times. The mixture was then cooled to −40° C., and a solution of 2-chloroacetyl isocyanate (65 μL, 0.76 mmol) in THF (1 mL) was added dropwise. The reaction mixture was allowed to stir at −40° C. for 1 h and then quenched at that temperature by dilution with EtOAc (5 mL) and saturated aqueous NaHCO (5 mL). The mixture was then allowed to warm to room temperature, and the organic layer was removed. The aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the combined organic layers were then washed with saturated aqueous NaCl (10 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0–18% EtOAc in hexanes to give the title compound (161 mg, 90%) as a white solid. ES-MS m / z 302.2, 304.0 (M-Boc+H).

[0684] Preparation 284 tert-Butyl (1-(2-(2,4-dioxoimidazolidin-1-yl)-4-fluorophenyl)-2-methylpropan-2-yl)carbamate

[0685] [ka] A mixture of tert-butyl (1-(2-(3-(2-chloroacetyl)ureido)-4-fluorophenyl)-2-methylpropan-2-yl)carbamate (161 mg, 98% wt, 0.393 mmol) in DMF (4 mL) was degassed and refilled with N three times. NaH (34 mg, 60% wt, 0.85 mmol) was then added in one portion. The reaction mixture was stirred at room temperature for 3 h. The mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0–3% MeOH / DCM gradient) to afford the title compound (97 mg, 63%) as a white solid. ES / MS m / z 266.2 (M-Boc+H).

[0686] Preparation 285 (2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorophenyl)boronic acid

[0687] [ka] To a solution of tert-butyl (1-(2-bromo-4-fluorophenyl)-2-methylpropan-2-yl)carbamate (20.0 g, 95% wt, 54.9 mmol) in MeOH (200 mL) was added potassium acetate (13.5 g, 8.58 mL, 137 mmol) and ethylene glycol (10.2 g, 9.18 mL, 165 mmol). The mixture was purged and backfilled with N three times. Diboronic acid (9.84 g, 110 mmol) and chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (183 mg, 274 μmol) were added. The mixture was purged and backfilled with N three times. The reaction mixture was stirred at 35 °C for 20 h. The reaction was filtered and washed with MeOH (100 mL). The filtrate (combined with 19.5 g of tert-butyl (1-(2-bromo-4-fluorophenyl)-2-methylpropan-2-yl)carbamate from another reaction batch) was concentrated under reduced pressure. The residue was poured into water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-20% EtOAc / petroleum ether gradient) to give the title compound (28.5 g, 75%) as a dark brown oil. ES / MS m / z 312.0 (M+H)

[0688] Preparation 286 tert-Butyl (1-(4-fluoro-2-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)-2-methylpropan-2-yl)carbamate

[0689] [ka] A mixture of (2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-fluorophenyl)boronic acid (366 mg, 1.06 mmol), 6-bromo-3-methylpyrimidin-4(3H)-one (200 mg, 1.06 mmol), sodium carbonate (336 mg, 3.17 mmol), and XPhos Pd G3 (179 mg, 212 μmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was degassed and refilled with N2 three times. The mixture was stirred at 85 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding HO (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-30% EtOAc / hexanes gradient) to afford the title compound (281 mg, 64%) as a white solid. ES / MS m / z 376.0 (M+H)

[0690] Preparation 287 4-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1-cyclopropylpyridin-2(1H)-one hydrochloride

[0691] [ka] To tert-butyl-(1-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2yl)carbamate (155 mg, 352 μmol) in DCM (1.0 mL) was added hydrogen chloride in dioxane (460 μL, 4 molar, 1.84 mmol). The reaction was stirred at room temperature for 19 hours. The reaction was concentrated under a stream of N2 and carried forward without further purification assuming quantitative yield. ES / MS m / z 341.0

[0692] The compounds in the following table were prepared in a manner similar to that described in Preparation 287, using the appropriate carbamate. Different reaction temperatures and times may be used. Such variations will be apparent to one skilled in the art.

[0693] [Table 35-1]

[0694] [Table 35-2]

[0695] [Table 35-3]

[0696] [Table 35-4]

[0697] Preparation 314 6-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridazin-3(2H)-one dihydrochloride

[0698] [ka] To a solution of (300 mg, 1 eq, 773 μmol) in 1,4-dioxane (2 mL) under a N atmosphere was added hydrogen chloride in dioxane (2 mL, 4 molar, 7.73 mmol). The mixture was stirred at 40° C. overnight. The next morning, the reaction was cooled to room temperature and additional hydrogen chloride in dioxane (2 mL, 4 molar, 7.73 mmol) was added. The mixture was stirred at 40° C. over the weekend. The reaction was concentrated under reduced pressure to give the title compound as a white solid. Estimated quantitative yield and the material was carried forward without further purification. ES / MS m / z 302.2 (M+H)

[0699] Preparation 315 2-Methyl-1-(5-(6-(oxetan-3-yl)pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-amine

[0700] [ka] To a mixture of tert-butyl (2-methyl-1-(5-(6-(oxetan-3-yl)pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (44.0 mg, 1 equiv., 100 μmol) in DCM (1.0 mL) was added TFA (222 mg, 150 μL, 19.5 equiv., 1.95 mmol) at 0° C. The reaction was stirred for 2 h before being diluted with DCM and quenched with saturated aqueous Na2CO3. The layers were separated and the aqueous layer was extracted with DCM (×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (39.2 mg, 93% purity, 110%) as a pale yellow solid. ES / MS m / z 341.2 (M+H)

[0701] Preparation 316 1-(methyl-d3)-1H-pyrazole-4-carbaldehyde

[0702] [ka] To a solution of 1H-pyrazole-4-carbaldehyde (10.1 g, 1 equiv., 105 mmol) and cesium carbonate (33.6 g, 0.981 equiv., 103 mmol) in DMF (200 mL) under a N atmosphere was added iodomethane-d (18.0 g, 7.73 mL, 1.18 equiv., 124 mmol). The reaction was stirred at 60 °C for 20 h. The reaction was cooled to room temperature and then poured into a separatory funnel with HO (400 mL) and EtOAc (250 mL). The layers were separated, and the aqueous layer was washed with EtOAc (250 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-80% EtOAc / hexanes gradient) to give the title compound (4.06 g, 34% yield) as a colorless oil. ES / MS m / z 114.2 (M+H).

[0703] Preparation 317 Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)acrylate

[0704] [ka] To a solution of 1-(methyl-d3)-1H-pyrazole-4-carbaldehyde (4.0 g, 1 equiv., 35 mmol) and methyl 2-{[(tert-butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (12.0 g, 1.1 equiv., 40.4 mmol) in DCM (48 mL) under a N2 atmosphere, DBU (6.1 g, 6.0 mL, 1.1 equiv., 40 mmol) was added dropwise so that the internal temperature did not exceed 30 °C. The reaction was stirred at room temperature overnight, at which point it was added to a separatory funnel along with DCM (30 mL). The organic layer was washed with water (50 mL), saturated aqueous (NH4)2SO4 (50 mL), and aqueous saturated K2CO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-100% EtOAc / hexanes gradient) to give a colorless foam, which was dissolved in DCM (15 mL) and heptane (20 mL). The mixture was concentrated under reduced pressure to give the title compound (7.56 g, 75% yield) as a white solid. ES / MS m / z 285.4 (M+H).

