GIP receptor agonist compounds

Abstract

To provide a human glucose-dependentinsulinotropicpolypeptide (GIP) receptor agonist.SOLUTION: A compound of the following formula or a pharmaceutically acceptable salt thereof is provided: Wherein A is phenyl, 6-membered N-containing heteroaryl or thienyl, wherein said phenyl, heteroaryl or thienyl is optionally substituted with one or two substituents independently selected from halo, CF3, CHF2, CH3, cyclopropyl, OH and CN, or when R1 is an optionally substituted 8, 9 or 10 membered N-containing bicyclic heterocycle, A may be absent and X is O or S.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to cyclopropane-carboxamide 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 may be useful in the treatment of type 2 diabetes mellitus (T2DM). The compounds may also be useful in 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 treatment 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 undesirable health outcomes and morbidity. In the desired treatment of obese patients, excess 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 drugs have many drawbacks, including inconvenience, pain, and the possibility of irritation at the injection site. Therefore, patients often prefer orally administered drugs. For example, there are many GLP-1R agonists in clinical development for oral administration, including orforglipron (Frias et al., Lancet 2023:402:472-83), but at present, there are no such GIPR 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

[0007] In a first aspect, the compound of formula:

[0008] [ka] A compound of the formula During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, Oxo, CN, Hello, CD3, and an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii)NR 16 COR 12 , iii) OH, or iv) a 5- or 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH, oxo, OCH, CN, halo, and C-C alkyl optionally substituted with OH; R 12 However, NHR 13 , pyridyl, phenyl, OCH3, CH3 or C3-C6 cycloalkyl, wherein the pyridyl, phenyl or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13 is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; R 16 is H or CH3, A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein the phenyl, heteroaryl, or thienyl is optionally substituted with 1 or 2 substituents independently selected from halo, CF, CHF, CH, cyclopropyl, OH, or CN; or R 1 is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R 2 is H, CH3, halo, CF3 or CHF2, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents selected from oxo, halo, and CH3; or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with one or two substituents selected from CH, CD, CHF, OH, and CHCN; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl, cyclobutyl, oxetane, tetrahydrofuran, pyrrolidine or piperidine, wherein cyclopropyl or cyclobutyl is optionally substituted with 1 or 2 halo, and pyrrolidine or piperidine is optionally substituted with CH3; R 8 But, H, D, OH, CO2R 18 , or

[0009] [ka] and R 18 is H or C1-C4 alkyl optionally substituted with OC(O)C1-C4 alkyl or morpholine, and R 8’ is H and R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8is D and R 8’ is D and R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH, CF, and oxo; R 8’ is H, R 10 is CF3, CF2H, halo, or cyclopropyl; R 11 but, i) Hello, OH, C1-C4 alkoxy, CD3, C1-C4 haloalkoxy, SO2NH2, CN, C1-C4 haloalkyl, C3-C6 cycloalkyl, C(O)NH2, a 4-6 membered heterocycle optionally substituted with oxo or CH3; Oxo, CR 14 R 15 OP(O)(OH)2, (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 19 (wherein n is 0 or 1, and R 19 However, OCH3, NR 14 R 15 or a 4- to 6-membered heterocycle), vii)(CH2) m P(O)(R 17 )2, viii) C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle or phenyl, wherein the heterocycle or phenyl is optionally substituted with CH3; ix) CN, or x) Halo, C1-C4 alkyl, (CH2) m P(O)(R 17 )2, COOH and NR 14 R 15 wherein the C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 are independently H or CH3; Each R 17 are independently C1-C4 alkyl, m is 0 or 1; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0010] In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula IX, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0011] 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 IX, or a pharmaceutically acceptable salt thereof.

[0012] 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 IX, or a pharmaceutically acceptable salt thereof.

[0013] In a fifth aspect, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0014] In a sixth aspect, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

[0015] In a seventh aspect, there is provided a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in treating obesity. DETAILED DESCRIPTION OF THE INVENTION

[0016] In one embodiment of Formula IX, there is provided a compound of Formula IXa:

[0017] [ka]

[0018] In one embodiment of Formula IX, R 8 H, D, OH, CO2R 18 , or

[0019] [ka] and R 18is H or C1-C4 alkyl optionally substituted with OC(O)C1-C4 alkyl or morpholine, and R 8’ is H and R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 is D and R 8’ is D and R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH, CF, and oxo; R 8’ is H, R 10 is CF3, CF2H, halo or cyclopropyl, R 11 teeth, i) Hello, OH, C1-C4 alkoxy, CD3, C1-C4 haloalkoxy, SO2NH2, CN, C1-C4 haloalkyl, C3-C6 cycloalkyl, C(O)NH2, a 4-6 membered heterocycle optionally substituted with oxo or CH3; Oxo, (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi)(CH2) n C(O)R 19 (wherein n is 0 or 1, and R 19 However, OCH3, NR 14 R 15 or a 4- to 6-membered heterocycle), vii)(CH2) m P(O)(R 17 )2, viii) C1-C4 alkyl optionally substituted with a 4- to 6-membered heterocycle or phenyl, wherein the heterocycle or phenyl is optionally substituted with CH3; ix) CN, or x) Halo, C1-C4 alkyl, (CH2) m P(O)(R 17 )2, COOH and NR 14 R 15 wherein the C1-C4 alkyl is optionally substituted with OH.

[0020] In one embodiment, the compounds of the present invention are prodrugs. In certain embodiments, the prodrug is a dihydrogen phosphate (OP(O)(OH)2) prodrug. The dihydrogen phosphate prodrug can be formed from any aliphatic alcohol substituent. Alternatively, the dihydrogen phosphate prodrug group can be present, for example, on the 6-oxapyridazine ring.

[0021] In one embodiment of Formula IX, R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 and R 11 is substituted with R 11 is CR 14 R 15 substituted with OP(O)(OH)2, and optionally Hello, OH, C1-C4 alkoxy, CD3, C1-C4 haloalkoxy, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4-6 membered heterocycle optionally substituted with oxo or CH3; Oxo, (CH2) m P(O)(R 17 )2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 , a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle further substituted with 1 to 3 substituents independently selected from C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl optionally substituted with halo.

[0022] In certain embodiments, R 11is a 5- or 6-membered N-containing heteroaryl selected from 6-oxapyridazine, pyridine, and pyrimidine, and the heteroaryl is CR 14 R 15 It is substituted with OP(O)(OH)2.

[0023] In one embodiment, a compound of formula V is provided:

[0024] [ka]

[0025] In one embodiment of Formula V, the compound is R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , iii) OH, or iv) a 5- or 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH3, C1-C4 alkyl, oxo, and CN; R 12 However, NHR 13 , pyridyl, phenyl, or C3-C6 cycloalkyl, wherein the pyridyl, phenyl, or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein the phenyl, heteroaryl, or thienyl is optionally substituted with 1 or 2 substituents independently selected from halo, CF, CHF, CH, cyclopropyl, or CN; or R 1 is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R 2 is H, CH3, halo, CF3 or CHF2, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CD, CHF, or OH; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl; R 8 is H, CH3, CO2H, or C(O)OCH3, R9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 but, i) Hello, OH, OCH3, CD3, OCHF2, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi) C(O)OCH3, or vii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14and R 15 is independently H or CH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0026] In one embodiment of Formula V, a compound of Formula Va is provided:

[0027] [ka]

[0028] In one embodiment of any of the above formulas, R 8 is H, CH3, CO2H, or C(O)OCH3, and R9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 teeth, i) Hello, OH, OCH3, CD3, OCHF2, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi) C(O)OCH3, or viii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH.

[0029] In one embodiment of any of the above formulas, R 9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 and R 11 is substituted with R 11 is CR 14 R 15 substituted with OP(O)(OH)2, and optionally Hello, OH, OCH3, CD3, OCHF2, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 , a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle further substituted with 1 to 3 substituents independently selected from C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl optionally substituted with halo.

[0030] In one embodiment of any of the above formulas, R 3 is H and R 4 is H, CH, or CD. In an alternative embodiment of any of the above formulas, R 3 and R 4 combine to form -CH2-CH2-.

[0031] In one embodiment of any of the above formulas, R 2 is H or CH3.

[0032] In one embodiment of Formula IX, R 1 teeth, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii)NR 16 COR 12 , or iii) a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH, oxo, OCH, halo, and C-C alkyl optionally substituted with OH; R 12 is NHR 13 , OCH3 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, and R 13 is phenyl optionally substituted with one or two halo, and R 16 is H or CH3.

[0033] In one embodiment of any of the above formulas, R 1 teeth, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , or iii) a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH3, C1-C4 alkyl, and oxo; R 12 is NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with one or two halo.

[0034] In one embodiment of any of the above formulas, R 1 teeth, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , or iii) a 6-membered heterocycle optionally substituted with C(O)CH; R 12 is NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with one or two halo.

[0035] In one embodiment of Formula IX, A is phenyl, pyridyl, pyrimidinyl, or thienyl, wherein the phenyl, pyridyl, pyrimidinyl, or thienyl is optionally substituted with one or two substituents independently selected from F, Cl, CF, CHF, CH, cyclopropyl, and OH, or R 1 When is an optionally substituted 8-, 9-, or 10-membered N-containing bicyclic heterocycle, A may be absent.

[0036] In one embodiment of any of the above formulas, A is phenyl, pyridyl, pyrimidinyl, or thienyl, wherein the phenyl, pyridyl, pyrimidinyl, or thienyl is optionally substituted with a substituent selected from F, Cl, CF3, CHF2, and CH3, or R 1 When is an optionally substituted 8-, 9-, or 10-membered N-containing bicyclic heterocycle, A may be absent.

[0037] In one embodiment of any of the above formulas, A is phenyl, pyridyl, pyrimidinyl, or thienyl, wherein the phenyl, pyridyl, pyrimidinyl, or thienyl is optionally substituted with a substituent selected from F, Cl, CF3, CHF2, and CH3.

[0038] In one embodiment of any of the above formulas, R 5 teeth, i) a 9-membered N-containing bicyclic heterocycle, or ii) A 5-membered N-containing heteroaryl substituted with CH3, CD3, or CHF2.

[0039] In one embodiment of Formula IX, R 6 and R 7 are each CH3 or together form cyclopropyl.

[0040] In one embodiment of any of the above formulas, R 8 is H. In one embodiment of Formula IX, R 8 and R 8’ is H.

[0041] In one embodiment of any of the above formulas, R 9 teeth, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with

[0042] In one embodiment of Formula IX, R 9 teeth, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 teeth, i) Hello, OH, CD3, C1-C4 haloalkoxy, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, vi) P(O)(CH3)2, or vii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo, P(O)(CH), and C-C alkyl, wherein C-C alkyl is optionally substituted with OH; R 14 and R 15 are independently H or CH3.

[0043] In one embodiment of any of the above formulas, R 9 teeth, R 10 Or R 10 and R11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 teeth, i) Hello, OH, CD3, OCHF2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, or vi) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 are independently H or CH3.

[0044] In one embodiment of any of the above formulas, R 9teeth, R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 teeth, i) Hello, OH, CD3, OCHF2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, or vi) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 are independently H or CH3.

[0045] In one embodiment, a compound of formula VI:

[0046] [ka] A compound of the formula During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii)NR 16 COR 12 , or iii) a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH, oxo, OCH, halo, and C-C alkyl optionally substituted with OH; R 12 However, NHR 13 , OCH3 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo; R 13 is phenyl optionally substituted with 1 or 2 halo; R 16 is H or CH3, A is phenyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyridyl, pyrimidinyl or thienyl is optionally substituted with one or two substituents independently selected from F, Cl, CF3, CHF2, CH3, cyclopropyl and OH; or R 1is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R 2 is H or CH3, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH, CD, or CHF; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl; R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, R 11 but, i) Hello, OH, CD3, C1-C4 haloalkoxy, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, vi) P(O)(CH3)2, or vii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo, P(O)(CH), and C-C alkyl, wherein C-C alkyl is optionally substituted with OH; R 14 and R 15 is independently H or CH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0047] In one embodiment, there is provided a compound of formula VI, wherein: R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , or iii) a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH3, C1-C4 alkyl, and oxo; R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo; R 13 is phenyl optionally substituted with 1 or 2 halo; A is phenyl, pyridyl, pyrimidinyl or thienyl, wherein the phenyl, pyridyl, pyrimidinyl or thienyl is optionally substituted with a substituent selected from F, Cl, CF3, CHF2 and CH3, or R 1 is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R 2 is H or CH3, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH, CD, or CHF; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl; R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, R 11 but, i) Hello, OH, CD3, OCHF2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, or vi) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15is independently H or CH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0048] In one embodiment of Formula VI, a compound of Formula VIa is provided:

[0049] [ka]

[0050] In one embodiment of Formula VI, R 3 is H and R 4 is H, CH, or CD. In an alternative embodiment of Formula VI, R 3 and R 4 combine to form -CH2-CH2-.

[0051] In one embodiment, a compound of formula VII:

[0052] [ka] A compound of the formula: In the formula, R 1 , A, R 2 , R 4 , R 5 , X, R 6 , R 7 and R 9 is as defined in any of the formulas above.

[0053] In one embodiment of Formula VII, there is provided a compound of Formula VIIa:

[0054] [ka]

[0055] In a further embodiment of Formula VII, there is provided a compound of Formula VIIb:

[0056] [ka]

[0057] In one embodiment, a compound of formula VIII:

[0058] [ka] A compound of the formula: In the formula, R 1 , A, R 5 , X, R 6 , R 7 and R 9 is as defined in any of the formulas above.

[0059] In one embodiment of Formula VIII, there is provided a compound of Formula VIIIa:

[0060] [ka]

[0061] In an alternative embodiment, the compound of formula I:

[0062] [ka] A compound of the formula: During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , or iii) OH, R 12 However, NHR 13 , pyridyl, phenyl, or C3-C6 cycloalkyl, wherein the pyridyl, phenyl, or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13 is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein the phenyl, heteroaryl, or thienyl is optionally substituted with 1 or 2 substituents independently selected from halo, CF3, CHF2, CH3, and cyclopropyl; R 2 is H, CH3, halo, CF3 or CHF2, R 3 is H and R 4 is H or CH3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CHF, or OH; R 6 and R 7 are each CH3 or together form cyclopropyl; R 8 is H, CH3, CO2H or C(O)OCH3, and R 9 but, phenyl optionally substituted with one or two substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with Or R 8 and R 9together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 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; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0063] In one embodiment of Formula I, there is provided a compound of Formula Ia:

[0064] [ka]

[0065] In one embodiment of Formula I, R 6 and R 7 are CH3, respectively.