[0705] Preparation 318 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)propanoate

[0706] [ka] In a Parr stirred autoclave under a N atmosphere, methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)acrylate (5.71 g, 1 equiv., 20.1 mmol), Rh-COD-[(R)-MaxPhos]-BF4 (612 mg, 0.05 equiv., 1.09 mmol), and 2,2,2-trifluoroethanol (80 mL) were added. The autoclave was purged with H2 and pressurized to 200 psi. The reaction was stirred at 40 °C for 5 days. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 75-100% EtOAc / hexanes gradient) to afford the title compound (4.82 g, 84%) as an off-white solid. The material was analyzed by chiral LC (Lux 5 mm i-amylose-3, 4.6 x 100 mm column, elution with 15% IPA (0.2% IPAm) / CO2 at 5 mL / min, detection at 225 nm) showing 92% ee of the faster eluting isomer. ES-MS m / z 287.4 (M+H)

[0707] Preparation 319 Lithium (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)propanoate

[0708] [ka] A 40 mL vial was charged with methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d-tolyl)-1H-pyrazol-4-yl)propanoate (1.18 g, 4.12 mmol) and t-BuOH (8 mL) along with a stir bar. The vial was capped under air and sonicated until a homogeneous solution was obtained. The reaction mixture was then stirred at 0° C. for 5 minutes, after which aqueous lithium hydroxide (0.13 g, 2.7 mL, 2 M, 5.4 mmol) was added dropwise. After the addition was complete, the reaction mixture was removed from the ice bath and allowed to warm to room temperature with stirring for 1 hour. The reaction was then quenched with aqueous hydrochloric acid (58 mg, 1.6 mL, 1 M, 1.6 mmol) and lyophilized to afford the title compound as a white foam (1.11 g, 3.99 mmol, 97%). ES / MS m / z: 273.2 (M+H).

[0709] Preparation 320 tert-Butyl (R)-(1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0710] [ka] A solution of lithium (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)propanoate (1.00 g, 1 equiv., 3.59 mmol) and 2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-amine, HCl (1.31 g, 1.09 equiv., 3.90 mmol) in DMSO (5 mL) was sonicated until most of the solids dissolved. TEA (0.73 g, 1.0 mL, 2.0 equiv., 7.2 mmol) and HATU (1.68 g, 1.23 equiv., 4.42 mmol) were then added, and the reaction was stirred under air at room temperature for 30 minutes. The reaction mixture was quenched with water (5 mL), loaded onto a diatomaceous earth cartridge, and purified by reverse-phase chromatography (C18, gradient 0-100% HO (0.1% FA) / ACN) to afford the title compound (1.97 g, 99% purity, 98% yield) as a pink foam. ES-MS m / z 554.4 (M+H).

[0711] Preparation 321 Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)acrylate

[0712] [ka] A 250 mL three-necked RBF equipped with a magnetic stirrer, addition funnel, and thermometer was charged with imidazo[1,2-a]pyrimidine-3-carbaldehyde (10.00 g, 67.9 mmol) dissolved in DCM (50 mL). Methyl 2-(dimethoxyphosphoryl)-2-((isopropoxycarbonyl)amino)acetate (23.10 g, 81.6 mmol) was added to the flask. DBU (11.38 g, 11.27 mL, 74.8 mmol) was then added dropwise via the addition funnel at 15 °C. The reaction mixture was stirred at 20 °C for 16 h. Upon completion, the reaction was extracted with water. The organic phase was separated, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude product. The crude material was triturated with DCM and filtered to give the title compound (14 g, 44 mmol, 64%, 99% purity) as a yellow solid. 1 H-NMR(400MHz,DMSO):8.55(1H,J=2.4Hz,d),8.44(1H,J=2.4Hz,d),7.96(1H,s),7.37(1H,J= 8.4Hz,d),4.30-4.28(1H,m),3.65(3H,s),3.12-3.08(1H,m),2.51-2.50(1H,m),1.31(9H,s).

[0713] Preparation 322 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanoate

[0714] [ka] In a nitrogen-under-glove box, methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)acrylate (20.84 g, 65.47 mmol) and Rh-COD-[(R)-MaxPhos]-BF (770 mg, 1.37 mmol) were added to a 600 mL Parr stirred autoclave. Degassed 1,1,1,3,3,3-hexafluoroisopropanol (33 mL) and 2,2,2-trifluoroethanol (367 mL) were then added. The autoclave was sealed, removed from the glove box, purged with hydrogen, and pressurized to 250 psi with H. The temperature was gradually increased to 60 °C and stirred for 5 h. The autoclave was then evacuated and the heat was turned off. The autoclave was purged with nitrogen and slowly stirred. This was then transferred to a tared 1 L flask, and EtOAc was used to rinse the autoclave. The solvent was removed by rotary evaporation, and the resulting residue was recrystallized with MTBE. The solid was collected and washed with 100 mL of cold MTBE. Finally, the solid was dried on a filter under airflow to give the title compound (9.30 g, 44%) as a tan solid with ee >99%. ES / MS m / z: 321.4 (M+H).

[0715] Preparation 323 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-methylpyridin-3-yl)propanoate

[0716] [ka] The reaction was carried out in a dry 100 mL three-neck flask equipped with a magnetic stir bar. To a mixture of 5-iodo-2-methylpyridine (3.00 g, 13.7 mmol), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (6.77 g, 20.6 mmol), nickel chloride-dimethoxyethane adduct (605 mg, 2.75 mmol), and pyridine-2,6-bis(carboximidamide) dihydrochloride (721 mg, 90 wt%, 2.75 mmol) in DMA (40 mL) was added zinc (1.80 g, 27.5 mmol). The mixture was degassed and purged with N three times and stirred at 40 °C for 16 h. Upon completion, the mixture was diluted with EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc (50 mL). The filtrate was then diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The filter cake was quenched by adding 1 N HCl (30 mL). The residue was purified by flash silica gel chromatography (0–40% EtOAc / hexane gradient eluent) to give the title compound (2.80 g, 9.3 mmol, 68%, 98% purity) as a colorless oil. ES / MS m / z: 295.2 (M+H).

[0717] Preparation 324 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(isothiazol-4-yl)propanoate

[0718] [ka] To a solution of 4-bromoisothiazole (5.0 g, 30 mmol) and (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (CAS 2467738-31-2, 23 g, 57 mmol) in DMF (50 mL) was added tris(dibenzylideneacetone)dipalladium (2.8 g, 3.0 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl (1.3 g, 3.0 mmol). The mixture was stirred under nitrogen at 65 °C for 16 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The filter cake was quenched with saturated NH4Cl (aq), and the residue was diluted with water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (300 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-5% DCM / MeOH gradient eluent) to give the title compound (10.3 g, 34 mmol, 110%, 95% purity) as a brown oil. ES / MS m / z: 286.9 (M+H).

[0719] Preparation 325 3-Bromo-8-methoxyimidazo[1,2-a]pyrazine

[0720] [ka] To a solution of 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (20 g, 95% wt, 82 mmol) in DCM (100 mL) and MeOH (100 mL) was added sodium methoxide (6.8 g, 98% wt, 0.12 mol) at 25 °C. The mixture was stirred at 40 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent. It was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (21.3 g, 84 mmol, 100%, 90% purity) as a white solid. ES / MS m / z: 229.8 (M+H).

[0721] Preparation 326 3-Bromoimidazo[1,2-a]pyrazin-8(7H)-one

[0722] [ka] A mixture of 3-bromo-8-methoxyimidazo[1,2-a]pyrazine (21.3 g, 90% wt, 84.1 mmol) and HBr (33% acetic acid) (118 g, 80.0 mL, 33% wt, 481 mmol) was stirred at 80° C. for 16 hours. The mixture was then diluted with water (200 mL) and the pH was adjusted to about 8 by the slow addition of NaOH. The reaction mixture was filtered and the residue was concentrated under reduced pressure to give the title compound (14.2 g, 60 mmol, 71%, 90% pure) as a white solid. ES / MS m / z: ( 79 Br / 81 Br)214.1 / 216.1(M+H).

[0723] Preparation 327 3-Bromo-7-methylimidazo[1,2-a]pyrazin-8(7H)-one

[0724] [ka] To a mixture of 3-bromoimidazo[1,2-a]pyrazin-8(7H)-one (14.2 g, 90% wt, 59.7 mmol) and cesium carbonate (48.6 g, 11.9 mL, 149 mmol) in THF (100 mL) was added methyl iodide (25.4 g, 11.6 mL, 179 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by flash silica gel chromatography (0-6% MeOH / DCM gradient elution) to give the title compound (9.6 g, 38 mmol, 63%, 90% purity) as a white solid. ES / MS m / z: 230.1 (M+H).

[0725] Preparation 328 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)propanoate

[0726] [ka] The reaction was carried out in a dry 250 mL three-neck RBF equipped with a magnetic stir bar. A mixture of zinc (2.58 g, 494 μL, 39.5 mmol) and chlorotrimethylsilane (386 mg, 450 μL, 3.55 mmol) in DMA (10 mL) was degassed and purged with nitrogen (N) three times. The reaction mixture was stirred under a nitrogen atmosphere at 19 °C for 20 minutes. Then, methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (8.70 g, 26.4 mmol) in DMA (15 mL) was added to the mixture. The resulting solution was stirred under nitrogen at 50 °C for 1 hour. In a separate 40 mL sealed tube, a mixture of 3-bromo-7-methylimidazo[1,2-a]pyrazin-8(7H)-one (3.00 g, 90% purity, 11.8 mmol) in DMA (20 mL) was stirred at 80 °C for 30 min using a magnetic stir bar. Next, a mixture of 3-bromo-7-methylimidazo[1,2-a]pyrazin-8(7H)-one (3.00 g, 90% purity, 11.8 mmol) in DMA (20 mL) and XPhos palladacycle (2.1 g, 2.7 mmol) was added to a 250 mL three-neck RBF, and the reaction mixture was degassed and purged with nitrogen three times. The mixture was then stirred under nitrogen at 80 °C for 2 h. After the reaction was complete, the mixture was cooled to ambient temperature. It was filtered, and the filter cake was washed with EtOAc (30 mL × 3). The filtrate was diluted with water (70 mL) and extracted with EtOAc (70 mL × 7). The combined organic layers were washed with saturated aqueous NaCl (40 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0–7% MeOH / DCM gradient eluent) to give the title compound (2.21 g, 4.4 mmol, 37%, 70% purity) as a colorless oil. ES / MS m / z: 351.0 (M+H).

[0727] Preparation 329 (R)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanoic acid

[0728] [ka] To a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanoate (1.04 g, 3.26 mmol) in MeOH (6.0 mL) was added water (6.0 mL) and LiOH (2.0 M in water, 3.3 mL, 6.6 mmol). The reaction mixture was stirred at room temperature for 3.5 h and then quenched with HCl (4.0 M in 1,4-dioxane) (0.8 mL, 3 mmol). The mixture was concentrated under a stream of N to afford a quantitative yield of the title compound (1.43 g, 73% purity) as an off-white solid. ES / MS m / z 307.2 (M+H).

[0729] The compounds in the following table were prepared in a manner similar to that described in Preparation 329, using the appropriate methyl ester. Different reaction temperatures and times may be used. Such variations will be apparent to one skilled in the art.

[0730] [Table 36]

[0731] Preparation 333 tert-Butyl ((2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (mixture of isomers)

[0732] [ka] To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (850 mg, 2.78 mmol), 3-(2-(2-amino-2-methylpropyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)-1-methylpyrrolidin-2-one hydrochloride (racemic mixture) (1.20 g, 80% purity, 2.82 mmol), and HATU (1.61 g, 4.23 mmol) in DMA (10 mL) was added DIEA (2.50 mL, 14.4 mmol). The reaction mixture was stirred at 20 °C for 2 h, then diluted with HO (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated aqueous NaCl (3 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound (1.71 g, 84% purity, 87%) as a yellow solid. ES-MS m / z 592.4 (M+H).

[0733] Preparation 334 tert-Butyl (R)-(3-(imidazo[1,2-a]pyrimidin-3-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0734] [ka] The title compound was purified on silica using (R)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanoic acid and 2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-amine hydrochloride in DMF eluting with a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-100% EtOAc in EtOAc (3:1 EtOAc / EtOH) prepared essentially as described in preparation 333. ES-MS m / z 588.4 (M+H).

[0735] Preparation 335 tert-Butyl (R)-(1-((1-(5-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(6-methylpyridin-3-yl)-1-oxopropan-2-yl)carbamate

[0736] [ka] The title compound was prepared essentially as described in preparation 333 using (R)-2-((tert-butoxycarbonyl)amino)-3-(6-methylpyridin-3-yl)propanoic acid and 4-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1-(difluoromethyl)pyridin-2(1H)-one hydrochloride, purified on silica eluting with 0-80% EtOAc in hexanes. ES-MS m / z 613.4 (M+H).

[0737] Preparation 336 tert-Butyl (R)-(3-(isothiazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0738] [ka] The title compound was prepared essentially as described in preparation 333 using (R)-2-((tert-butoxycarbonyl)amino)-3-(isothiazol-4-yl)propanoic acid and 2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-amine hydrochloride, purified on silica eluting with 0-50% EtOAc in hexanes. ES-MS m / z 554.2 (M+H).

[0739] Preparation 337 tert-Butyl (R)-(1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-1-oxopropan-2-yl)carbamate

[0740] [ka] The title compound was prepared essentially as described in preparation 333 using (R)-2-((tert-butoxycarbonyl)amino)-3-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)propanoic acid and 2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-amine hydrochloride, purified on silica eluting with 0-4% MeOH in DCM. ES-MS m / z 618.4 (M+H).

[0741] Preparation 338 (R)-2-Amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)propanamide hydrochloride (mixture of isomers)

[0742] [ka] To a mixture of tert-butyl ((2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(1-(1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (mixture of isomers) (1.71 g, 84% purity, 2.43 mmol) in MeOH (10 mL) was added 2.0 M HCl in dioxane (20.0 mL, 40.0 mmol). The reaction mixture was stirred at 20° C. for 1 h and then concentrated under reduced pressure. The crude residue was triturated with DCM (15 mL) at 20° C. for 0.5 h. The mixture was filtered and the filter cake was dried in vacuo to give the title compound (1.29 g, 97%) as an off-white solid. ES-MS m / z 492.0 (M+H).

[0743] The compounds in the following table were prepared in a similar manner as described in Preparation 338 using the appropriate carbamate without DCM trituration or any further purification. Different equivalents of HCl (5-21 equivalents) and reaction times (1-20 hours) can be used. Such variations will be apparent to one skilled in the art.

[0744] [Table 37]

[0745] Preparation 344 Methyl (R)-2-(5-(6-cyano-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0746] [ka] A mixture of 5-chloro-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (3.68 g, 98% purity, 17.1 mmol), (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methoxy-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (8.28 g, 85% purity, 17.1 mmol), sodium carbonate (5.9 g, 56 mmol), and XPhos Pd G3 (3.1 g, 3.7 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was degassed and purged with N2 (3x) and stirred at 90 °C under N2 for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and then purified on silica (eluting with a gradient of 0-5% MeOH in DCM) to give a yellow solid (10.3 g, 82% purity), which was dissolved in DCM (20 mL). The solution was added dropwise to vigorously stirring hexane (50 mL), and stirring was continued for 10 min and then stopped. After standing for 30 min, the solid was collected by filtration. Purification on silica (eluting with a gradient of 0-3% (0.5% formic acid / MeOH) in DCM) gave the title compound (6.27 g, 72%) as a yellow solid. ES-MS m / z 542.2 (M+H).

[0747] The compounds in the following table were prepared in a similar manner as described in Preparation 344 using (R)-(2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methoxy-1-oxopropan-2-yl)-8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid or (R)-(8-fluoro-2-(1-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid and the appropriate heteroaryl halide. Different reaction temperatures, reaction times, catalysts, and purification conditions can be used. Such variations will be apparent to one skilled in the art.