[0066] In one embodiment of Formula I, R 3 is H and R 4 is H or CH3. In an alternative embodiment of Formula I, R 3 and R4 combine to form -CH2-CH2-.

[0067] In one embodiment of Formula I, R 2 is H or CH3.

[0068] In one embodiment of Formula I, R 1 teeth, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with one or two halo.

[0069] In one embodiment of Formula I, A is phenyl, pyridyl, or thienyl, wherein the phenyl, pyridyl, or thienyl is optionally substituted with a substituent selected from F, CF3, and CH3.

[0070] In one embodiment of Formula I, R 5 teeth, i) a 9-membered N-containing bicyclic heterocycle, or ii) A 5-membered N-containing heteroaryl substituted with CH3 or CHF2.

[0071] In one embodiment of Formula I, R 8 is H.

[0072] In one embodiment of Formula I, R 9 teeth, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with

[0073] In one embodiment of Formula I, R 9 teeth, R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 teeth, i) Hello, 4- to 6-membered heterocycles, oxo or a 5- or 6-membered heterocycle optionally substituted with 1 or 2 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 oxo or C(O)O(CH3)3; iii) C3-C5 cycloalkyl, iv) halo, or v) C(O)OCH3.

[0074] In a further alternative embodiment, the compound of formula II:

[0075] [ka] A compound of the formula: During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo; A is phenyl, pyridyl, or thienyl, wherein the phenyl, pyridyl, or thienyl is optionally substituted with a substituent selected from F, CF3, and CH3; R 2 is H or CH3, R 3 is H and R 4 is H or CH3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH3 or CHF2; R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 but, i) Hello, 4- to 6-membered heterocycles, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 or 2 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 oxo or C(O)O(CH3)3; iii) C3-C5 cycloalkyl, iv) halo, or v) C(O)OCH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0076] In one embodiment of Formula II, there is provided a compound of Formula IIa:

[0077] [ka]

[0078] In one embodiment of Formula II, R 3 is H and R 4 is H or CH3. In an alternative embodiment of Formula II, R 3 and R 4 combine to form -CH2-CH2-.

[0079] In a further alternative embodiment, the compound of formula III:

[0080] [ka] A compound of the formula In the formula, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo; A is phenyl, pyridyl, or thienyl, wherein the phenyl, pyridyl, or thienyl is optionally substituted with a substituent selected from F, CF3, and CH3; R 4 is H or CH3, R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH3 or CHF2; R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 but, i) Hello, 4- to 6-membered heterocycles, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 or 2 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 oxo or C(O)O(CH3)3; iii) C3-C5 cycloalkyl, iv) halo, or v) C(O)OCH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0081] In one embodiment of Formula III, there is provided a compound of Formula IIIa:

[0082] [ka]

[0083] In a further embodiment of Formula III, there is provided a compound of Formula IIIb:

[0084] [ka]

[0085] In a further alternative embodiment, the compound of formula IV:

[0086] [ka] A compound of the formula In the formula, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo; A is phenyl, pyridyl, or thienyl, wherein the phenyl, pyridyl, or thienyl is optionally substituted with a substituent selected from F, CF3, and CH3; R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH3 or CHF2; R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with R 10 is CF3, CF2H or F, and R 11 but, i) Hello, 4- to 6-membered heterocycles, oxo, and a 5- or 6-membered heterocycle optionally substituted with 1 or 2 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 oxo or C(O)O(CH3)3; iii) C3-C5 cycloalkyl, iv) halo, or v) C(O)OCH3; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0087] In one embodiment of Formula IV, there is provided a compound of Formula IVa:

[0088] [ka]

[0089] In a further embodiment of Formula IV, there is provided a compound of Formula IVb:

[0090] [ka]

[0091] The following embodiments are embodiments of any or all of the applicable formulae above.

[0092] In one embodiment, X is O.

[0093] In some embodiments, R 6 and R 7 are CH3, respectively.

[0094] In one embodiment, R 2 is H or CH3. Preferably, R 2 is H.

[0095] In one embodiment, R 1 teeth, i)

[0096] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii)NR 16 COR 12 (In the formula, R 12 However, NHR 13 , OCH3 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, and R 13 is phenyl optionally substituted with one or two halo, and R 16 is H or CH3), or iii) piperazine optionally substituted with C(O)CH; pyridine optionally substituted with one or two substituents independently selected from OCH3, halo, and C1-C4 alkyl optionally substituted with OH; or It is a pyrimidine optionally substituted with one or two substituents independently selected from OCH3, CH3 and oxo.

[0097] In one embodiment, R 1 teeth, i)

[0098] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo, or iii) optionally substituted with C(O)CH

[0099] [ka] is.

[0100] In one embodiment, R 1 teeth, i)

[0101] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 (In the formula, R 12 However, NHR 13or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo, or iii) optionally substituted with C(O)CH

[0102] [ka] is.

[0103] In an alternative embodiment, R 1 teeth, i)

[0104] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with one or two halo.

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

[0106] [ka] is selected from cyclopropyl optionally substituted with —CH3, optionally difluorosubstituted cyclobutyl; Azetidinyl substituted with CH3, OCH3, CF3, CHF2, CF2CH3, Oxo, CH3, CH2CH3, CH2OCH3, (CH2)2OH, C(CH3)2OH, CH2-cyclopropyl, CH2-cyclobutyl, CN, Fluoro, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from chloro; ii)NR 16 COR 12 (In the formula, R 12 but,

[0107] [ka] OCH3, difluoro-substituted cyclohexyl or difluoro-substituted cyclobutyl; R 16 is H or CH3), or iii) C(O)CH3 substituted piperazines; pyridine substituted with one or two substituents independently selected from OCH3, F and C(CH3)2OH; It is a pyrimidine substituted with one or two substituents independently selected from OCH3, CH3 and oxo.

[0108] In one embodiment, R 1 teeth, i)

[0109] [ka] is selected from cyclopropyl optionally substituted with —CH3, optionally difluorosubstituted cyclobutyl; Azetidinyl substituted with CH3, OCH3, CF3, CHF2, CF2CH3, Oxo, CH3, CH2CH3, CH2OCH3, (CH2)2OH, C(CH3)2OH, CH2-cyclopropyl, CN, Fluoro, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from chloro; ii) NHCOR 12 (In the formula, R 12 but,

[0110] [ka] difluoro-substituted cyclobutyl or difluoro-substituted cyclobutyl), or iii) Substituted with C(O)CH3

[0111] [ka] is.

[0112] In one embodiment, R 1 teeth, i)

[0113] [ka] is selected from cyclopropyl optionally substituted with —CH3, optionally difluorosubstituted cyclobutyl; Azetidinyl substituted with CH3, OCH3, CF3, CHF2, CF2CH3, Oxo, CH3, CH2CH3, CH2OCH3, (CH2)2OH, C(CH3)2OH, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from CH2-cyclopropyl; ii) NHCOR 12 (In the formula, R 12 but,

[0114] [ka] difluoro-substituted cyclobutyl or difluoro-substituted cyclobutyl), or iii) Substituted with C(O)CH3

[0115] [ka] is.

[0116] In an alternative embodiment, R 1 teeth, i)

[0117] [ka] cyclopropyl optionally substituted by CH3, optionally difluorosubstituted cyclobutyl, 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted by 1 or 2 substituents independently selected from CF3, CHF2, CF2CH3, CH3, CH2CH3, CHOCH3 and CH2-cyclopropyl; ii) NHCOR 12 (In the formula, R 12 but,

[0118] [ka] difluoro-substituted cyclobutyl or difluoro-substituted cyclobutyl).

[0119] In a further embodiment, R 1 teeth,

[0120] [ka] In a further embodiment, R 1 teeth,

[0121] [ka] In a further embodiment, R 1 teeth,

[0122] [ka] In an alternative embodiment, R 1 teeth,

[0123] [ka] is selected from.

[0124] In a further embodiment, R 1 teeth,

[0125] [ka] In a further embodiment, R 1 teeth,

[0126] [ka] In a further embodiment, R 1 teeth,

[0127] [ka] In an alternative embodiment, R 1 teeth,

[0128] [ka] is selected from.

[0129] In one embodiment, R 1 teeth, C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0130] In one embodiment, R 1 teeth, C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0131] In an alternative embodiment, R 1 teeth, C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0132] In one embodiment, R 1 teeth,

[0133] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0134] In one embodiment, R 1 teeth,

[0135] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0136] In an alternative embodiment, R 1 teeth,

[0137] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, and and a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo.

[0138] In one embodiment, R 1 teeth,

[0139] [ka] is selected from cyclopropyl optionally substituted with —CH3, optionally difluorosubstituted cyclobutyl; Azetidinyl substituted with CH3, OCH3, CF3, CHF2, CF2CH3, Oxo, CH3, CH2CH3, CH2OCH3, (CH2)2OH, C(CH3)2OH, CH2-cyclopropyl, CN, Fluoro, and is a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from chloro.

[0140] In one embodiment, R 1 teeth,

[0141] [ka] is selected from cyclopropyl optionally substituted with —CH3, optionally difluorosubstituted cyclobutyl; Azetidinyl substituted with CH3, OCH3 CF3, CHF2, CF2CH3, Oxo, CH3, CH2CH3, CH2OCH3, (CH2)2OH, C(CH3)2OH, and is a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from CH2-cyclopropyl.

[0142] In an alternative embodiment, R 1 teeth,

[0143] [ka] and is a 9- or 10-membered N-containing bicyclic heteroaryl optionally substituted with 1 or 2 substituents independently selected from cyclopropyl optionally substituted by CH, optionally difluoro-substituted cyclobutyl, CF, CHF, CFCH, CH, CHCH, CHOCH, and CH-cyclopropyl.

[0144] In a further embodiment, R 1 teeth,

[0145] [ka] In a further embodiment, R 1 teeth,

[0146] [ka] In an alternative embodiment, R 1 teeth,

[0147] [ka] is selected from.

[0148] In a further embodiment, R 1 teeth,

[0149] [ka] In a further embodiment, R 1 teeth,

[0150] [ka] In an alternative embodiment, R 1 teeth,

[0151] [ka] is selected from.

[0152] In certain embodiments, R 1 teeth,

[0153] [ka] In certain embodiments, R 1 teeth,

[0154] [ka] In certain embodiments, R 1 teeth,

[0155] [ka] is.

[0156] In certain embodiments, R 1 teeth, NHCOR 12 where R 12 is NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with one or two halo.

[0157] In a further embodiment, R 1 teeth, NHCOR 12 where R 12 teeth,

[0158] [ka] It is a difluoro-substituted cyclobutyl or a difluoro-substituted cyclobutyl.

[0159] In a further embodiment, R 1 teeth,

[0160] [ka] is selected from.

[0161] In a further embodiment, A is

[0162] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl, or A is absent.

[0163] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl. In a further embodiment, A is

[0164] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl. In an alternative embodiment, A is

[0165] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl.

[0166] In a further embodiment, A is

[0167] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl, or A is absent.

[0168] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl. In a further embodiment, A is

[0169] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl. In an alternative embodiment, A is

[0170] [ka] wherein a is selected from R 1 and b is the point of attachment to cyclopropyl.

[0171] In certain embodiments, A is

[0172] [ka] In certain embodiments, A is

[0173] [ka] In certain embodiments, A is

[0174] [ka] is.

[0175] In a further embodiment, R 5 teeth,

[0176] [ka] In an alternative embodiment, R 5 teeth,

[0177] [ka] In an alternative embodiment, R 5 teeth,

[0178] [ka] In certain embodiments, R 5 teeth,

[0179] [ka] is.

[0180] In one embodiment, R 8 is H.

[0181] In a further embodiment, R 9 teeth,

[0182] [ka] or

[0183] [ka] In a further embodiment, R 9 teeth,

[0184] [ka] or

[0185] [ka] is a 5- or 6-membered N-containing heteroaryl selected from:

[0186] In a further embodiment, R 9 teeth,

[0187] [ka] or

[0188] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0189] [ka]

[0190] [ka] a 5- or 6-membered heterocycle selected from ii)

[0191] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv)Br, v) C(O)OCH3, vi) P(O)(CH3)2, or vii)

[0192] [ka] In certain embodiments, R 9 teeth,

[0193] [ka] and R 11 is selected from the group shown above.

[0194] In a further embodiment, R 9 teeth,

[0195] [ka] or

[0196] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0197] [ka] a 5- or 6-membered heterocycle selected from ii)

[0198] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv)Br, v) C(O)OCH3, or vi)

[0199] [ka] In certain embodiments, R 9 teeth,

[0200] [ka] and R 11is selected from the group shown above.

[0201] In a further embodiment, R 9 teeth,

[0202] [ka] or

[0203] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0204] [ka] a 5- or 6-membered heterocycle selected from ii)

[0205] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv)Br, v) C(O)OCH3, or vi)

[0206] [ka] In certain embodiments, R 9 teeth,

[0207] [ka] and R 11 is selected from the group shown above.

[0208] In an alternative embodiment, R 9 teeth,

[0209] [ka] or

[0210] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0211] [ka] a 5- or 6-membered heterocycle selected from ii)

[0212] [ka] a 9-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv) Br, or v) C(O)OCH3.

[0213] In a further embodiment, R 9 teeth,

[0214] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0215] [ka] a 5- or 6-membered heterocycle selected from ii)

[0216] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, iv) C(O)OCH3, v) P(O)(CH3)2, or vii)

[0217] [ka] In certain embodiments, R 9 teeth,

[0218] [ka] and R 11 is selected from the group shown above.

[0219] In a further embodiment, R 9 teeth,

[0220] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0221] [ka] a 5- or 6-membered heterocycle selected from ii)

[0222] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, or viii) C(O)OCH3. In certain embodiments, R 9 teeth,

[0223] [ka] and R 11 is selected from the group shown above.

[0224] In a further embodiment, R 9 teeth,

[0225] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 teeth, i)

[0226] [ka] a 5- or 6-membered heterocycle selected from ii)

[0227] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, or vii) C(O)OCH3. In certain embodiments, R 9 teeth,

[0228] [ka] and R 11 is selected from the group shown above.

[0229] In an alternative embodiment, R 9 teeth,

[0230] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3 or F, and R 11 teeth, i)

[0231] [ka] a 5- or 6-membered heterocycle selected from ii) cyclopropyl, or iii) C(O)OCH3.

[0232] In certain embodiments, R 9 teeth,

[0233] [ka] and R 11 teeth,

[0234] [ka] is a 5- or 6-membered heterocycle selected from:

[0235] In certain embodiments, R 9 teeth,

[0236] [ka] and R 11 teeth,

[0237] [ka] is a 5- or 6-membered heterocycle selected from:

[0238] In an alternative embodiment, R 9 teeth,

[0239] [ka] and R 11 teeth,

[0240] [ka] is a 5- or 6-membered heterocycle selected from:

[0241] In a further embodiment, R 9 teeth,

[0242] [ka]

[0243] [ka] is selected from.

[0244] In a further embodiment, R 9 teeth,

[0245] [ka] is selected from.

[0246] In certain embodiments, R 9 teeth,

[0247] [ka] is selected from.

[0248] In certain embodiments, R 9 teeth,

[0249] [ka] is selected from.

[0250] In alternative particular embodiments, R 9 teeth,

[0251] [ka] is selected from.

[0252] In certain embodiments, R 9 teeth,

[0253] [ka] is selected from.

[0254] In one embodiment, the compound is

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260]

change

[0261]

change

[0262]

change

[0263]

change

[0264]

change

[0265]

change

[0266]

change

[0267]

change

[0268]

change

[0269]

change

[0270]

change

[0271] [ka]

[0272] [ka]

[0273] [ka] or a pharmaceutically acceptable salt thereof.

[0274] Numbered Embodiments 1. Formula:

[0275] [ka] A compound of the formula During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , or iii) OH, R 12 However, NHR 13 , pyridyl, phenyl, or C3-C6 cycloalkyl, wherein the pyridyl, phenyl, or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; R2 is H, CH3, halo, CF3, or CHF2; R 3 is H and R 4 is H or CH3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CHF, or OH; R 6 and R 7 are each CH3 or together form cyclopropyl; R 8 is H, CH3, CO2H or C(O)OCH3, and R 9 but, phenyl optionally substituted with one or two substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; or R 10 Or R 10 and R 11 is a 5- or 6-membered N-containing heteroaryl optionally substituted with Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 but, i) Hello, OH, OCH3, SO2NH2, 4- to 6-membered heterocycles, oxo or 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; The compound, or a pharmaceutically acceptable salt thereof.

[0276] 2. R 6 and R 7 and R are each CH3; or a pharmaceutically acceptable salt thereof.

[0277] 3. R 3 is H and R 4 is H or CH3, or a pharmaceutically acceptable salt thereof.

[0278] 4. R 3 and R 4 or a pharmaceutically acceptable salt thereof.

[0279] 5. R 2 is H or CH3; or a pharmaceutically acceptable salt thereof.

[0280] 6. R 1 but, i)

[0281] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; C1-C4 haloalkyl, a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3 or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; or ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo; A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0282] 7. R 1 but,

[0283] [ka] or a pharmaceutically acceptable salt thereof.

[0284] 8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyridyl, or thienyl, wherein the phenyl, pyridyl, or thienyl is optionally substituted with a substituent selected from F, CF3, and CH3.

[0285] 9. A,

[0286] [ka] is selected from In the formula, a is R 1 and b is a point of attachment to cyclopropyl; or a pharmaceutically acceptable salt thereof.

[0287] 10. R 5 but, a 9-membered N-containing bicyclic heterocycle, or a 5-membered N-containing heteroaryl substituted with CH3 or CHF2; A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof.

[0288] 11. R 5 but,

[0289] [ka] That is, 11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof.

[0290] 12. R 8 is H; or a pharmaceutically acceptable salt thereof.

[0291] 13. R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 or a pharmaceutically acceptable salt thereof.

[0292] 14. R 9 but,

[0293] [ka] or

[0294] [ka] is a 5- or 6-membered N-containing heteroaryl selected from 14. A compound according to embodiment 13, or a pharmaceutically acceptable salt thereof.

[0295] 15. R 9 but,

[0296] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 but, i) a 5- or 6-membered heterocycle optionally substituted with one or two substituents independently selected from halo, a 4- to 6-membered heterocycle, oxo, or C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with OH, OCH3, a 4- to 6-membered heterocycle, and a C3-C4 cycloalkyl optionally substituted with halo; ii) a 9-membered N-containing bicyclic heterocycle optionally substituted with oxo or C(O)O(CH3)3; iii) C3-C5 cycloalkyl, iv) halo, or v) The compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein:

[0297] 16. R 11 but, i)

[0298] [ka] a 5- or 6-membered heterocycle selected from ii)

[0299] [ka] a 9-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv) Br, or v) The compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein:

[0300] 17. Formula:

[0301] [ka] A compound of the formula R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , iii) OH, or iv) a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH3, C1-C4 alkyl, and oxo; R 12 However, NHR 13 , pyridyl, phenyl, or C3-C6 cycloalkyl, wherein the pyridyl, phenyl, or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13 is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein the phenyl, heteroaryl, or thienyl is optionally substituted with 1 or 2 substituents independently selected from halo, CF3, CHF2, CH3, and cyclopropyl; R 2 is H, CH3, halo, CF3 or CHF2, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R 5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CD, CHF, or OH; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl; R 8 is H, CH3, CO2H, or C(O)OCH3, R9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 but, i) Hello, OH, OCH3, CD3, OCHF2, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi) C(O)OCH3, or vii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 is independently H or CH3; The compound, or a pharmaceutically acceptable salt thereof.

[0302] 18. Formula:

[0303] [ka] A compound of the formula: During the ceremony, R 1 but, i) C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, Oxo, CN, Halo, and an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 , iii) OH, or iv) a 5- or 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from C(O)CH3, C1-C4 alkyl, oxo, and CN; R 12 However, NHR 13 , pyridyl, phenyl, or C3-C6 cycloalkyl, wherein the pyridyl, phenyl, or C3-C6 cycloalkyl is optionally substituted with 1 or 2 halo; R 13 is C1-C4 alkyl or phenyl optionally substituted with 1 or 2 halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein the phenyl, heteroaryl, or thienyl is optionally substituted with 1 or 2 substituents independently selected from halo, CF, CHF, CH, cyclopropyl, or CN; or R 1 is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R 2 is H, CH3, halo, CF3 or CHF2, R 3 is H and R 4 is H, CH3 or CD3, or R 3 and R 4 together form -CH2-CH2-, R5 but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) a 5- or 6-membered N-containing heteroaryl optionally substituted with CH, CD, CHF, or OH; X is O or S; R 6 and R 7 are each CH3 or together form cyclopropyl; R 8 is H, CH3, CO2H, or C(O)OCH3, R9 is a 5- or 6-membered N-containing heteroaryl or phenyl, and the heteroaryl or phenyl is R 10 Or R 10 and R 11 or wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo, CF3, and pyrazine optionally substituted with CF2H or OCH3; Or R 8 and R 9 together form a 9-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from CH3, CF3, and oxo; R 10 is CF3, CF2H or halo, R 11 but, i) Hello, OH, OCH3, CD3, OCHF2, SO2NH2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR 14 R 15 OP(O)(OH)2, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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, CH, halo, oxo, C(O)O(CH) and OH; iii) C1-C4 alkoxy, iv) C3-C5 cycloalkyl, v) Halo, vi) C(O)OCH3, or vii) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 is independently H or CH3; The compound, or a pharmaceutically acceptable salt thereof.

[0304] 19. The compound of embodiment 17 or embodiment 18, wherein X is O, or a pharmaceutically acceptable salt thereof.

[0305] 20. R 6 and R 7 and R are each CH3; or a pharmaceutically acceptable salt thereof.

[0306] 21. R 3 is H and R 4 The compound of any one of embodiments 17-20, or a pharmaceutically acceptable salt thereof, wherein is H, CH3, or CD3.

[0307] 22. R 3and R 4 or a pharmaceutically acceptable salt thereof.

[0308] 23. R 2 is H or CH3; or a pharmaceutically acceptable salt thereof.

[0309] 24. R 1 but, i)

[0310] [ka] is selected from C3-C4 cycloalkyl optionally substituted with 1 or 2 halo or CH3; a 4-membered heterocycle optionally substituted with CH3; C1-C4 alkoxy, C1-C4 haloalkyl, oxo, and a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from OCH3, OH, or C1-C4 alkyl optionally substituted with C3-C4 cycloalkyl, wherein C3-C4 cycloalkyl is optionally substituted with 1 or 2 halo; ii) NHCOR 12 (In the formula, R 12 However, NHR 13 or C3-C6 cycloalkyl optionally substituted with 1 or 2 halo, R 13 is phenyl optionally substituted with 1 or 2 halo, or iii) optionally substituted with C(O)CH

[0311] [ka] 24. The compound of any one of embodiments 17-23, wherein:

[0312] 25. R 1 but,

[0313] [ka] 25. The compound of embodiment 24, selected from:

[0314] 26. The compound of any one of embodiments 17-25, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyridyl, pyrimidyl, or thienyl, wherein the phenyl, pyridyl, pyrimidyl, or thienyl is optionally substituted with a substituent selected from F, Cl, CF3, CHF2, and CH3.

[0315] 27. A,

[0316] [ka] wherein a is selected from R 1 and b is a point of attachment to cyclopropyl; or a pharmaceutically acceptable salt thereof.

[0317] 28. R 5 but, i) a 9-membered N-containing bicyclic heterocycle, or ii) a 5-membered N-containing heteroaryl substituted with CH, CD, or CHF; A compound according to any one of embodiments 17 to 27, or a pharmaceutically acceptable salt thereof.

[0318] 29. R 5 but,

[0319] [ka] That is, 29. A compound according to embodiment 28, or a pharmaceutically acceptable salt thereof.

[0320] 30. R 8 is H; or a pharmaceutically acceptable salt thereof.

[0321] 31. R 9 but, phenyl substituted with F, or R 10 Or R 10 and R 11 or a pharmaceutically acceptable salt thereof.

[0322] 32. R 9 but,

[0323] [ka] or

[0324] [ka] is a 5- or 6-membered N-containing heteroaryl selected from 32. A compound according to embodiment 31, or a pharmaceutically acceptable salt thereof.

[0325] 33. R 9 but,

[0326] [ka] is a 5- or 6-membered N-containing heteroaryl selected from R 10 is CF3, CF2H or F, and R 11 but, i) Hello, OH, CD3, OCHF2, CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, C(O)NH2, a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C1-C4 alkyl, wherein the C1-C4 alkyl is OH, OCH3, C(O)NR 14 R 15 , C.N., N.R. 14 R 15 a 4- to 6-membered heterocycle, or a 5- or 6-membered heterocycle optionally substituted with 1 to 4 substituents independently selected from C1 to C4 alkyl optionally substituted with C3 to C4 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 CH, halo, oxo, and C(O)O(CH); iii) C3-C5 cycloalkyl, iv) halo, v) C(O)OCH3, or vi) phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with OH; R 14 and R 15 is independently H or CH3; or a pharmaceutically acceptable salt thereof.

[0327] 34. R 11 but, i)

[0328] [ka] a 5- or 6-membered heterocycle selected from ii)

[0329] [ka] a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, or iv) C(O)OCH3, 34. A compound according to embodiment 33, or a pharmaceutically acceptable salt thereof.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] Reference to formula IX should be understood to refer to compounds of formula IX, along with any and all subformulas disclosed herein, including formulas I, II, III, IV, V, VI, VII, VIII and IX.

[0355] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0356] "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.

[0357] "C1~C n The term "haloalkyl" refers to a C1-C3 alkyl group, as defined herein, substituted with one or more halogens. n It refers to an alkyl group. Examples of C1-C4 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0358] "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.

[0359] "C1~C n The term "haloalkoxy" refers to a C1-C3 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.

[0360] "C3~C n The term "cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 3 to n carbon atoms.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] In the compounds of Formula IX 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 alkyl, where one to up to a maximum of the hydrogens present may be replaced with deuterium. For example, ethyl is C2H5, or C2H5 in which one to five hydrogens are replaced with deuterium, e.g., C2D x H 5-x 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%.

[0365] 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.

[0366] 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.

[0367] The term "therapeutically effective amount" refers to the amount or dose of a compound of formula IX, or a pharmaceutically acceptable salt thereof, 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 results obtained under similar circumstances. Factors to be considered in determining the therapeutically effective amount or dose 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 dosing regimen; and other relevant circumstances.

[0368] 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.

[0369] As used herein, the term "patient" includes mammals. The patient is preferably human.

[0370] 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.

[0371] The compound of formula IX can be formulated as a pharmaceutical composition to 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 IX 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).

[0372] 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 IX 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.

[0373] Abbreviation: "aq." refers to aqueous "BOC" or "Boc" refers to tert-butyloxycarbonyl "n-BuOH" refers to n-butanol "CDCl3" refers to deuterated chloroform "ACN" refers to acetonitrile "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene "DCE" refers to dichloroethane "DCM" refers to dichloromethane "DEPBT" refers to diethyl(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)phosphate "DIEA" refers to N,N-diisopropylethylamine "DMA" stands for N,N-dimethylacetamide "DMAP" refers to N,N-dimethylpyridine-4-amine "DMEA" refers to N,N-dimethylethylamine "DME" refers to 1,2-dimethoxyethane "DMEM" refers to Dulbecco's Modified Eagle's Medium "DMF" refers to N,N-dimethylformamide "DMSO" refers to dimethyl sulfoxide "dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride "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 "eq" stands for 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 "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid "HFIP" refers to 1,1,1,3,3,3-hexafluoroisopropanol " 1 "H-NMR" refers to proton nuclear magnetic resonance "Prep-HPLC" refers to preparative high-performance liquid chromatography "HOAc" refers to acetic acid "IPA" refers to isopropanol "IPAm" refers to isopropylamine "KOAc" stands for potassium acetate "LiHMDS" refers to lithium bis(trimethylsilyl)amide "MeOH" refers to methanol "mPa" stands for millipascal "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 "NCS" refers to N-chlorosuccinimide "NH4OAc" refers to ammonium acetate "NMP" refers to N-methyl pyrrolidine-2-one "PDA" stands for photodiode array detection "PE" stands for petroleum ether "Ph" stands for phenyl "PPh3" refers to triphenylphosphine "ppm" stands for parts per million "Prep" refers to preparation "psi" stands for pounds per square inch "Raney® Ni" refers to Raney® nickel "RT" refers to room temperature "Rt" refers to retention time "Rf" stands for retention factor "sat." means saturated "SFC" stands for supercritical fluid chromatography "SPE" stands for solid phase extraction "TBAI" refers to tetrabutylammonium iodide "tBu" refers to tert-butyl "TEA" refers to triethylamine "Temp" refers to temperature "TFA" refers to trifluoroacetic acid "THF" refers to tetrahydrofuran "2-MeTHF" refers to 2-methyltetrahydrofuran "wt%" refers to percentage by weight

[0374] Catalyst abbreviation: "(A- ta"Phos)2PdCl2" refers to bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (CAS number 887919-35-9) "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) "cataCXium® A Pd G3" refers to [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate (CAS number 1651823-59-4) "cataCXium Pd G4" refers to [di(adamantan-1-yl)(butyl)phosphine](methanesulfonato-κO)[2'-(methylamino)-2-biphenylyl]palladium (CAS number 2230788-67-5) or mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-MeNH-1,1'-biphenyl)]palladium(II). "CPhos Pd G3" refers to methanesulfonato(2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (CAS number 1447963-73-6) "(dtbbpy)NiCl2" refers to [4,4-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (CAS number 1034901-50-2) "[Ir(dF(CF3)ppy)2(dtbpy)]PF6" refers to [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (CAS number 870987-63-6) "[Ir(OMe)(1,5-cod)]2" refers to (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (CAS number 12148-71-9) "Pd(amphos)Cl2" refers to bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (CAS number 887919-35-9) "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" or "PdCl2(dppf)·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) "(Ru(OAc)2[(R)-BINAP]" refers to diacetato[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) (CAS number 325146-81-4) "Ru-(R)-Pheox" refers to ruthenium-tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-κN3]phenyl-κC]-hexafluorophosphate (CAS number 1421679-43-7) "XantPhos Pd G4" refers to (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]-palladium (CAS number 1621274-19-8) "XPhos" refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (CAS number 564483-18-7) "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)

[0375] In the following scheme, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8’ , R9, R 10 , R 11 , A and Z are as defined in formula IX.