[0748] [Table 38-1]

[0749] [Table 38-2] a: 0.1 equivalent of 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride was used as catalyst b: From 3,5-dichloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile; purified on silica (eluted with a gradient of 0-60% EtOAc in hexanes) c: From 5-bromo-3,6-difluoro-1-(methyl-d3)-1H-pyrazolo[4,3-b]pyridine (eluted with a gradient of 0–2% MeOH in DCM) d: 80 °C, 3 h from 5-bromo-3-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine; purified on silica (eluted with a gradient of 0-50% EtOAc in hexanes) e: 90 °C, 80 min, from 6-chloro-5-methoxy-2-methylpyridazin-3(2H)-one and using 0.15 equivalents of XPhos Pd G4 as catalyst; purified on silica (eluted with a gradient of 0-8% MeOH in DCM) f: From 5-bromo-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridine; purified on silica (eluted with a gradient of 0-2% MeOH in DCM) g: From 4-chloro-5-fluoro-2-methoxypyrimidine; purified on silica (eluted with a gradient of 0-60% EtOAc in hexanes) h: From 6-chloro-5-fluoro-2-methylnicotinonitrile; purified on silica (eluted with a gradient of 0-44% EtOAc in hexanes) i: From 3,5-dichloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile; purified on silica (eluted with isocratic 2% MeOH in DCM)

[0750] Preparation 353 (R)-2-(5-(6-cyano-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid

[0751] [ka] To a mixture of methyl (R)-2-(5-(6-cyano-3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (2.34 g, 86% purity, 3.72 mmol) in tBuOH (60 mL) and water (26 mL) was added 1N aqueous LiOH (10.5 mL, 10.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The mixture was adjusted to about pH 3 with 1N aqueous HCl, then diluted with HO (80 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: PrePulite XP tC18 50 × 250 mm, 10 μm; elution with a gradient of 15 to 55% ACN in 0.225% aqueous formic acid) to give the title compound (1.22 g, 59%) as a light yellow solid. ES-MS m / z 528.0 (M+H).

[0752] The compounds in the following table were prepared in a similar manner as described in Preparation 353, using the appropriate methyl ester prepared above. The compounds may be left as crude residues or may be further purified, as would be apparent to one skilled in the art.

[0753] [Table 39-1]

[0754] [Table 39-2]

[0755] Preparation 362 3-Bromo-2-(2-chloroethyl)-N-((2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (mixture of isomers)

[0756] [ka] A mixture of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)propanamide hydrochloride (mixture of isomers) (794 mg, 96% purity, 1.44 mmol) and TEA (2.00 mL, 14.3 mmol) in THF (10 mL) was cooled to 0° C. in an ice-water bath, and then a solution of 3-bromo-2-(2-chloroethyl)-6-fluorobenzoyl chloride (938 mg, 74% purity, 2.31 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 20°C for 1 hour, then diluted with HO (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. Purification on silica eluting with a gradient of 0-5% MeOH in DCM gave the title compound (1.03 g, 83%) as a yellow solid. ES-MS m / z ( 79 Br / 81 Br, 35 Cl / 37 Cl) 754.2, 755.9, 758.1 (M+H).

[0757] The compounds in the following table were prepared in a manner similar to that described in Preparation 362, using the appropriate primary amine and acid chloride prepared above. Different reaction temperatures and times may be used. Such variations will be apparent to one skilled in the art.

[0758] [Table 40] a. The reaction solvent used was DCM b. The reaction base was DIEA

[0759] Preparation 368 (2R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)propanamide (mixture of isomers)

[0760] [ka] A mixture of 3-bromo-2-(2-chloroethyl)-N-((2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(1-((RS)-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (1.03 g, 88% purity, 1.20 mmol) in ACN (10 mL) was treated with CsCO (595 mg, 1.83 mmol) in a dry 100 mL RBF containing a magnetic stir bar and stirred at 20 °C for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, gradient 0-5% MeOH in DCM) afforded the compound (831 mg, 88%) as a white solid. ES-MS m / z 717.9 / 720.0 (M+H)(Br 79 / 81 ).

[0761] The compounds in the following table were prepared in a manner similar to that described in Preparation 368, using the appropriate alkyl halides prepared above. Bases such as cesium carbonate can be used in solvents such as ACN, DMF, and NMP. Different reaction temperatures and reaction times can be used. Such variations will be apparent to one skilled in the art.

[0762] [Table 41]

[0763] Preparation 374 (2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(8-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-methyl-1-(1-(-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)propanamide (mixture of isomers)

[0764] [ka] In an N2-filled glove box, (2R)-2-(5-bromo-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(1-((RS)-1-methyl-2-oxopyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)propanamide ( A mixture of 830 mg (91% pure, 1.05 mmol), bis(pinacolato)diborane (2.142 g, 8.435 mmol), potassium acetate (327 mg, 3.33 mmol), and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (92.4 mg, 106 μmol) was added to a dry 40 mL vial. DMF (15 mL) was added, and the sealed vial was stirred at 100 °C for 16 h, diluted with HO (50 mL), and extracted with EtOAc (30 mL × 3). The combined organics were washed with saturated aqueous NaCl (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-4% MeOH in DCM) afforded the compound (624 mg, 60%) as a white solid. ES-MS m / z 766.2 (M+H).

[0765] The compounds in the following table were prepared in a manner similar to that described in Preparation 374, using the appropriate aryl halides prepared above. Different reaction temperatures, reaction times, and catalysts can be used. Such variations will be apparent to one skilled in the art.

[0766] [Table 42-1]

[0767] [Table 42-2] a. PdCl2(dppf)-CH2Cl2 adduct as catalyst and 1,4-dioxane as solvent b. (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate as catalyst, DMF as solvent

[0768] preparation 380 Methyl (E)-2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-chloro-6-fluorobenzoate

[0769] [ka] To a solution of methyl 2-bromo-3-chloro-6-fluorobenzoate (2.89 g, 95% purity, 10.3 mmol) in 1,4-dioxane (120 mL) and HO (24 mL) was added (E)-tert-butyldimethyl{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]oxy}silane (3.68 g, 12.3 mmol), sodium carbonate (3.26 g, 30.8 mmol), and PdCl(dppf) (920 mg, 1.26 mmol). The reaction mixture was evacuated and backfilled with N three times, then gradually heated to 100 °C and stirred for 3 h. The reaction mixture was diluted with EtOAc (50 mL), filtered through a short pad of NaSO, and concentrated under reduced pressure. Column chromatography (SiO, 20:1 hexanes:EtOAc) afforded the title compound (3.367 g, 80% purity, 73%) as a light yellow oil. ES-MS m / z 226.9 / 229.0 (M-TBSO)(Cl 35 / 37 ).

[0770] Preparation 381 Methyl 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloro-6-fluorobenzoate

[0771] [ka] A solution of methyl (E)-2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-chloro-6-fluorobenzoate (3.08 g, 80% purity, 6.87 mmol) and 1,1′-bis(di-isopropylphosphino)ferrocene(1,5-cyclooctadiene)rhodium tetrafluoroborate (290 mg, 382 μmol) in MeOH (150 mL) and THF (15 mL) was degassed three times with N, then evacuated and backfilled three times with H. The mixture was stirred under 50 psi of H at 19° C. for 16 h and then concentrated under reduced pressure. Column chromatography (SiO, 20:1 hexanes:EtOAc) afforded the title compound (2.38 g, 70% purity, 67%) as a colorless oil. ES-MS m / z 361.0 / 363.0(M+H)(Cl 35 / 37 ).