[0376] Scheme 1

[0377] [ka] Scheme 1 illustrates the preparation of intermediates 3 and 7, which are useful in preparing compounds of the present invention. Imidazole intermediates 1 and 5 are reacted with oxathiazolidine intermediate 4 using a carbonate base such as CsCO in a solvent such as DMA at elevated temperature to give intermediates 2 and 6, respectively. The nitrogen protecting group (represented as "PG" in the scheme above) of intermediates 2 and 6 can then be removed under conditions known to those skilled in the art, e.g., 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 give intermediates 3 and 7, respectively. The same steps can be used to introduce a single R group at the 3-position. 10 Substituted intermediates can also be prepared.

[0378] Scheme 2

[0379] [ka] Scheme 2 illustrates the preparation of intermediate 13, which is useful in the preparation of compounds of the present invention. Amine 8 is first reacted with 2,4,6-triphenylpyrylium tetrafluoroborate 9 in a suitable solvent such as DCM to give intermediate 10. Nitro intermediate 11 is reacted with an alkoxide base, such as sodium methoxide, in an alcoholic solvent such as MeOH, and the resulting product is reacted with intermediate 10 in a solvent such as DMSO at elevated temperature to give 12. The nitro group is then reduced under conditions known to those skilled in the art, for example, using Raney® nickel catalyst and H2, to give amine 13.

[0380] Scheme 3

[0381] [ka] Scheme 3 illustrates the preparation of intermediates 17 and 21, useful for preparing compounds of the present invention. Aryl / heteroaryl halide 14 (where "Z" is a halogen, such as bromine) is coupled with trifluoroborate intermediate 15 (where "W" is an alkyl group, such as methyl, ethyl, or tert-butyl) using a palladium catalyst, such as cataCXium Pd G4, and a carbonate base, such as CsCO3, in an aqueous solvent mixture, such as toluene / water, at elevated temperatures to provide 16. Alternatively, vinyl intermediate 18 is reacted with diazo compound 19 (where "W" is an alkyl group, such as methyl, ethyl, or tert-butyl), in the presence of rhodium(II) acetate in a solvent, such as THF, to provide 20. Ester intermediates 16 and 20 are then converted to acids 17 and 21, respectively, under conditions known to those skilled in the art. For example, tert-butyl esters are converted to acids under acidic conditions (eg, TFA in chlorinated solvents such as DCM), and methyl and ethyl esters are hydrolyzed under aqueous basic conditions (eg, LiOH in aqueous THF at room temperature or elevated temperatures).

[0382] Scheme 4

[0383] [ka] Scheme 4 illustrates the preparation of compounds of the present invention. Alkyl bromide 22 is reacted with tetrahydrothiophene 23 in a solvent such as acetone or ACN, optionally with silver tetrafluoroborate, to give 24, which is subsequently reacted with 3-methylenedihydrofuran-2(3H)-one 25 in a solvent such as THF using a base such as lithium bis(trimethylsilyl)amide to give intermediate 26. Intermediate 26 is reacted with SOCl, benzyltriethylammonium chloride, and BF etherate in a solvent such as DCE, and then with amine intermediate 27 in a solvent such as DCM using an organic base such as TEA to give intermediate 28. Intermediate 28 is then cyclized to the spirocycle of formula IX using a carbonate base such as CsCO in a solvent such as NMP.

[0384] Scheme 5

[0385] [ka] Scheme 5 illustrates the preparation of amino acid derivatives useful in the preparation of compounds of the invention. Alkyl iodide 30 is reacted with aryl / heteroaryl iodide 31 (where "W" is an alkyl group, e.g., methyl, ethyl, or tert-butyl, and "PG" is a protecting group, e.g., Boc or benzyloxycarbonyl) using pyridine-2,6-bis(carboximidamide) dihydrochloride, nickel(II) chloride, and zinc in a solvent such as DMA to give 32. Alternatively, phosphoryl compound 33 (where "W" and "PG" are as described above) undergoes a Horner-Wadsworth-Emmons reaction with aldehyde 34 using a base such as DBU in a solvent such as DCM, followed by hydrogenation of the resulting olefin to give 32. Conditions for the reduction of olefins are known to those skilled in the art and can be achieved asymmetrically by hydrogenation using a catalyst such as Rh-COD-[(R)-MaxPhos]-BF4 at elevated temperatures in fluorinated alkane solvents (e.g., 1,1,1,3,3,3-hexafluoroisopropanol and 2,2,2-trifluoroethanol). If orthogonal protecting groups are selected for "PG" and "W," the protected amino acid 32 can be deprotected to either amine 35 or acid 36 under conditions known to those skilled in the art. For example, when "W" is methyl or ethyl, aqueous LiOH in a solvent such as TFH converts 32 to acid 36; when "PG" is Boc, 36 can be prepared from 32 under acidic conditions (e.g., using a solution of HCl in 1,4-dioxane). Acid 36 can be converted to N-methyl amino acid 38 by first reacting it with paraformaldehyde using p-toluenesulfonic acid at elevated temperature in a solvent such as toluene to give cyclic compound 37, which is then ring-opened with triethylsilane in TFA, HCl (as a solution in 1,4-dioxane), and DCE to give 38.

[0386] Scheme 6

[0387] [ka] Scheme 6 illustrates the preparation of compounds of the present invention, which can be prepared from various amine and acid intermediates using amide coupling and deprotection chemistry in various sequences of steps. The reaction conditions used to couple an amine with a carboxylic acid are known to those skilled in the art. This can include reacting a mixture of the amine and carboxylic acid with an organic base such as HATU and DIEA in a solvent such as DMF, DMA, or DMSO at temperatures between 0°C and room temperature. The reaction conditions used to deprotect a Boc- or benzyloxycarbonyl-protected amine are known to those skilled in the art and can include reacting a Boc-protected amine with HCl in 1,4-dioxane or reacting a benzyloxycarbonyl-protected amine with H2 in the presence of a palladium-on-carbon catalyst in an alcohol solvent. The reaction conditions used to convert a carboxylic acid ester to a carboxylic acid are also known to those skilled in the art. For example, methyl and ethyl esters can be hydrolyzed to the carboxylic acid using aqueous carbonate base at elevated temperatures. Amine 39 (where "PG" is a protecting group such as Boc or benzyloxycarbonyl) is coupled with 40 to give 41, which is then deprotected and coupled with 42 to give 44. Alternatively, 41 can be reacted with Lawesson's reagent in an organic solvent such as THF at elevated temperature to give 43, which is then deprotected and coupled with 42 to give 45.

[0388] Scheme 7

[0389] [ka] Scheme 7 illustrates the preparation of compounds of the invention, starting with coupling of acid 42 with amine 46, followed by ester hydrolysis to give 47. Acid 47 is then coupled with amine 40 to give compound 48. Suitable coupling and ester hydrolysis conditions are described in Scheme 6.

[0390] Scheme 8

[0391] [ka] Scheme 8 starts with intermediate 26, which is reacted with SOCl, benzyltriethylammonium chloride, and BF etherate in a solvent such as DCE, followed by reaction with amine intermediate 49 using an organic base such as TEA in a solvent such as THF and / or DMA to give intermediate 50. Intermediate 50 is then cyclized to spirocyclic compound 51 using a carbonate base such as CsCO in a solvent such as NMP or THF. Ester 51 is hydrolyzed using aqueous LiOH in tert-butanol to give 52, which is then coupled with amine 40 under amide coupling conditions known to those skilled in the art, such as DEPBT and N-methylmorpholine in a solvent such as DMA, to give compound 44.

[0392] Scheme 9

[0393] [ka] In Schemes 3, 4, 6, 7, and 8, when ring A contains a halogen, R defined in formula IX 1 or in a subsequent step R 1 At various points along the synthetic pathway, R can be converted to 1 can be introduced onto ring A. Scheme 9 illustrates these synthetic steps. For example, if ring A bears a halogen (intermediate 59 where "Z" is a halogen), a boronic acid (e.g., intermediate 58 or R) can be prepared using a palladium catalyst (e.g., Pd(dppf)Cl) and a carbonate base (e.g., CsCO) in an organic / aqueous solvent mixture (e.g., 1,4-dioxane / water). 1is a heterocycle defined by Formula IX) to give 60. An alternative approach is to react 59 with bis(pinacolato)diboron using a palladium catalyst such as Pd(dppf)Cl and a base such as KOAc in a solvent such as 1,4-dioxane at elevated temperature to give the boronate intermediate 61. Intermediate 61 can then be coupled with 62 (where "Z" is a halogen) under palladium coupling conditions (e.g., those described for the coupling of 58 and 59).

[0394] Alternatively, tert-butyl carbamate 57 can be coupled with 59 using a palladium catalyst such as Pd(dba) with XPhos and a carbonate base (e.g., CsCO) in an organic solvent such as 1,4-dioxane at elevated temperature to give 53. Boc deprotection using conditions described above (e.g., HCl in MeOH) provides the —NH group on ring A (intermediate 54), which can then be reacted with an isocyanate (e.g., intermediate 55) in the presence of an organic base (e.g., TEA) in a solvent such as DCM to give 56.

[0395] Scheme 10

[0396] [ka] Scheme 10 shows the R-type cation of pyrazole 63. 11 (where R 11denotes the introduction of an aromatic ring as defined in Formula IX), where "Z" is a halogen, and 63 represents a compound also depicted in Schemes 1, 4, 6, 7, or 8. Compound 63 can be coupled with boronic acid 64 (or an analogous boronic ester) using a palladium catalyst such as Pd(dppf)Cl and a carbonate base such as CsCO at elevated temperature in an organic / aqueous solvent such as 1,4-dioxane and water to give compound 65. Alternatively, halide 63 can be reacted with tetrahydroxydiboron, XPhos Pd G3, and KOAc in MeOH and DCE to give boronic acid 66, which is then coupled with 67 (where "Z" is a halogen) using a palladium catalyst such as Pd(dtbpf)Cl2 or XPhos Pd G3 and a carbonate base such as Na2CO3 or K2CO3 at elevated temperature in an organic / aqueous solvent mixture such as 1,4-dioxane / water or 1,4-dioxane / ethanol / water to give compound 65.

[0397] Scheme 11

[0398] [ka] In Schemes 3, 4, 6, 7, and 8, when Ring A is a 2-chloro-substituted pyridine, the 6-membered heterocycle may be modified by adding R 1 Scheme 11 shows that 2-chloropyridine analog 68 can be converted to the S-form of 6-membered heterocycle 69 in an organic solvent such as DMSO at elevated temperature. N It is shown that the compound 70 undergoes Ar reaction to give compound 70.

[0399] Scheme 12

[0400] [ka] Scheme 12 illustrates R 3 hydroxybenzoates containing a 6-oxopyridazine ring. 11Introduction of a methyl-dihydrogen phosphate group onto the 6-oxopyridazine compound 71 is shown. 6-Oxopyridazine compound 71 is reacted with di-tert-butyl(chloromethyl)phosphate using lithium tert-butoxide and sodium iodide in a solvent such as THF to give 72, which is then reacted with TFA in a solvent such as DCM to give 73.

[0401] Scheme 13

[0402] [ka] Compounds of the invention bearing an aliphatic alcohol substituent can be converted to dihydrogen phosphate (—OP(O)(OH)), as shown in Scheme 13. Alcohol 74 is reacted with diallyl-N,N-diisopropylphosphoramidite using tetrazole in a solvent such as ACN at 0° C., and the mixture is treated with aqueous HO or anhydrous tert-butyl hydroperoxide to give diallyl phosphate 75, which is then converted to phosphate 76 using phenylsilane and Pd(PPh) in a solvent such as DCM at 0° C.

[0403] Preparation 1 1-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2(1H)-one

[0404] [ka] A mixture of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (1.0 g, 4.7 mmol), pyridin-2(1H)-one (0.44 g, 4.7 mmol), K2CO3 (1.3 g, 9.3 mmol), copper(I) iodide (0.44 g, 2.3 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.33 g, 2.3 mmol) was purged with N2. 1,4-Dioxane (10 mL) was added, and the resulting mixture was stirred at 100 °C overnight. The reaction mixture was concentrated, and the residue was purified by reverse-phase flash chromatography using a gradient of 20–100% ACN / 10 mM aqueous NH4HCO3, pH = 10 (containing 5% MeOH) to give the title compound (0.21 g, 20%) as a dark green solid. ES-MS m / z 230 (M+H).

[0405] Preparations 2 and 3 1-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-1H-1,2,3-triazole

[0406] [ka] and 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-2H-1,2,3-triazole

[0407] [ka] A mixture of 2H-1,2,3-triazole (193 mg, 2.79 mmol), copper(I) iodide (111 mg, 0.582 mmol), and CsCO (1.36 g, 4.19 mmol) was purged with argon. 1,4-Dioxane (9.304 mL), N,N'-dimethylethylenediamine (150 μL, 1.40 mmol), and 3-bromo-5-(trifluoromethyl)-1H-pyrazole (500 mg, 2.33 mmol) were added, and the resulting mixture was stirred at room temperature for 2 minutes. After stirring at 120 °C for 4 days in a sealed 20 mL vial, most of the solvent was evaporated to give a paste. MeOH (15 mL) was added, and the mixture was filtered. The collected residue was washed with MeOH (3 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a gradient of 0 to 35% ACN / 10 mM aqueous NH4HCO3, pH = 10 (containing 5% MeOH) over 15 min to give the first eluting isomer, 1-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-1H-1,2,3-triazole (51.3 mg, 11%) as a pale yellow solid. ES-MS (m / z) 204.0 (M+H). The second eluting isomer, 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-2H-1,2,3-triazole (99.2 mg, 21%), also as a yellow solid. ES-MS m / z 204 (M+H).

[0408] Preparation 4 tert-Butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0409] [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 by silica gel chromatography using a gradient of 0-10% MTBE in heptane to give the second eluting isomer as the title compound (4.11 g, 67%). ES-MS m / z 330, 332 (M-tBu+H).

[0410] Preparation 5 Methyl 1-(2-(tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0411] [ka] The title compound was prepared using methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (stirring at 90°C for 30 minutes) as described in Preparation 4 and isolated as the first eluting isomer (major regioisomer) when purified by silica gel chromatography using 0-15% MTBE in heptane. ES-MS m / z 310 (M-tBu+H).

[0412] Preparation 6 tert-Butyl (2-methyl-1-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0413] [ka] A mixture of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (30.0 g, 119 mmol), 4-(trifluoromethyl)-1H-pyrazole (24.4 g, 179 mmol), and CsCO (77.8 g, 239 mmol) in DMA (199 mL) was heated at 90 °C overnight with vigorous stirring. The mixture was cooled to room temperature. Water (100 mL) and EtOAc (100 mL) were added, followed by the dropwise addition of 1 M aqueous HCl (298 mL, 298 mmol). The layers were separated, and the aqueous layer (pH approximately 2-3) was extracted with EtOAc (2 × 150 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-25% MTBE in cyclohexane to give the title compound (26.8 g, 73%) as a white solid. ES-MS m / z 252 (M-tBu+H).

[0414] The compounds in the following table were prepared as described in Preparation 1, using the appropriate pyrazole. 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.

[0415] [Table 1] a: First eluting isomer (silica, gradient 0-20% MTBE / heptane), major positional isomer b: Second eluting isomer (silica, gradient 0-50% MTBE / heptane) c: Second eluting isomer (silica, gradient 0-35% MTBE / CHX), minor positional isomer d: Approximately 1:4 mixture of regioisomers by high pH LCMS, with the title compound predominating after purification (silica, gradient 0-30% MTBE / heptane)

[0416] Preparation 11 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0417] [ka] A mixture of methyl 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (221 mg, 603 μmol), THF (3 mL), and 2 M aqueous LiOH·HO (1.81 mL, 3.62 mmol) was stirred at 50 °C overnight in a sealed 20 mL vial. The reaction mixture was cooled to room temperature and treated with 4 M HCl in 1,4-dioxane (905 μL, 3.62 mmol). After stirring for 5 min, the mixture was concentrated under a stream of N to afford the title compound in quantitative yield as a white solid. ES-MS m / z 350 m / z (M−H).

[0418] Preparation 12 tert-Butyl (1-(5-carbamoyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0419] [ka] A mixture of 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (300 mg, 854 μmol), 1H-benzo[d][1,2,3]triazol-1-ol ammonium salt (195 mg, 1.28 mmol), EDCI (246 mg, 1.28 mmol), THF (4.3 mL), and DIEA (0.44 mL, 2.56 mmol) was stirred at room temperature for 5 days in a sealed 40 mL vial. The reaction mixture was treated with additional 1H-benzo[d][1,2,3]triazol-1-ol ammonium salt (195 mg, 1.28 mmol), EDCI (246 mg, 1.28 mmol), DIEA (0.44 mL, 2.56 mmol), and THF (4.3 mL). The resulting mixture was stirred vigorously at room temperature for 2 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with saturated aqueous NaCl (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a quantitative yield of the title compound as a pale pinkish-orange gel. ES-MS (m / z) 251.2 (M-BOC+H).

[0420] Preparation 13 tert-Butyl (1-(5-(4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0421] [ka] A mixture of tert-butyl (1-(5-carbamoyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (299 mg, 854 μmol) in dry toluene (4.3 mL) was treated with 1,1-dimethoxy-N,N-dimethyl-methanamine (341 μL, 2.56 mmol). The resulting mixture was stirred at 50° C. in a sealed 20 mL vial for 1 h and then concentrated under reduced pressure to give a quantitative yield of tert-butyl (1-(5-(((dimethylamino)methylene)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate as a yellow gel. ES / MS (m / z) 406.2 m / z (M+H). HOAc (3.4 mL, 58 mmol) and hydrazine·HO (208 μL, 4.27 mmol) were added, and the mixture was stirred at room temperature for 30 min. The resulting pale yellow solution was concentrated under a stream of N. The residue was partitioned between EtOAc (15 mL) and saturated aqueous NaHCO (10 mL), and the aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and concentrated under reduced pressure to give the title compound in quantitative yield as a pale yellow gel. ES-MS m / z 319.2 (M-tBu+H).

[0422] Preparation 14 tert-Butyl (1-(5-(2-(methoxymethyl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0423] [ka] A mixture of tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (1.50 g, 3.88 mmol), 2-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (1.39 g, 5.83 mmol), and KPO (2.47 g, 11.7 mmol) in DME (15.5 mL) was sparged with argon for 5 min. Pd(PPh) (898 mg, 777 μmol) was added, and argon degassing was continued for 3 min. The resulting mixture was stirred at 95 °C overnight. The reaction mixture was cooled to room temperature and partitioned between water (30 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with water (15 mL), then saturated aqueous NaCl (15 mL), dried over Na2SO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-30% (3:1 EtOAc:EtOH) in heptane to afford the title compound (0.914 g, 55%) as a yellow solid. ES-MS m / z 363.0 (M-tBu+H).

[0424] Preparation 15 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

[0425] [ka] To 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 by silica gel chromatography using a gradient of 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).

[0426] The compounds in the following table were prepared using the appropriate commercially available boron esters or boronic acids as described in Preparation 15. A variety of reaction temperatures, bases and purification techniques can be used and will be apparent to those skilled in the art.

[0427] [Table 2] a: 3 eq of cyclopropylboronic acid and K2CO3 were used, heated at 90°C, and extracted with EtOAc. b: K2CO3 (3 eq) was used, heated at 95 °C and extracted with 1:1 EtOAc:toluene (no further purification).

[0428] Preparation 18a tert-Butyl (1-(5-cyclobutyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0429] [ka] tert-Butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (97 mg, 0.25 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate or [Ir(d A solution of [F(CF3)ppy)2(dtbpy)]PF6 (CAS no. 870987-63-6, 2.8 mg, 2.5 μmol), [4,4-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride, or (dtbbpy)NiCl2 (CAS no. 1034901-50-2, 5.0 mg, 13 μmol), and tris(trimethylsilyl)silane (78 μL, 0.25 mmol) in DME was sparged with N2 for 5 min. 2,6-Lutidine (0.15 mL, 1.3 mmol) and bromocyclobutane (50 mg, 0.37 mmol) were added, and the resulting mixture was irradiated overnight at 465 nm in a photochemical reactor. The reaction mixture was passed through a syringe filter and purified by reverse-phase prep-HPLC (Kinetex® EVO C18, 30 × 100 mm, 5 μm, 85 mL / min) using a gradient of 50–86% ACN in 10 mM aqueous NH4HCO3, pH = 10 (containing 5% MeOH) over 6 min to give the title compound (20 mg, 22%) as a yellow oil. ES-MS m / z 362.0 (M+H).

[0430] Preparation 19 (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid

[0431] [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 by silica gel chromatography using a gradient of 0-4% (0.1% FA / MeOH) in DCM to give the title compound (1.45 g, 80%) as a brown oil. ES-MS m / z 352.3 (M+H).

[0432] Preparation 20 tert-Butyl (2-methyl-1-(5-(2-methyl-1H-imidazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0433] [ka] To a solution of (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (500 mg, 1.40 mmol), 5-bromo-2-methyl-1H-imidazole (562 mg, 3.49 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added KCO (579 mg, 4.19 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride or PdCl(dtbpf) (CAS number 95408-45-0, 182 mg, 279 μmol) at room temperature. The resulting mixture was stirred under N at 100 °C for 12 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-60% EtOAc in PE to give the title compound (140 mg, 21%) as a yellow solid. ES-MS m / z 388.7 (M+H).

[0434] Preparation 21 tert-Butyl (1-(5-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0435] [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 (3×15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 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).

[0436] Preparation 22 1-(5-Bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine hydrochloride

[0437] [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 1,4-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 / 81 Br) 286.0 / 288.0 (M+H).

[0438] The compounds in the following table were prepared from the appropriate tert-butyl carbamate as described in Preparation 22. Various reaction times (2-43 hours), eq of HCl (4-18 eq), and co-solvents (MeOH, EtOH, EtOAc, 1,4-dioxane) can be used and will be apparent to those skilled in the art.

[0439] [Table 3-1]

[0440] [Table 3-2] a. 36-hour reaction time, 10 eq. of HCl was used b. 16 hour reaction time c. EtOAc as co-solvent, 12 eq HCl; d. Using EtOH as a co-solvent and 18 eq of HCl for a reaction time of 2.5 hours, a mixture of approximately 1:4 regioisomers was obtained in favor of the title compound. e. EtOAc was used as a co-solvent, reaction time was 5 hours, 10 eq of HCl was used f. 6 h reaction time, 10 eq HCl was used, and the product was triturated with DCM / ether to give a solid. g. EtOAc was used as a co-solvent, 12 eq of HCl was used, and the reaction time was 43 h. h. 10 eq of HCl was used i. 1,4-dioxane was used as the solvent, and the reaction time was 16 hours.

[0441] Preparation 35 3-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2(1H)-one hydrochloride

[0442] [ka] A solution of tert-butyl (1-(5-(2-methoxypyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (132.2 mg, 239.2 μmol, approximately 75% purity) in DCM (957 μL) was treated with 4 M HCl in 1,4-dioxane (179 μL, 718 μmol). After stirring overnight at room temperature, an additional portion of 4 M HCl in 1,4-dioxane (897 μL, 3.59 mmol) was added, and the resulting mixture was stirred at 50° C. for 3 days. HBr in HOAc (33 wt% in HOAc, 130.0 μL, 718 μmol) was added, and stirring was continued at 50° C. for 24 h. The reaction mixture was concentrated under a stream of N to afford a quantitative yield of the title compound (143.1 mg, approximately 55% purity) as a brown solid. ES-MS m / z 301.2 (M+H).

[0443] Preparation 36 (6-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2(1H)-one hydrochloride

[0444] [ka] The title compound was prepared in a similar manner as described in Preparation 35 using tert-butyl (1-(5-(6-methoxypyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate. ES-MS m / z 301.2 (M+H).

[0445] Preparation 37 1-((5-fluoropyridin-2-yl)methyl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate

[0446] [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 under vacuum 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 + ).

[0447] Preparation 38 5-Fluoro-2-(2-methyl-2-nitropropyl)pyridine

[0448] [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 under reduced pressure overnight. To the white solid was added 1-((5-fluoropyridin-2-yl)methyl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate (19 g, 38 mmol) and DMSO (50 mL) in a 250 mL three-neck flask equipped with a mechanical stirrer under N2. 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 ether (3 x 50 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 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).

[0449] Preparation 39 1-(5-fluoropyridin-2-yl)-2-methylpropan-2-amine hydrochloride

[0450] [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® Ni (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 0.41 MPa 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 with 996 mg of 5-fluoro-2-(2-methyl-2-nitropropyl)pyridine. The combined filtrate was concentrated. The residue was dissolved in ether (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. ES / MS m / z 169.0 (M+H). This oil was dissolved in ether (200 mL) and treated with 4 M HCl in 1,4-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 fluffy, yellow, hygroscopic solid. ES-MS m / z 268.8 (M+H).

[0451] Preparation 40 Methyl (Z)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)acrylate

[0452] [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 under N at 0–5 °C. 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).

[0453] The compounds in the following table were prepared using the appropriate phosphonate and aldehyde as described in Preparation 40. The compounds can be purified using a variety of methods that will be apparent to those skilled in the art.

[0454] [Table 4] a. The product was purified by trituration with ACN.

[0455] Preparation 42 Methyl 2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoate, enantiomerically enriched in the (R)-enantiomer (approximately 3:1)

[0456] [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 under reduced pressure and purged with H2 several times. After stirring under H2 (3.00 MPa) 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 10 reactions were combined to give the title compound (6.80 kg, 97%) as a yellow oil: ES-MS m / z 318.1 (M+H).

[0457] Preparation 43 (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid

[0458] [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 reduced pressure at 45°C to give enantiomerically enriched (R)-enantiomer 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). 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 0°C solution of the salt (1.01 kg, 1.96 mol) in water (15 L) was adjusted to pH 9 with 20% aqueous NaCO and extracted with EtOAc (3 x 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 x 4 L). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (10.0 L) for 2 hours at 20°C, 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). D 20= -4.98°C (C = 1.0, ACN:HO, 5:1). >98% ee, Rt = 3.44 min (SFC, Chiralpak® AD-3, 150 × 4.6 mm, 3 μm, 35 °C, gradient 10 to 50% IPA in CO (with 0.1% IPAm) for 3.5 min, 2.5 mL / min, 220 nm).

[0459] Preparation 44 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanoate

[0460] [ka] In a glovebox under N2, methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)acrylate (20.28 g, 63.71 mmol) and Rh-COD-[(R)-MaxPhos]-BF4 (CAS No. 1263077-53-7, 778 mg, 1.39 mmol) were added to a 600 mL autoclave. 1,1,1,3,3,3-Hexafluoroisopropanol (33 mL, degassed) and 2,2,2-trifluoroethanol (367 mL, degassed) were added. The autoclave was sealed, purged with H2, and then pressurized to 1.7 MPa with H2. The reaction temperature was gradually increased from room temperature to 60 °C over 30 min with stirring. After heating for 8 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The orange liquid residue was dissolved in DCM (200 mL) and concentrated under reduced pressure twice, followed by a third concentration with MTBE (250 mL) to give an orange glass (28.8 g) that was crystallized from MTBE (200 mL). The solid was collected by filtration and rinsed with cold MTBE (100 mL). Drying under reduced pressure at 50° C. gave the title compound (8.13 g, 40%) as a tan powder. ES-MS m / z 321.1 (M+H). [a] D 20 =+48.8°(C=0.2,MeOH). [a] D 20=-10°(c=0.2,CHCl3). >99%ee, Rt=1.33 min (SFC, ChiralCel® OD-H, 4.6 x 100 mm, 5 μm, 40°C, 20% IPA:80% CO2, 5 mL / min, 225 nm).