[0772] Preparation 382 3-chloro-6-fluoro-2-(3-hydroxypropyl)benzoic acid

[0773] [ka] To a mixture of methyl 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloro-6-fluorobenzoate (1.0 g, 70% purity, 1.9 mmol) in THF (9 mL) and MeOH (9 mL) was added lithium hydroxide monohydrate (0.80 g, 19 mmol) in HO (6 mL) at 13 °C. The reaction mixture was stirred at 70 °C for 16 h, concentrated under reduced pressure, diluted with HO (30 mL), washed with DCM (30 mL), and the organic layer was discarded. The aqueous layer was adjusted to approximately pH 1 with 1 M HCl and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, 3–4% MeOH in DCM) afforded the title compound as a yellow solid (410 mg, 90% purity, 82%). ES-MS m / z 232.8 / 234.7(M+H)(Cl 35 / 37 ).

[0774] Preparation 383 3-chloro-2-(3-chloropropyl)-6-fluorobenzoyl chloride

[0775] [ka] To a mixture of 3-chloro-6-fluoro-2-(3-hydroxypropyl)benzoic acid (149 mg, 90% purity, 576 μmol) in SOCl (4 mL) was added one drop of DMF at 8 °C. The reaction mixture was degassed and purged with N three times, stirred at 70 °C for 12 h, and concentrated in vacuo. The residue was coevaporated with toluene (1 mL) to give the title compound (200 mg, 75% purity, 97%) as a yellow oil. A sample of the corresponding methyl ester was prepared by quenching the crude product with excess MeOH: ES-MS m / z 264.8 (M+H).

[0776] Preparation 384 (R)-3-chloro-2-(3-chloropropyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide

[0777] [ka] To a mixture of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide hydrochloride (361 mg, 671 μmol) and TEA (950 μL, 6.82 mmol) in THF (6 mL) at 0° C. was added 3-chloro-2-(3-chloropropyl)-6-fluorobenzoyl chloride (200 mg, 75% purity, 557 μmol) in THF (6 mL). The reaction mixture was stirred at 15 °C for 1 h, diluted with EtOAc (50 mL), washed with HO (30 mL × 2) and saturated aqueous NaCl (30 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, 3-4% MeOH in DCM) afforded the title compound as a white solid (410 mg, 90% purity, 90%). ES-MS m / z 733.9 (M+H).

[0778] Preparation 385 (R)-2-(6-chloro-9-fluoro-1-oxo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0779] [ka] To a mixture of (R)-3-chloro-2-(3-chloropropyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (410 mg, 90% purity, 502 μmol) in ACN (12 mL) was added CsCO (503 mg, 1.54 mmol). The reaction mixture was stirred at 80 °C for 5 h, diluted with HO (50 mL), and extracted with EtOAc (50 mL × 2). The combined organics were washed with saturated aqueous NaCl (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (YMC Triart C18 250 * 30mm * The residue was purified by HPLC (5 μm; gradient 44-74% ACN in 10 mM aqueous NH4HCO3), fractions were concentrated under reduced pressure to remove ACN, and the aqueous residue was extracted with EtOAc (30 mL × 2). The combined organics were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was lyophilized to afford the title compound (260 mg, 95% purity, 70%) as a white solid. ES-MS m / z 698.0 (M+H).

[0780] Preparation 386 (R)-2-Amino-3-bromo-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide

[0781] [ka] To a solution of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide hydrochloride (411 mg, 92 wt%, 723 μmol), 2-amino-3-bromo-6-fluorobenzoic acid (178 mg, 761 μmol), and HATU (425 mg, 1.12 mmol) in DMA (5 mL) in a dry 40 mL sealed tube was added DIEA (400 μL, 2.30 mmol). The mixture was stirred at 20° C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, gradient 0-4% MeOH in DCM) afforded the title compound as a yellow solid (553 mg, 75% purity, 82%). ES-MS m / z 702.0 / 703.9 (M+H).

[0782] Preparation 387 (R)-2-(8-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0783] [ka] In a 40 mL sealed tube, a solution of (R)-2-amino-3-bromo-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-6-fluorobenzamide (232 mg, 75 wt%, 248 μmol) in EtOH (0.5 mL) was treated with triethoxymethane (3.00 mL, 18.0 mmol) and acetic acid (100 μL, 1.75 mmol). The reaction mixture was stirred at 80° C. for 3 days. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (5 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. Column chromatography (SiO, gradient 0-4% MeOH in DCM) afforded the title compound (148 mg, 80% purity, 67%) as a yellow oil. ES-MS m / z 712.0 / 713.9 (M+H).

[0784] Preparation 388 (R)-(3-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid

[0785] [ka] In a N2-filled glovebox, (R)-2-(8-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide (148 mg, 80 wt%, 166 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (356 mg, 1.40 mmol), potassium acetate (53 mg, 0.54 mmol), and SPhos Pd G3 (18 mg, 21 μmol) were added to a dry 40 mL sealed tube. DMF (4 mL) was added to the mixture, and then the vial was sealed and removed from the glovebox. The reaction mixture was stirred at 90 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (15 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, gradient 0-6% MeOH in DCM) afforded the title compound (44 mg, 82% purity, 32%) as a yellow oil. ES-MS m / z 678.1 (M+H).

[0786] Preparation 389 2-Bromo-3-chloro-N-cyclopropyl-6-fluoro-N-(4-methoxybenzyl)benzamide

[0787] [ka] In a 20 mL vial, 2-bromo-3-chloro-6-fluorobenzoic acid (500 mg, 1.97 mmol) and N-(4-methoxybenzyl)cyclopropylamine (368 mg, 2.08 mmol) were dissolved in DMF (10 mL). TEA (420 μL, 3.01 mmol) was then added, followed by HATU (831 mg, 2.19 mmol), and the reaction was stirred at room temperature overnight. The mixture was quenched by slow addition to rapidly stirring water (200 mL), and the resulting suspension was stirred overnight. The quenched mixture was filtered, and the aqueous filtrate was discarded. The solid was dissolved in methanol and filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (SiO2, 0-100% EtOAc in heptane gradient) afforded the title compound (750 mg, 98% purity, 90%) as a yellow oil. ES-MS m / z 412.0 / 414.0(M+H).

[0788] Preparation 390 rac-(1aR,7bR)-7-chloro-4-fluoro-2-(4-methoxybenzyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinolin-3-one

[0789] [ka] A solution of 2-bromo-3-chloro-N-cyclopropyl-6-fluoro-N-(4-methoxybenzyl)benzamide (750.3 mg, 1.818 mmol), KPO (656 mg, 1.70 equiv, 3.09 mmol), 1-adamantanecarboxylic acid (66.6 mg, 369 μmol), bis(dibenzylideneacetone)palladium (52.5 mg, 91.3 μmol), and bis(1,1-dimethylethyl)(methyl)phosphine tetrafluoroborate (47.9 mg, 193 μmol) in toluene (7.3 mL) was sparged with argon for approximately 5 minutes, then stirring was started and the reaction was heated to 135° C. After 38 h, the reaction was cooled to room temperature, diluted with EtOAc, and filtered through a plug of diatomaceous earth. The filtrate was concentrated under reduced pressure and purified twice by silica gel chromatography using a gradient of 0-100% EtOAc in heptane to give the title compound (401.6 mg, 88% purity, 59% yield) as an orange oil. ES-MS m / z 332.2, 334.2 (M+H).

[0790] Preparation 391 rac-(1aR,7bR)-7-chloro-4-fluoro-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinolin-3-one

[0791] [ka] A solution of rac-(1aR,7bR)-7-chloro-4-fluoro-2-(4-methoxybenzyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinolin-3-one (401.6 mg, 1.210 mmol) and anisole (660 μL, 6.04 mmol) in TFA (2 mL) was prepared, stirring was initiated, and the mixture was heated to 65 °C. After 18.75 h, the mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting solid was triturated with approximately 10 mL of MTBE and then collected by filtration, using additional MTBE to aid transfer and rinse the filter cake. The filter cake was then collected to give the title compound (196.5 mg, 96% purity, 74% yield) as a white solid. ES-MS m / z 212.0, 214.0 (M+H).