[0461] Preparation 45 Benzyl (R)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxooxazolidine-3-carboxylate

[0462] [ka] A solution of (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (190 g, 626 mmol) in toluene (7.22 L) was treated with p-toluenesulfonic acid monohydrate (23.8 g, 125 mmol) and paraformaldehyde (73.3 g, 2.44 mol). The resulting mixture was stirred at 120 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (145 g, 73%) as a colorless oil. ES-MS m / z 316.3 (M+H).

[0463] Preparation 46 (R)-2-(((benzyloxy)carbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid

[0464] [ka] To a solution of benzyl (R)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxooxazolidine-3-carboxylate (145 g, 460 mmol) in DCE (1.45 L) was added triethylsilane (534 g, 4.60 mol), TFA (1.57 kg, 13.80 mol), and 4 M HCl / dioxane (115 mL). The resulting mixture was stirred at 70 °C for 3 h and then concentrated under reduced pressure. HO (500 mL) was added, followed by 5 N aqueous NaOH to bring the mixture to pH > 10. Extraction was performed with DCM (2 × 500 mL). The aqueous layer was acidified with 5 N HCl to pH < 2 and extracted with DCM (2 × 500 mL). The organic layers of this second set were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 g, 68.5%) as a colorless oil. ES-MS m / z 318.1 (M+H). [a] D 20 = +38.7°C (C = 1.0, ACN). 97.5% ee, Rt = 2.38 min (SFC, Chiralpak® IG-3, 4.6 × 100 mm, 3 μm, 35 °C, gradient 10–50% EtOH (containing 0.2% 7 M NH in MeOH) in CO over 3.4 min, 3.4 mL / min, 220 nm).

[0465] Preparation 47 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoate

[0466] [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 organic layers were combined and 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 by silica gel column chromatography using a gradient of 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, Rt = 0.55 min (SFC, Chiralcel® OJ-3, 4.6 × 150 mm, 3 μm, 35 °C, gradient 5–50% EtOH (with 0.05% DMEA) in CO for 1.4 min, 3 mL / min, 220 nm).

[0467] Preparation 48 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0468] [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 organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 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, Rt = 1.38 min (SFC, Chiralpak® AD-3, 4.6 × 150 mm, 3 μm, 35 °C, gradient 10-50% EtOH (with 0.2% 7 M NH in MeOH) in CO for 3 min, 2.5 mL / min, 220 nm).

[0469] Preparation 50 (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid

[0470] [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 under reduced pressure afforded the title compound (10.5 g, 94%) as a white solid. ES-MS m / z 250.1 (M-tBu+H). >99% ee, Rt=2.73 min (SFC, Chiralpak® AD-3, 4.6×150 mm, 3 μm, 35° C., 15% IPA (with 0.5% IPAm):85% CO , 2.5 mL / min, 220 nm).

[0471] The compounds in the following table were prepared as described in Preparation 50. 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.

[0472] [Table 5]

[0473] Preparation 53 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

[0474] [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 by silica gel chromatography using a gradient of 50-65% MTBE in heptane to give the title compound (14.4 g, 96%) as a white foam. ES-MS m / z 517, 519 (M-tBu+H).

[0475] The compounds in the following table were prepared as described in Preparation 53 using the appropriate carboxylic acid and the appropriate amine. The reactants can 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) can be varied, and different methods can 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.

[0476] [Table 6-1]

[0477] [Table 6-2]

[0478] [Table 6-3]

[0479] [Table 6-4]

[0480] [Table 6-5]

[0481] Preparation 79 tert-Butyl (R)-(1-((1-(5-(2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0482] [ka] A solution of tert-butyl (1-(5-(2-(methoxymethyl)-2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (914 mg, 2.18 mmol) in EtOAc (6.2 mL) was treated with 4 M HCl in 1,4-dioxane (6.6 mL, 26.2 mmol). The resulting mixture was stirred at room temperature for 17 h, then at 45° C. for 5 h, followed by room temperature for 3 days. TFA (2.0 mL, 26.2 mmol) was added and heating was resumed at 45° C. for 19 h. The mixture was concentrated under a stream of N2. The residue was dissolved in TFA (6.2 mL, 54.7 mmol) and heating resumed at 45 °C for 1.25 h, after which it was concentrated under a stream of N to give a quantitative yield of 1-(5-(2H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine trifluoroacetate. ES-MS m / z 275.2 (M+H). The residue and R)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (588 mg, 2.19 mmol) were combined in DMF (5.5 mL) and treated with HATU (790 mg, 3.28 mmol) and DIEA (381 μL, 2.19 mmol). After stirring overnight at room temperature, DIEA (381 μL, 2.19 mmol) and HATU (790 mg, 3.28 mmol) were added, and stirring was continued for 2.25 h. The reaction mixture was partitioned between saturated aqueous NaHCO (15 mL) and 1:1 EtOAc:toluene (20 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with saturated aqueous NaCl (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–20% (7M NH / MeOH) in DCM to afford the title compound (282 mg, 25%) as a yellow liquid. ES-MS m / z 526.2 (M+H).

[0483] Preparation 80 Benzyl ((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

[0484] [ka] To a mixture of benzyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (13.4 g, 23.5 mmol) and Na2CO3 (7.46 g, 70.4 mmol) in MeOH (50 mL) was sparged with N2 for 30 min. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(amphos)Cl2 (CAS number 887919-35-9, 1.66 g, 2.35 mmol), and 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (10.8 g, 38.7 mmol) were added, and degassing was continued for 2 min. The vessel was sealed and stirred at 75 °C overnight. The reaction mixture was partitioned between EtOAc and water. Saturated aqueous NaCl was added, and the layers were separated. The aqueous layer was extracted twice more with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-30% (3:1 EtOAc:EtOH) in cyclohexane to give the title compound (12.8 g, 85%) as a yellow glass. ES-MS m / z 644.4 (M+H).

[0485] Preparation 81 2-(4-Bromopyridin-2-yl)propan-2-ol

[0486] [ka] A mixture of ethyl 4-bromopicolinate (2.2 g, 9.6 mmol) in THF (10 mL) was treated with 3 M methylmagnesium bromide (9.6 mL, 29 mmol) in EtO at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, then quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 18% EtOAc in PE to give the title compound (1.6 g, 69%) as a colorless oil. ES-MS m / z 216, 218 (M+H).

[0487] Preparation 82 4-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridine

[0488] [ka] A solution of 2-(4-bromopyridin-2-yl)propan-2-ol (1.6 g, 7.0 mmol), TEA (2 mL, 10 mmol), and DMAP (86 mg, 0.70 mmol) in DMF (10 mL) at 0° C. was treated with tert-butyldimethylsilyl chloride (1.5 g, 10 mmol), and the resulting mixture was stirred at 100° C. for 48 h. The reaction mixture was cooled and combined with a second reaction carried out in a similar manner with 650 mg of 2-(4-bromopyridin-2-yl)propan-2-ol. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×20 mL). The organic layers were combined, washed with saturated aqueous NaCl (2×30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-6% EtOAc in PE to give the title compound (1.4 g, 42%) as a yellow oil. ES-MS m / z 330, 332 (M+H).

[0489] Preparation 83 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0490] [ka] To an N-sparged solution of 4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridine (1.4 g, 4.0 mmol), bis(pinacolato)diborane (2.6 g, 10 mmol), and KOAc (99 mg, 10 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl (290 mg, 0.40 mmol). The mixture was stirred at 100 °C under N for 4 h. The reaction mixture was cooled, and water (20 mL) was added. The mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with saturated aqueous NaCl (3 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0–25% EtOAc in PE to give the title compound (1.2 g, 63%, 80% pure). TLC (1:3 EtOAc:PE) f =0.6.

[0491] Preparation 84 tert-Butyl (R)-(1-((1-(5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0492] [ka] To an N-sparged solution of 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (220 mg, 466 μmol, 80% purity), tert-butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (300 mg, 502 μmol, 90% purity) and NaCO (125 mg, 1.18 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was added Pd(dppf)Cl (40 mg, 55 μmol). The resulting mixture was stirred at 90° C. under N for 16 hours, then diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The organic layers were combined, washed with saturated aqueous NaCl (2×20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-4% MeOH / DCM to give the title compound (380 mg, 83%, 72% purity) as a white solid. ES-MS m / z 708.7 (M+H).

[0493] The compounds in the following table were prepared as described in Preparation 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.

[0494] [Table 7] a: 3 eq of boron ester, 100℃, 32 hours b: 3 eq of boron ester, purified at 100 °C for 16 h, 0–90% EtOAc / PE. c:90℃, 5 hours.

[0495] Preparation 88 tert-Butyl (R)-(1-((1-(5-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0496] [ka] A 0° C. solution of tert-butyl (R)-(1-((1-(5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (370 mg, 376 μmol) in THF (3 mL) was treated with 1 M tetrabutylammonium fluoride in THF (1 mL, 1 mmol), and the mixture was stirred at 15° C. for 2 days. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with saturated aqueous NaCl (2×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-8% MeOH in DCM to give the title compound (180 mg, 79%) as a white solid. ES-MS m / z 594.2 (M+H).

[0497] Preparation 89 (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

[0498] [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% pure) 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 the title compound in quantitative yield (140 mg, approximately 70% pure) as a yellow solid. ES-MS m / z 462.2 (M+H).

[0499] Preparation 90 Benzyl (R)-(1-((2-methyl-1-(1'-methyl-5-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazol]-2-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0500] [ka] A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (102 mg, 490 μmol), benzyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (140 mg, 245 μmol), and KPO (156 mg, 735 μmol) in DME (1.2 mL) was sparged with argon for 2 min. Pd(PPh) (28.3 mg, 24.5 μmol) was added, and argon degassing was continued for 3 min. After stirring overnight at 95°C, the reaction mixture was cooled and treated with additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (102 mg, 490 µmol), KPO (156 mg, 735 µmol), and Pd(PPh) (28.3 mg, 24.5 µmol). Stirring was resumed at 95°C for 4 hours. The reaction mixture was cooled and partitioned between water (10 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with water (10 mL), then saturated aqueous NaCl (10 mL), dried over NaSO, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% (3:1 EtOAc:EtOH) in heptane to give a quantitative yield of the title compound as a yellow gel: ES-MS m / z 573.4 (M+H).

[0501] Preparation 91 tert-Butyl (R)-(3-(imidazo[1,2-a]pyrimidin-3-yl)-1-((2-methyl-1-(1'-methyl-5-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazol]-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate

[0502] [ka] The title compound was prepared using tert-butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)-1-oxopropan-2-yl)carbamate as described in Preparation 90. ES-MS m / z 576.2 (M+H).

[0503] Preparation 92 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

[0504] [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 1,4-dioxane / water (20 mL) under N and sparged with 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 by silica gel chromatography using a gradient of 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).

[0505] Preparation 93 (R)-(1-(2-(2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid

[0506] [ka] The title compound was prepared as described in Preparation 20 using tert-butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate and purified on silica using 0-20% (0.1% FA / MeOH) in DCM. ES-MS m / z 503.3 (M+H).

[0507] Preparation 94 tert-Butyl (R)-(1-((1-(5-(1,2,4-thiadiazol-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0508] [ka] A solution of (R)-(1-(2-(2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (100 mg, 195 μmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was diluted with 3-bromo-[1,2,4]thiadiazole (42.3 mg, 254 μmol), Na2CO3 (62.7 mg, 585 μmol) and methanesulfonato(2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), CPhos Pd The resulting mixture was treated with G3 (CAS No. 1447963-73-6, 31.8 mg, 39.0 μmol). The resulting mixture was purged with N2 and stirred under N2 at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0-7% MeOH in DCM to afford the title compound (82 mg, 47%, 61% purity) as a brown solid. ES-MS m / z 543.3 (M+H).

[0509] Preparation 95 (R)-2-Amino-N-(1-(4-fluoro-5'-(trifluoromethyl)-1H,2'H-[3,3'-bipyrazol]-2'-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride

[0510] [ka] A solution of 3-bromo-4-fluoro-1H-pyrazole (500 mg, 3.03 mmol) in DMF (8 mL) at 0° C. was treated with NaH (60 wt% in mineral oil, 145 mg, 3.64 mmol). After stirring at 0° C. for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (644 μL, 3.64 mmol) was added. The resulting mixture was stirred at 20° C. for 1 h and then diluted with EtOAc (30 mL) and water (20 mL). The organic layer was washed with water (2×20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-3% EtOAc / PE to give a mixture of regioisomeric 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and 5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (560 mg, 62%) as a colorless oil. ES-MS m / z 295, 297 (M+H).

[0511] A portion of the regioisomeric mixture (209 mg, 351 μmol) was combined with (R)-(1-(2-(2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (180 mg, 351 μmol) and Na2CO3 (74.4 mg, 702 μmol) in 1,4-dioxane (4 mL) and water (0.4 mL), and XPhos Pd G3 (59.5 mg, 70.2 μmol) was added in a glovebox. After stirring at 90 °C under N2 for 16 h, the reaction mixture was diluted with EtOAc (10 mL) and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-3% MeOH / DCM to give the regioisomers tert-butyl((2R)-1-((1-(4'-fluoro-5-(trifluoromethyl)-2'-((2-(trimethylsilyl)ethoxy)methyl)-2H,2'H-[3,3'-bipyrazol]-2-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropane-2- A mixture of (R)-(1-((1-(4-fluoro-5'-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,2'H-[3,3'-bipyrazol]-2'-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (138 mg, 45%, purity 77%) was obtained as a yellow oil. ES-MS m / z 695.4 (M+Na).

[0512] The mixture of regioisomers was dissolved in 1,4-dioxane (1 mL) and treated with 2 M HCl in 1,4-dioxane (2.00 mL, 4.00 mmol). The resulting mixture was stirred at 20° C. for 16 hours and then concentrated to give the title compound (110 mg, 95%, 65% purity) as a yellow solid. ES-MS m / z 443.3 (M+H).