[0792] Preparation 392 rac-Ethyl 2-((1aR,7bR)-7-chloro-4-fluoro-3-oxo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)acetate

[0793] [ka] A solution of rac-(1aR,7bR)-7-chloro-4-fluoro-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinolin-3-one (196.5 mg, 928.6 μmol) and CsCO (396.9 mg, 1.218 mmol) in DMF (3 mL) was treated with ethyl bromoacetate (140 μL, 1.26 mmol). Stirring was then started and the reaction was heated to 60 °C. After 1 h, the reaction was removed from the heat and quenched by slow addition to a rapidly stirring solution of HO (approximately 100 mL) and HCl (1.5 mL of a 1 M aqueous solution). The resulting suspension was stirred for approximately 20 min, and then the solid was collected by filtration. The filter cake was washed with water, then collected and purified by silica gel chromatography using a gradient of 0-100% EtOAc in heptane to give the title compound (243.9 mg, 96% purity, 85% yield) as a white solid. ES-MS m / z 298.2, 300.2 (M+H).

[0794] Preparation 393 rac-Methyl-2-((cis)-7-chloro-4-fluoro-3-oxo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoate (mixture of isomers)

[0795] [ka] A mixture of rac-ethyl 2-((1aR,7bR)-7-chloro-4-fluoro-3-oxo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)acetate (243.9 mg, 819.3 μmol) and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (236.2 mg, 922.9 μmol) was placed under an argon atmosphere and suspended in THF (8.2 mL). Stirring was initiated and the mixture was cooled to −78° C. NaHMDS (940 μL of a 2 M solution in THF, 1.88 mmol) was then added in one portion, after which the cooling bath was immediately removed and the reaction was allowed to gradually warm to room temperature. After 30 min, the reaction was quenched by the addition of 900 μL of MeOH. The reaction was then diluted with EtOAc and saturated aqueous NH4Cl. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-100% 3:1 EtOAc:EtOH in heptane to afford the title compound (179.6 mg, 88% purity, 51% yield, diastereomeric ratio approximately 55:45) as a colorless oil. ES-MS m / z 378.2, 380.2 (M+H).

[0796] Preparation 394 rac-(R)-2-((1aS,7bS)-7-chloro-4-fluoro-3-oxo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-N-(1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide (mixture of isomers)

[0797] [ka] A solution of rac-methyl-2-((cis)-7-chloro-4-fluoro-3-oxo-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanoate (179.6 mg, 470.0 μmol) in THF (3.5 mL) was cooled to 0 °C, stirring was initiated, and LiOH (700 μL of a 2 M aqueous solution, 40 mmol) was then added. After 3.7 h, the reaction was quenched by the addition of HCl (1.5 mL of a 1 M aqueous solution), which brought the pH to approximately 4. The reaction was then diluted with water and DCM. The organic layer was removed, and the aqueous layer was extracted three times with a 3:1 solution of CHCl:IPA. The combined organic layers were then dried over NaSO, filtered, and concentrated under reduced pressure to give the crude acid as a colorless waxy solid. To this was added 1-(5-(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-aminium chloride (237.3 mg, 643.5 μmol). The solid was suspended in DMF (2.5 mL), and then TEA (320 μL, 2.30 mmol) was added. The mixture was allowed to stir for approximately 3 minutes, and then HATU (271.8 mg, 714.8 μmol) was added, and the reaction was allowed to proceed at room temperature. After 14.3 hours, the reaction was quenched by slowly adding it to approximately 150 mL of rapidly stirring water. The resulting suspension was allowed to stir for approximately 1.5 hours, after which the solid was collected by filtration and rinsed with copious amounts of water. The filter cake was then collected and purified by silica gel chromatography using a gradient of 0-100% 3:1 EtOAc:EtOH in heptane to afford the title compound (200.1 mg, 98% purity, 61% yield of approximately a 2:1 mixture of diastereomers) as a white solid. ES-MS m / z 678.2, 680.2 (M+H).

[0798] Preparation 395 3-Iodo-4,5-dihydro-7H-thieno[2,3-c]pyran-7-one

[0799] [ka] To a solution of 4,5-dihydro-7H-thieno[2,3-c]pyran-7-one (394 mg, 2.56 mmol) in DCE (5 mL) was added I (588 mg, 2.32 mmol) and (diacetoxy)iodobenzene (756 mg, 2.35 mmol). The mixture was stirred at 65 °C for 2 h and then quenched by the addition of saturated aqueous NaSO (10 mL). The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were then washed with saturated aqueous NaCl (2 × 10 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0–20% EtOAc in hexanes to give the title compound (272 mg, 95% purity, 36% yield) as a white solid. ES-MS m / z 280.9 (M+H).

[0800] Preparation 396 (R)-3-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-4-iodothiophene-2-carboxamide

[0801] [ka] To a solution of 3-iodo-4,5-dihydro-7H-thieno[2,3-c]pyran-7-one (272 mg, 95 wt%, 923 μmol) in SOCl (3.0 mL, 41.11 mmol) was added DMF (50 μL, 0.65 mmol). The reaction mixture was degassed and purged with N three times, then stirring was initiated under a N atmosphere and the reaction was heated to 80 °C for 16 h. The crude reaction mixture was then concentrated to dryness under reduced pressure to give the crude dichloride (420 mg, 37% purity, 50% yield) as a yellow oil, which was dissolved in THF (3 mL). In a separate vessel, a solution of (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide hydrochloride (210 mg, 390 μmol) in THF (4 mL) was treated with TEA (200 μL, 1.43 mmol). The above solution of dichloride was then added to the mixture, and the reaction was stirred at 20° C. for 1 h. The mixture was then diluted with HO (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-4% MeOH in DCM to give the title compound (212 mg, 88% purity, 60% yield) as a white solid. ES-MS m / z 799.9, 801.9 (M+H).

[0802] Preparation 397 (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(3-iodo-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide

[0803] [ka] To a solution of (R)-3-(2-chloroethyl)-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-4-iodothiophene-2-carboxamide (212 mg, 88 wt%, 233 μmol) in ACN (5 mL) was added CsCO (241 mg, 740 μmol) and the resulting mixture was stirred at 20 °C for 2 h. The reaction was then diluted with HO (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-4% MeOH in DCM to give the title compound (191 mg, 89% purity, 95% yield) as a white solid. ES-MS m / z 764.0 (M+H).

[0804] Preparation 398 (R)-(6-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-((2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)boronic acid

[0805] [ka] (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(3-iodo-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)propanamide (191 mg, 1 equiv., 223 μmol), 4,4,4′,4′,5 A mixture of 5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (463 mg, 8.19 equiv., 1.82 mmol), potassium acetate (68 mg, 3.1 equiv., 0.69 mmol), and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (24 mg, 0.12 equiv., 27 μmol) was heated to 90 °C under a N atmosphere for 16 h. After cooling to room temperature, the reaction was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (15 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO, 0-6% MeOH / DCM gradient) to give the title compound (122 mg, 92% purity, 74%) as a white solid. ES-MS m / z 682.0 (M+H).

[0806] Preparation 399 6-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0807] [ka] To a mixture of 5-bromo-6-fluoro-1-methyl-1H-indazole (200 mg, 873 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (273 mg, 1.08 mmol) in 1,4-dioxane (3 mL) was added KOAc (265 mg, 2.70 mmol) and PdCl(dppf) (64.4 mg, 88.0 μmol). The mixture was degassed and purged with N three times, then the reaction mixture was gradually heated to 100 °C and stirred at that temperature for 16 h. The reaction was then cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in hexanes to afford the title compound (182 mg, 64%) as a yellow solid. ES-MS m / z 276.7(M+H).

[0808] Preparation 400 rac-tert-butyl(1-(1-(1-(2-fluorophenyl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methylpropan-2-yl)carbamate

[0809] [ka] To a solution of tert-butyl (2-methyl-1-(4-(trifluoromethyl)-1H-imidazol-2-yl)propan-2-yl)carbamate (75 mg, 0.24 mmol) in DMF (0.51 mL) was added potassium carbonate (118 mg, 0.85 mmol). The mixture was stirred at room temperature for 30 minutes, then 1-(1-bromoethyl)-2-fluorobenzene (87 mg, 0.43 mmol) was added. An additional 0.5 mL of DMF was added and heated to 60° C. The mixture was stirred at 60° C. for 15 hours, then cooled to room temperature. The mixture was diluted with DCM, transferred to a 10 mL vial, and concentrated under N2. The residue was diluted with water (5 mL) and DCM (5 mL). The mixture was filtered through an SPE phase separation cartridge and then rinsed with DCM (5 mL). The organic phase was concentrated under N2. The residue was purified by reverse-phase HPLC using a gradient of 50-100% ACN in aqueous NH4HCO3 to give the title compound (81 mg, 77%). ES-MS m / z 430.2 (M+H).

[0810] Preparation 401 rac-1-(1-(1-(2-fluorophenyl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methylpropan-2-amine dihydrochloride

[0811] [ka] To rac-tert-butyl (1-(1-(1-(2-fluorophenyl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methylpropan-2-yl)carbamate (80 mg, 0.19 mmol) in a 40 mL vial was added DCM (7 mL), followed by HCl in dioxane (4 M, 0.47 mL, 1.9 mmol). ...

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, X is CH ２ , OCH ２ , or CH ２ CH ２ and Y is CHR １８ and 【Chemistry 2】 is a single bond, or X is CH and Y is CR １８ and 【Transformation 3】 is a double bond, or X is CHR １４ and Y is CHR １５ and 【Chemistry 4】 is a single bond, and R １４ and R １５ together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH; 【Transformation 5】 is a double bond, or X is CH and Y is N; 【Transformation 6】 is a double bond, R １８ is H or CH ３ and A is, 【Transformation 7】 and R １ is an 8-, 9-, or 10-membered N-containing bicyclic heterocycle, phenyl, or a 5- or 6-membered N-containing heterocycle, and said heterocycle or phenyl is C.N., Hello, OCH ３ C optionally substituted with １ -C ４ Alkyl, C １ -C ４ haloalkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkoxy, CD ３ 、 Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH; OCH ３ benzyl optionally substituted with NHC(O)R １６ , and CH ３ and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with R １６ However, N.H.C. １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, NHC ３ -C ６ Cycloalkyl, halo or CH ３ pyridyl optionally substituted with, or phenyl optionally substituted with halo; R ２ and R ２’ are independently H, halo, or OCH ３ and R ３ but, i) CH ３ , CDs ３ , CHF ２ , OH, and CH ２ a 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CN; ii) oxo, CH ３ and halo; R ４ and R ５ are CH ３ or together form cyclopropyl, cyclobutyl, oxetane, tetrahydrofuran, pyrrolidine, or piperidine, wherein said cyclopropyl or cyclobutyl is optionally substituted with one or two halo, and said pyrrolidine or piperidine is CH ３ and optionally substituted with R ６ But H, D, OH, CH ３ , CO ２ R １０ , or 【Transformation 8】 wherein R １０ is H or OC(O)C １ -C ４ C optionally substituted with alkyl or morpholine １ -C ４ alkyl, and R ６’ is H and R ７ is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R ８ In or R ８ and R ９ optionally replaced by R ６ is D and R ６’ is D and R ７ is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R ８ In or R ８ and R ９ optionally replaced by R ６ and R ７ Together, CH ３ , C.F. ３ and oxo, forming a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from ６’ is H, R ８ But CF ３ , C.F. ２ H, halo, cyclopropyl, CH ３ , or H, R ９ but, i) Hello, OH, C １ -C ４ Alkoxy, SO ２ NH ２ 、 CH ３ or a 4- to 6-membered heterocycle optionally substituted with oxo; C.N., C ３ -C ６ cycloalkyl, CD ３ 、 C １ -C ４ haloalkyl, CR １２ R １３ OP(O)(OH) ２ Oxo, C １ -C ４ haloalkoxy, C(O)NR １２ R １３ 、 (CH ２ ) ｍ P(O)(R １７ ) ２ , and C １ -C ４ alkyl, wherein the C １ -C ４ Alkyl is OH, OCH ３ , N.R. １２ R １３ , C(O)NR １２ R １３ , CN, a 4- to 6-membered heterocycle, or C optionally substituted with halo ３ -C ４ C optionally substituted with cycloalkyl １ -C ４ a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from alkyl, ii) CN, oxo, C(O)O(CH ３ ) ３ , OH, CH ３ and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from halo; iii) C １ -C ４ Alkoxy, iv) C ３ -C ５ cycloalkyl, v) halo, vi) (CH ２ ) ｎ C(O)R １１ (wherein n is 0 or 1, and R １１ But OCH ３ , N.R. １２ R １３ or a 4- to 6-membered heterocycle), vii) 4- to 6-membered heterocycle, phenyl, NHS(O) ２ (CH ３ ), or NR １２ R １３ C optionally substituted with １ -C ４ alkyl, wherein the heterocycle or phenyl is CH ３ C optionally substituted with １ -C ４ Alkyl, viii) C.N.; ix) C(O)OH, (CH ２ ) ｍ P(O)(R １７ ) ２ , N.R. １２ R １３ , and C １ -C ４ phenyl optionally substituted with 1 to 3 substituents independently selected from alkyl, １ -C ４ phenyl, wherein alkyl is optionally substituted with OH; or x) (CH ２ ) ｍ P(O)(R １７ ) ２ and R １２ and R １３ are independently H or CH ３ and Each R １７ But independently, C １ -C ４ is alkyl, a compound wherein m is 0 or 1; or a pharmaceutically acceptable salt thereof.

2. A is, 【Chemistry 9】 2. The compound of claim 1, wherein:

3. R ２ is F and R ２’ 3. The compound of claim 2, wherein is H, or a pharmaceutically acceptable salt thereof.

4. X is CH ２ or CH ２ CH ２ and Y is CH ２ and 【Chemistry 10】 is a single bond, or X is CHR １４ and Y is CHR １５ and 【Chemistry 11】 is a single bond, and R １４ and R １５ together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH; 【Chemistry 12】 is a double bond, or X is CH and Y is N; 【Chemistry 13】 The compound according to any one of claims 1 to 3, wherein is a double bond. or a pharmaceutically acceptable salt thereof.

5. X is CH ２ and Y is CH ２ and 【Chemistry 14】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is a single bond.

6. R ４ and R ５ are CH ３ 6. The compound according to any one of claims 1 to 5, wherein:

7. R １ but, an 8- or 9-membered N-containing bicyclic heterocycle, phenyl, or a 6-membered N-containing heterocycle, wherein said heterocycle or phenyl is C.N., Hello, C １ -C ４ Alkyl, C １ -C ４ haloalkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkoxy, CD ３ 、 Oxo, OCH ３ benzyl optionally substituted with CH ３ The compound of any one of claims 1 to 6, optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with or a pharmaceutically acceptable salt thereof.

8. R １ but, 【Chemistry 15】 and C.N., F. Cl, CH ３ 、 CF ３ 、 OCH ３ 、 OCHF ２ 、 CD ３ 、 Oxo, OCH ３ benzyl substituted with, and CH ３ 8. The compound of claim 7, optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle substituted with or a pharmaceutically acceptable salt thereof.

9. R １ but, 【Chemistry 16】 and C.N., F, and CH ３ The compound of claim 8, optionally substituted with 1 to 3 substituents independently selected from or a pharmaceutically acceptable salt thereof.

10. R ３ But CH ３ , CDs ３ or CHF ２ 5- or 6-membered N-containing heteroaryl optionally substituted with, or oxo and CH ３ or a pharmaceutically acceptable salt thereof.