[0513] Preparation 96 (R)—N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-(methylamino)propanamide

[0514] [ka] Benzyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)(methyl)carbamate (1.50 g, 2.56 mmol), 1-methyl-5-(4,4,5,5-tetramethyl- To a mixture of 1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.51 g, 6.41 mmol), Pd(dppf)Cl.CHCl (CAS no. 95464-05-4, 314 mg, 384 μmol), and KCO (1.06 g, 7.69 mmol) was added 1,4-dioxane (13 mL) and water (4.3 mL) under N. After sparging with N for 5 min, the reaction vessel was sealed and the mixture was stirred at 95 °C for 30 min, then at 37 °C for 24 h, and then at 55 °C for 22 h. The resulting mixture was cooled to room temperature and diluted with 0.1 M aqueous HCl (75 mL) and EtOAc (60 mL). The layers were separated, and the organic layer was extracted with 0.1 M aqueous HCl (4 × 50 mL). The aqueous layers were combined, basified with 2M aqueous LiOH, and extracted with EtOAc (6×50 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (1.23 g, 85%, 85% purity) as a solid. ES-MS m / z 480.2 (M+H).

[0515] Preparation 97 tert-Butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)hydrazine-1-carboxylate

[0516] [ka] To a solution of tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate (9.0 g, 48 mmol) in MeOH (100 mL) were 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 hours, and then NaBHCN (4.5 g, 72 mmol) was added. After stirring at 25 °C for 16 hours, 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 by silica gel chromatography using a 0-10% EtOAc / PE gradient to give the title compound (13.2 g, 86%) as a white solid. ES-MS m / z 304.2 (M+H).

[0517] Preparation 98 1-(2-amino-2-methylpropyl)-3-(difluoromethyl)-1H-pyrazol-5-ol formate

[0518] [ka] A solution of tert-butyl 2-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)hydrazine-1-carboxylate (13.2 g, 41.3 mmol) in MeOH (50 mL) was treated with 2 M HCl in MeOH (50 mL, 100 mmol). The resulting mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure to give 1-hydrazinyl-2-methylpropan-2-amine hydrochloride (8.5 g, 92%) as a white solid. A portion of this solid (1.57 g, 14.4 mmol) was added to a solution of ethyl 4,4-difluoro-3-oxobutanoate (2.00 g, 12.0 mmol) and FA (1.36 mL, 36.1 mmol) in MTBE (20 mL) and water (5 mL) at 5 °C. The cooling bath was removed, and the reaction mixture was stirred at 22°C for 24 hours, then concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (Xtimate® C18, 40 x 150 mm, 10 µm) eluting with a gradient of 0-20% ACN (containing 0.1% FA) in water to give the title compound (3.6 g, 40%, purity 34%) as a yellow oil. ES-MS (m / z) 205.9 (M+H).

[0519] Preparation 99 tert-Butyl (R)-(1-((1-(3-(difluoromethyl)-5-hydroxy-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0520] [ka] To a solution of 1-(2-amino-2-methylpropyl)-3-(difluoromethyl)-1H-pyrazol-5-ol (700 mg, 1.16 mmol, 34% purity) in DMA (2 mL) was added (R)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanoic acid (263 mg, 0.93 mmol), HATU (882 mg, 2.32 mmol), and DIEA (808 μL, 4.64 mmol) at 25° C. After stirring for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×35 mL). The organic layers were combined, washed with water (3×40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-7% DCM / MeOH to give the title compound (334 mg, 54%, 85% purity) as a yellow oil. ES-MS (m / z) 457.2 (M+H).

[0521] Preparation 100 (R)-1-(2-(2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-methylpropyl)-3-(difluoromethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate

[0522] [ka] A solution of tert-butyl (R)-(1-((1-(3-(difluoromethyl)-5-hydroxy-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (357 mg, 665 μmol, 85% purity) and phenyltriflimide (475 mg, 1.33 mmol) in THF (5 mL) was treated with potassium tert-butoxide (112 mg, 1.0 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 12 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in DCM to give the title compound (358 mg, 78%, 85% purity) as a yellow oil. ES-MS (m / z) 589.1 (M+H).

[0523] Preparation 101 tert-Butyl ((2R)-1-((1-(3-(difluoromethyl)-5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0524] [ka] To a mixture of (R)-1-(2-(2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)propanamido)-2-methylpropyl)-3-(difluoromethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (328 mg, 474 μmol, 85% purity), 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (145 mg, 521 μmol) and NaCO (100 mg, 947 μmol) in 1,4-dioxane (5 mL) and water (0.3 mL) was added Pd(dppf)Cl (69.3 mg, 94.7 μmol). The mixture was stirred under N2 at 90 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with saturated aqueous NaCl (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in DCM to give the title compound (140 mg, 49%) as a yellow solid. ES-MS m / z 592.3 (M+H).

[0525] Preparation 102 (R)-2-Amino-N-(1-(3-(difluoromethyl)-5-(2H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride

[0526] [ka] To a solution of tert-butyl ((2R)-1-((1-(3-(difluoromethyl)-5-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (140 mg, 234 μmol) in MeOH (3 mL) was added 2 M HCl in 1,4-dioxane (3 mL, 6 mmol) at 25° C. After stirring at 30° C. for 3 h, the mixture was concentrated under reduced pressure to give the title compound (164 mg, 95%, purity 60%) as a yellow solid. ES-MS m / z 408.1 (M+H).

[0527] Preparation 103 (R)-2-Amino-N-(2-methyl-1-(1'-methyl-5-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazol]-2-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide trifluoroacetate

[0528] [ka] A solution of benzyl (R)-(1-((2-methyl-1-(1'-methyl-5-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazol]-2-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (140.0 mg, 244.5 μmol) in TFA (2.5 mL) was stirred at 45° C. for 33 h. The reaction mixture was concentrated under a stream of N2 to give the title compound in quantitative yield as a yellow gel. ES-MS m / z 439.4 (M+H).

[0529] Preparation 104 (R)-2-Amino-N-1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide trifluoroacetate

[0530] [ka] The title compound was prepared using benzyl (R)-(1-((1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate as described in Preparation 103. ES-MS m / z 399.2 (M+H).

[0531] Preparation 105 (R)-2-Amino-N-(1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide

[0532] [ka] A mixture of benzyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (9.9 g, 17 mmol) in TFA (100 mL) was stirred at 35 °C for 3 days. After concentration under reduced pressure, the oily residue was cooled at 0 °C, diluted with DCM (500 mL), and basified to approximately pH 8 with ice-cold 1 M aqueous NaOH. The layers were separated, and the aqueous layer was extracted with 3:1 CHCl / IPA (500 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-5% 7 M NH / MeOH in DCM. The mixed fractions were repurified by silica gel chromatography using a gradient of 50-100% EA / cyclohexane, then switched to 5% 7M NH3 / MeOH in DCM. These two batches were combined to give the title compound (4.6 g, 65%) as a colorless oil. ES-MS m / z 437, 439 (M-tBu+H).

[0533] Preparation 106 (R)-N-(1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-(methylamino)propanamide hydrochloride

[0534] [ka] A solution of benzyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)(methyl)carbamate (3.43 g, 5.86 mmol) in TFA (19.5 mL) was stirred at 55 °C for 2 days. After concentration under reduced pressure, the residue was partitioned between 3:1 heptane / EtOAc (150 mL) and 0.05 M aqueous HCl (150 mL). The organic layer was extracted with 0.05 M aqueous HCl (3 × 50 mL). The aqueous layers were combined, neutralized with saturated aqueous NaHCO (200 mL), adjusted to pH 10 with saturated aqueous NaCO, and extracted with DCM (4 × 100 mL). The combined DCM extracts were dried over NaSO and filtered. The filtrate was treated with 4.0 M HCl in 1,4-dioxane (7.3 mL, 29.3 mmol), and the resulting mixture was concentrated under a stream of N at 30° C. to give a quantitative yield of the title compound (3.27 g) as an off-white solid. ES-MS m / z 451, 453 (M+H).

[0535] Preparation 107 (R)-N-(2-methyl-1-(5-(2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-(methylamino)propanamide hydrobromide

[0536] [ka] A solution of benzyl (R)-methyl (1-((2-methyl-1-(5-(2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (122.6 mg, 204.5 μmol) in DCM (1.4 mL) was treated dropwise with 33 wt% HBr in HOAc (269 μL, 1.64 mmol). The resulting mixture was stirred at 40° C. for 2 h and then concentrated under a stream of N2. EtOAc (5 mL) was added to the residue, and the mixture was sonicated for 2 min. Heptane (5 mL) was added, and the mixture was sonicated for an additional 2 min. The mixture was concentrated under reduced pressure to give a quantitative yield of the title compound (155.6 mg) as a light brown powder: ES-MS m / z 466.2 (M+H).

[0537] Preparation 108 (R)-N-(2-methyl-1-(5-(6-oxo-1,6-dihydropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-(methylamino)propanamide hydrobromide

[0538] [ka] The title compound was prepared using benzyl (R)-methyl (1-((2-methyl-1-(5-(6-oxo-1,6-dihydropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate as described in Preparation 107. ES-MS m / z 466.2 (M+H).

[0539] Preparation 109 (R)-2-Amino-N-(2-methyl-1-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrobromide

[0540] [ka] To a solution of 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 (140 mg, 219 μmol) in DCM (4 mL) was added BBr3 (150 μL, 1.59 mmol) at 0° C. The mixture was stirred with cooling for 2 hours and then combined with the second reaction mixture (31 μmol scale). The combined mixture was suction filtered, and the collected solid was washed with EtOAc to give the title compound (140 mg, 65%, purity approximately 64%) as a white solid. ES-MS m / z 473.2 (M+H).

[0541] Preparation 110 (R)-2-Amino-N-(2-methyl-1-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide

[0542] [ka] To a mixture of 10% Pd / C (50% wet) (1.5 g, 1.4 mmol) wetted with EtOH (1 mL) under a blanket of N was added benzyl (R)-(1-((2-methyl-1-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (3.88 g, 7.9 mmol) and MeOH (40 mL). The resulting mixture was stirred under 0.31 MPa of H at room temperature overnight. The reaction was repeated on the same scale. The reaction mixtures were combined by filtration through the same bed of diatomaceous earth and rinsing with EA. The filtrate was concentrated under reduced pressure and the residue was dissolved in DCM, passed through a hydrophobic frit, and rinsed with DCM. The filtrate was concentrated under reduced pressure to give a quantitative yield of the title compound (5.84 g) as a clear, slightly yellow oil: ES-MS m / z 359.2 (M+H).

[0543] The compounds in the following table were prepared from the appropriate benzyl carbamate as described in Preparation 110. A variety of H pressures (0.10-0.31 MPa) and reaction times (4 hours to overnight) can be used and will be apparent to those skilled in the art.

[0544] [Table 8] a: Catalyst: 20% Pd(OH)2, 50% water wet state

[0545] Preparation 114 (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

[0546] [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 hours, the mixture was concentrated under a stream of N2 to give the title compound (1.1 g) in quantitative yield as a yellow solid. ES-MS m / z 520.0 (M+H).

[0547] The compounds in the following table were prepared from the appropriate tert-butyl carbamate as described in Preparation 114. Various reaction times (15 min-24 h), equivalents of HCl (3-25 eq), and co-solvents (such as EtOAc) can be used and will be apparent to those skilled in the art. The deprotected amines were isolated as the corresponding hydrochloride salts. The compounds may be used without determining the number of equivalents of HCl.

[0548] [Table 9-1]

[0549] [Table 9-2]

[0550] [Table 9-3]

[0551] [Table 9-4]

[0552] Preparation 137 ((R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride

[0553] [ka] To a mixture of ((R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide (70 g, 0.220 mol) in 1,4-dioxane (140 mL) was added 4 M HCl in 1,4-dioxane (175 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The solid was filtered and dried under reduced pressure at 40° C. to give a quantitative yield of the title compound (80.0 g) as a white solid. ES-MS m / z 319.0 (M+H).

[0554] Preparation 138 (R)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-((2-nitrophenyl)sulfonamido)propanamide

[0555] [ka] A mixture of (R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide hydrochloride (1.5 g, 3.8 mmol) in DCM (15 mL) was treated with TEA (1.1 mL, 8.0 mmol) and 2-nitrobenzenesulfonyl chloride (1.6 g, 7.1 mmol). The mixture was stirred at room temperature for 2 hours and then partitioned between saturated aqueous NH4Cl (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with water (30 mL), then saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound in quantitative yield as a yellow gel. ES-MS m / z 504.2 (M+H).

[0556] Preparation 139 (R)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-((N-methyl-2-nitrophenyl)sulfonamido)propanamide

[0557] [ka] A mixture of (R)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-((2-nitrophenyl)sulfonamido)propanamide (2.4 g, 4.8 mmol) in DMF (32 mL) was treated with CsCO (1.7 g, 5.2 mmol). After stirring at room temperature for 5 minutes, methyl iodide (0.93 mL, 14 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). The organic layers were combined, washed with water (3 × 40 mL), then washed with saturated aqueous NaCl (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-80% (3:1 EtOAc:EtOH) in heptane to give the title compound (1.5 g, 60%). ES-MS m / z 518.2 (M+H).

[0558] Preparation 140 (R)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-(methylamino)propanamide

[0559] [ka] A mixture of (R)—N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-2-((N-methyl-2-nitrophenyl)sulfonamido)propanamide (100 mg, 193 μmol) and LiOH (19 mg, 773 μmol) in DMF (1.3 mL) was treated with thioglycolic acid (36 mg, 386 μmol). The resulting mixture was stirred at room temperature for 1 h and then partitioned between saturated aqueous NH4Cl (5 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The organic layers were combined, washed with water (2 × 10 mL), then saturated aqueous NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% (3:1 EtOAc:EtOH) in DCM to give the title compound (32.7 mg, 50%). ES-MS: 333.2 m / z (M+H).

[0560] Preparation 141 5-Bromo-2-cyclobutyl-2H-pyrazolo[3,4-b]pyridine

[0561] [ka] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 15.0 mmol) in NMP (60 mL) was treated with NaH (1.02 g, 25.5 mmol, 60% in oil) in one portion, and the reaction mixture was stirred until gas evolution ceased (approximately 5 min). Bromocyclobutane (3.53 mL, 37.5 mmol) was added, and the resulting mixture was stirred at 115 °C for 42 h. The reaction mixture was cooled to room temperature, diluted with water (250 mL), and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5–50% EtOAc in heptane to afford the second-eluting (minor) isomer, the title compound (299 mg, 8%), as an off-white solid.