11. R ３ but, 【Chemistry 17】 The compound of claim 10, or a pharmaceutically acceptable salt thereof.

12. R ３ but, [Chemistry 18] 12. The compound of claim 11, wherein:

13. R ６ H, OH, CO ２ R １０ , or 【Chemistry 19】 and R ６’ is H or R ６ is D and R ６’ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is D.

14. R ６ is H and R ６’ is H, or a pharmaceutically acceptable salt thereof.

15. R ７ is a 5- or 6-membered N-containing heteroaryl, a 9-membered N-containing heteroaryl, or a phenyl, and the heteroaryl or phenyl is R ８ In or R ８ and R ９ and optionally substituted with R ８ But CF ３ , halo, cyclopropyl, CH ３ , or H, R ９ but, i) Hello, OH, C １ -C ４ Alkoxy, a 4- to 6-membered heterocycle, C.N., C ３ -C ６ cycloalkyl, CD ３ 、 C １ -C ４ haloalkyl, CR １２ R １３ OP(O)(OH) ２ oxo, and C １ -C ４ alkyl, wherein the C １ -C ４ The alkyl is OH, NR １２ R １３ or a 4- to 6-membered heterocycle, １ -C ４ a 4-, 5-, or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from alkyl, ii) a 9-membered N-containing bicyclic heterocycle; iii) C １ -C ４ Alkoxy, iv) C ３ -C ５ cycloalkyl, v) halo, vi) (CH ２ ) ｎ C(O)R １１ (wherein n is 0 or 1, and R １１ But NR １２ R １３ or a 4- to 6-membered heterocycle), vii) NHS(O) ２ (CH ３ ), N.R. １２ R １３ or C optionally substituted with phenyl １ -C ４ alkyl, wherein the phenyl is CH ３ C optionally substituted with １ -C ４ Alkyl, viii) C.N.; ix) C(O)OH, (CH ２ ) ｍ P(O)(R １７ ) ２ , and N.R. １２ R １３ or x) (CH ２ ) ｍ P(O)(R １７ ) ２ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. R ７ but, 【Chemistry 20】 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof.

17. R ７ but, 【Chemistry 21】 and R ９ but, 【Chemistry 22】 17. The compound of claim 16, selected from:

18. 10. A compound according to claim 1 of the formula: 【Chemistry 23】 During the ceremony, X is CH ２ , OCH ２ , or CH ２ CH ２ and Y is CH ２ and 【Chemistry 24】 is a single bond, or X is CHR １４ and Y is CHR １５ and 【Chemistry 25】 is a single bond, and R １４ and R １５ together with the carbon to which they are attached to form a fused cyclopropyl, or X is N and Y is CH; 【Chemistry 26】 is a double bond, or X is CH and Y is N; 【Chemistry 27】 is a double bond, A is, 【Chemistry 28】 and R １ is an 8-, 9-, or 10-membered N-containing bicyclic heterocycle, phenyl, or a 5- or 6-membered N-containing heteroaryl, and said heterocycle, phenyl, or heteroaryl is C.N., Hello, OCH ３ C optionally substituted with １ -C ４ Alkyl, C １ -C ４ haloalkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkoxy, CD ３ 、 Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH; OCH ３ benzyl optionally substituted with NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and CH ３ and optionally substituted with 1 to 3 substituents independently selected from a 9-membered N-containing bicyclic heterocycle optionally substituted with R ２ and R ２’ are independently H, halo, or OCH ３ and R ３ But CH ３ , CDs ３ , CHF ２ , OH, and CH ２ 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CN, or oxo and CH ３ is a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents selected from R ４ and R ５ are CH ３ or together form a cyclopropyl, R ６ But H, D, OH, CH ３ , CO ２ R １０ , or 【Chemistry 29】 and R １０ is H or OC(O)C １ -C ４ C optionally substituted with alkyl or morpholine １ -C ４ alkyl, and R ６’ is H, or R ６ is D and R ６’ is D, R ７ is a 5- or 6-membered N-containing heteroaryl or phenyl, and said heteroaryl or phenyl is R ８ Or R ８ and R ９ or said phenyl is optionally substituted with halo, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with R ８ But CF ３ , C.F. ２ H, halo, or cyclopropyl; R ９ but, i) Hello, OH, C １ -C ４ Alkoxy, SO ２ NH ２ 、 CH ３ a 4- to 6-membered heterocycle optionally substituted with C.N., C ３ -C ６ cycloalkyl, CD ３ 、 C １ -C ４ haloalkyl, CR １２ R １３ OP(O)(OH) ２ oxo, and C １ -C ４ alkyl, wherein the C １ -C ４ Alkyl is OH, OCH ３ , N(CH ３ ) ２ , a 4- to 6-membered heterocycle, or C optionally substituted with halo ３ -C ４ C optionally substituted with cycloalkyl １ -C ４ a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from alkyl, ii) CN, oxo, C(O)O(CH ３ ) ３ or a 9-membered N-containing bicyclic heterocycle optionally substituted with OH; iii) C １ -C ４ Alkoxy, iv) C ３ -C ５ cycloalkyl, v) halo, vi) (CH ３ ) ｎ C(O)R １１ (wherein n is 0 or 1, and R １１ But OCH ３ , N.R. １２ R １３ or a 4- to 6-membered heterocycle), vii) optionally substituted with a 4- to 6-membered heterocycle or phenyl, wherein said heterocycle or phenyl is CH ３ C optionally substituted by １ -C ４ Alkyl, viii) CN, or ix) phenyl optionally substituted with C(O)OH; R １２ and R １３ are independently H or CH ３ The compound of claim 1, or a pharmaceutically acceptable salt thereof.

19. 10. A compound according to claim 1 of the formula: 【Transformation 30】 During the ceremony, X is -CH ２ -, -OCH ２ - or -CH ２ CH ２ - and R １ but, i) C.N., Hello, OCH ３ C optionally substituted with １ -C ４ Alkyl, C １ -C ４ haloalkyl, Oxo, phenyl optionally substituted with 1 or 2 substituents independently selected from halo and OH, and OCH ３ benzyl optionally substituted with ii) C.N., NHC(O)pyridyl, wherein the pyridyl is optionally substituted with halo, and CH ３ a 9-membered N-containing bicyclic heterocycle optionally substituted with iii) CN and CH ３ is pyrazolyl optionally substituted with 1 to 3 substituents selected from R ２ is H, halo, or OCH ３ and R ３ But CH ３ , CHF ２ , OH, and CH ２ CN; R ４ and R ５ are CH ３ or together form a cyclopropyl, R ６ But H, OH, CH ３ , CO ２ R １０ , or 【Chemistry 31】 and R ７ but, i) Hello, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with ii) R ８ Or R ８ and R ９ is a 5- or 6-membered N-containing heteroaryl optionally substituted with R ８ But CF ３ , C.F. ２ H, halo, or cyclopropyl; R ９ but, i) Hello, OH, OCH ３ 、 SO ２ NH ２ 、 a 4- to 6-membered heterocycle, oxo, and C １ -C ４ alkyl, wherein the C １ -C ４ Alkyl is OH, OCH ３ , a 4- to 6-membered heterocycle, or C optionally substituted with halo ３ -C ４ C optionally substituted with cycloalkyl １ -C ４ a 5- or 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from alkyl, ii) CN, oxo, C(O)O(CH ３ ) ３ or a 9-membered N-containing bicyclic heterocycle optionally substituted with OH; iii) C １ -C ４ Alkoxy, iv) C ３ -C ５ cycloalkyl, v) halo, or vi)C(O)OCH ３ and R １０ is H or OC(O)C １ -C ４ C optionally substituted with alkyl or morpholine １ -C ４ The compound of claim 1, wherein the compound is alkyl. or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1 to 160.

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

22. A method for treating type II diabetes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

23. A method for treating obesity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

24. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in therapy.

25. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

26. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in treating obesity.

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