[0562] Preparation 142 6-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine

[0563] [ka] A mixture of 5-bromo-pyrimidin-2-ylamine (8.75 g, 50.3 mmol), DME (100 mL), and 3-bromo-1,1,1-trifluoroacetone (9.41 mL, 90.5 mmol) was obtained. After stirring at room temperature for 12 days, the reaction mixture was filtered, and the filter cake was washed with heptane (20 mL) and dried to give a tan solid (17.3 g), which was suspended in EtOH (150 mL). The suspension was stirred under reflux for 21 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to approximately 25 mL and diluted with heptane (40 mL). The mixture was stirred for 5 minutes and then filtered. The filter cake was dried under high vacuum to give the title compound (7.91 g, 59%) as a pale pink solid. ES-MS m / z 266, 268 (M+H).

[0564] Preparation 143 6-Bromo-2-methyl-1,8-naphthyridine

[0565] [ka] A mixture of sodium tert-butoxide (166 mg, 1.72 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene copper chloride (210 mg, 0.43 mmol) was sealed in an oven-dried vial, purged with N2, and treated with a solution of 4-hydroxy-4-methylpentan-2-one (1.00 g, 8.61 mmol) and 2-amino-5-bromonicotinaldehyde (1.73 g, 8.61 mmol) in toluene (20 mL). The resulting mixture was stirred at 70 °C for 5 h, then cooled, filtered through a pad of silica, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 40–70% EtOAc in cyclohexane to give the title compound (750 mg, 39% yield) as a white solid. ES-MS m / z 223, 225 (M+H).

[0566] Preparation 144 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole

[0567] [ka] A mixture of 4-bromo-2-methyl-2H-1,2,3-triazole (3.69 g, 22.1 mmol), bis(pinacolato)diboron (6.23 g, 24.3 mmol), KOAc (6.51 g, 66.3 mmol), Pd(dppf)Cl.CHCl (2.26 g, 2.77 mmol), and 1,4-dioxane (100 mL) was purged with N and then stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of silica (65 g), and rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with EtOAc in hexane and coevaporating with DCM, to give the title compound (3.86 g, 80%) as a light brown solid. 1 H NMR (CDCl3): 7.89 (s, 1H), 4.25 (s, 3H), 1.36 (s, 12H).

[0568] Preparation 146 2-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3,6,2-dioxyazaborocane

[0569] [ka] A solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (21.1 g, 70.7 mmol, 70% pure) in cyclopentyl methyl ether (210 mL) stirred at 55°C under N2 was treated with a solution of diethanolamine (7.13 mL, 74.2 mmol) in IPA (21 mL) in portions via pipette over 10 minutes. Stirring at 55°C was continued for 2 hours, and then the reaction mixture was allowed to cool slowly to room temperature with continuous stirring. After approximately 5 hours, the solid was collected by filtration, washed with 10:1 cyclopentyl methyl ether:IPA (110 mL), and dried overnight in a vacuum oven at 40°C to give the title compound (13.1 g, 93%) as a light gray solid. ES-MS m / z 197.0 (M+H).

[0570] Preparation 147 Methyl (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylate

[0571] [ka] A stirred solution of (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (12.0 g, 49.8 mmol, prepared as described in U.S. Patent Application Publication No. 2011 / 0201623(A1)) in MeOH (100 mL) was treated dropwise with SOCl (3.70 mL, 50.8 mmol) at room temperature. The resulting mixture was stirred at 50 °C overnight and then concentrated under reduced pressure. The residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO (100 mL), and the layers were separated. The organic layer was washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure to give a quantitative yield of the title compound (12.7 g) as a pale yellow oil. ES-MS m / z 255, 257 (M+H).

[0572] Preparation 148 Methyl (1S,2S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate

[0573] [ka] To a mixture of bis(pinacolato)diborane (7.47 g, 29.4 mmol), KOAc (5.77 g, 58.8 mmol), and Pd(dppf)Cl₂·CHCl₂ (1.60 g, 1.96 mmol) under N₂, 1,4-dioxane (245 mL) and methyl (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylate (5.00 g, 19.6 mmol) were added. The resulting mixture was sparged with N₂ at room temperature for 20 min and then stirred at 90 °C under N₂ overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0–50% EtOAc in cyclohexane to give the title compound (5.71 g, 96%). ES-MS m / z 303.0 (M+H).

[0574] Preparation 149 Methyl (1S,2S)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylate

[0575] [ka] A mixture of 5-bromo-2-methylpyrazolo[3,4-b]pyridine (5.00 g, 23.6 mmol), methyl (1S,2S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate (2.85 g, 9.43 mmol), CsCO (11.1 g, 34.0 mmol), and Pd(dppf)Cl·CHCl (1.16 g, 1.41 mmol) was treated with 1,4-dioxane (240 mL) and water (24 mL) under N. The resulting mixture was sparged with N for 30 min and then stirred at 90 °C overnight. After concentrating most of the solvent under reduced pressure, the residue was poured into water (200 mL) and saturated aqueous NaCl (50 mL). EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (4 x 100 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 15-100% (3:1 EtOAc:EtOH) in cyclohexane to afford the title compound (2.10 g, 72%) as a tan solid. ES-MS m / z 308.0 (M+H).

[0576] The compounds in the following table were prepared using the appropriate aryl bromide as described in Preparation 149. Compounds can be worked up or purified using different methods or gradients that will be apparent to those skilled in the art.

[0577] [Table 10]

[0578] Preparation 152 5-(4-Bromo-3-fluorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0579] [ka] To a suspension of (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (1.00 g, 5.65 mmol), Pd(dppf)Cl CHCl (923 mg, 1.13 mmol), 1-bromo-2-fluoro-4-iodobenzene (3.40 g, 11.3 mmol), and CsCO (7.36 g, 22.6 mmol) in 3:1 1,4-dioxane / water (25 mL) was sparged with N for 5 min. The resulting mixture was stirred at 60 °C for 2 h, then cooled and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (3 times). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-2% MeOH in DCM to give the title compound (1.64 g, 82%, 86% purity) as a yellow foam. ES-MS m / z 306, 308 (M+H).

[0580] The compounds in the following table were prepared using the appropriate aryl boronic acid and the appropriate aryl halide as described in Preparation 152. The compounds can be worked up or purified using different methods that will be apparent to those skilled in the art.

[0581] [Table 11] a. 1-Bromo-4-iodo-2-(trifluoromethyl)benzene was used at 90° C. for 1 hour. b. 6-Bromo-3-chloro-2-(trifluoromethyl)pyridine was used at 90° C. for 1 hour, and the precipitate was added with EtOAc and the solid was collected.

[0582] Preparation 155 Potassium ((1S,2S)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate carboxylate

[0583] [ka] The synthesis and chiral analysis of the title compound were carried out in a similar manner as described by Thach Nguyen, Sanil Sreekumar, Shuai Wang, Qi Jiang, Florian Montel, and Frederic Buono, Organic Process Research & Development 202226(10), 2979-2985. A solution of potassium vinyltrifluoroborate (250 g, 1.87 mol) and Ru-(R)-Pheox (CAS no. 1421679-43-7, 11.9 g, 18.7 mmol) in EtOAc (2.25 L) was treated dropwise with a solution of ethyl diazoacetate (426 g, 3.73 mol) in EtOAc (500 mL) at 0–5°C for 4 h under N2. The resulting mixture was warmed to 25°C and stirred for 5 h. MTBE (4.12 L) was added, and the resulting brown slurry was cooled to 0–5°C and stirred for 30 min. The reaction was repeated four times on the same scale, and all five reactions were combined for filtration. The combined filter cake was washed with 2:3 EtOAc / MTBE (5 L) and dried under reduced pressure at 50° C. for 5 hours to give the title compound (920 g, 45%) as a white solid. ES-MS m / z 181.1 (M+). [a] D 20 =+13.42°(C=1.0,ACN).

[0584] Preparation 156 Ethyl (1S,2S)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylate

[0585] [ka] A mixture of cataCXium Pd G4 (CAS number 2230788-67-5, 255 mg, 0.34 mmol), 5-(4-bromo-3-fluorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (1.05 g, 3.4 mmol), ethyl (1S,2S)-2-(trifluoro-14-boraneyl)cyclopropane-1-carboxylate, potassium salt (906 mg, 4.1 mmol), and Cs2CO3 (0.823 mL, 10.3 mmol) in toluene (15 mL) was degassed with N2, then water (1.5 mL) was added. The flask was evacuated and refilled with N2 three times. The reaction vessel was heated to 80 °C for 16 h, then cooled, diluted with EtOAc, dried over Na2SO4, filtered through diatomaceous earth, and concentrated. The residue was purified by silica gel chromatography using a gradient of 1-2% MeOH in DCM, followed by reverse-phase flash chromatography (150 g C18 column, 110 mL / min) using a gradient of 35-60% ACN / 10 mM aqueous NH4HCO3 (containing 5% MeOH) to give the title compound (600 mg, 52%) as an off-white solid. ES-MS m / z 340.2 (M+H).

[0586] The compounds in the following table were prepared from the appropriate aryl halide from Table 11 and either potassium ((1S,2S)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate or commercially available potassium rac-((trans)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate in a manner similar to that described in Preparation 156. The compounds can be worked up or purified using different methods that will be apparent to those skilled in the art.

[0587] [Table 12] a. The filtered and concentrated filtrate was used in the next step without purification. b. Purified by silica gel chromatography, 0-100% 3:1 EtOH:EtOAc in heptane. Heated at c. 110° C. and purified by silica gel chromatography using a gradient of 0-75% EtOAc in heptane.

[0588] Preparation 160 rac-Ethyl (trans)-2-(4-(3-(4-fluorophenyl)ureido)-3-methylphenyl)cyclopropane-1-carboxylate

[0589] [ka] A mixture of rac-ethyl (trans)-2-(4-amino-3-methylphenyl)cyclopropane-1-carboxylate (76.0 mg, 347 μmol) in DCM (2 mL) was treated with TEA (106 μL, 762 μmol) and 4-fluorophenyl isocyanate (47.2 μL, 416 μmol). The resulting mixture was stirred at room temperature for 16 h and then diluted with 0.2 M aqueous HCl (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 × 8 mL). The organic layers were combined, washed with saturated aqueous NaCl (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound in quantitative yield. ES-MS m / z 329.2 m / z (M+H).

[0590] Preparation 161 Methyl (1S,2S)-2-(4-((tert-butoxycarbonyl)amino)phenyl)cyclopropane-1-carboxylate

[0591] [ka] A solution of methyl (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylate (6.5 g, 25 mmol) in 1,4-dioxane (8 mL) was added to tert-butyl carbamate (4.5 g, 38 mmol), Pd(dba) (2.4 g, 2.5 mmol), XPhos (1.2 g, 2.5 mmol), and CsCO (13 g, 38 mmol). The mixture was degassed under high vacuum and purged with N (three times), then stirred at 100 °C under N for 16 h. The reaction mixture was cooled and filtered. The filtrate was diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The organic layers were combined, washed with saturated aqueous NaCl (150 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in PE, followed by a second purification on silica using a gradient of 0-100% DCM in PE to give the title compound (4.5 g, 60%) as a yellow solid. ES-MS m / z 236.1 (M-tBu+H).

[0592] Preparation 162 Methyl (1S,2S)-2-(4-aminophenyl)cyclopropane-1-carboxylate hydrochloride

[0593] [ka] A 0° C. solution of methyl (1S,2S)-2-(4-((tert-butoxycarbonyl)amino)phenyl)cyclopropane-1-carboxylate (2.2 g, 7.5 mmol) in MeOH (20 mL) was treated dropwise with 2 M HCl in MeOH (16 mL, 32 mmol) over 10 min. The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (1.5 g, 79%, 90% pure) as a yellow solid. ES-MS m / z 191.9 (M+H).

[0594] Preparation 163 Methyl (1S,2S)-2-(4-(3-(4-fluorophenyl)ureido)phenyl)cyclopropane-1-carboxylate

[0595] [ka] The title compound was purified by reverse-phase prep-HPLC (XSelect® CSH C18, 30 × 150 mm, 5 μm, 70 mL / min) using methyl (1S,2S)-2-(4-aminophenyl)cyclopropane-1-carboxylate hydrochloride as described in Preparation 160, eluting with 30-70% ACN / 10 mM aqueous NH4HCO3, pH 10 (containing 5% MeOH). ES-MS m / z 329.2 (M+H).

[0596] Preparation 164 (1S,2S)-2-(4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)cyclopropane-1-carboxylic acid

[0597] [ka] A mixture of methyl (1S,2S)-2-(4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)cyclopropane-1-carboxylate (3.5 g, 11 mmol) in ACN (35 mL) and water (35 mL) was treated with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 3.2 g, 23 mmol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was adjusted to pH 7 with 1 N aqueous HCl. The resulting precipitate was collected by suction filtration, washed with water (10 ml), and dried under reduced pressure to give the title compound (2.4 g, 72%) as a gray solid. ES-MS m / z 280.0 (M+H).

[0598] Preparation 165 (1S,2S)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylic acid

[0599] [ka] A solution of methyl (1S,2S)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylate (2.10 g, 6.83 mmol) in THF (34 mL) was treated with water (4.9 mL) and 2 M aqueous LiOH (10.2 mL, 20.5 mmol) and stirred at 40 °C for 3 h. The reaction mixture was cooled to room temperature, and 1 M aqueous HCl (30.7 mL, 30.7 mmol) was added. The mixture was concentrated under a stream of N to remove organics, filtered, and rinsed with copious amounts of water. The resulting tan solid was lyophilized to give the title compound (1.73 g, 86%). ES-MS m / z 294.2 (M+H).

[0600] The compounds in the following table were prepared as described in Preparation 165. Alternatively, after acidifying the reaction mixture, the product can be directly filtered or extracted with EtOAc. The compounds can also be isolated as their corresponding Li carboxylate salts without acidification.

[0601] [Table 13] a. Room temperature, 24 hours. b. 1.25 eq of 2 M LiOH aqueous solution was freeze-dried at 50°C for 20 hours to obtain the Li salt. c.40℃, 24 hours. d. 12 eq of 2M aqueous LiOH, rt in 1:1 THF:MeOH overnight, acidified with 12 eq of 4M HCl / dioxane and concentrated. e. 13 eq of 2M aqueous LiOH, 45° C. in 1:1 THF:MeOH overnight, acidified with 13 eq of 4M HCl / dioxane, and extracted with 4:1 CHCl 3 :IPA. f. 2:1 THF:MeOH, rt, 4 h, then acidified with 1 M aqueous HCl and extracted with EtOAc. g. 6 eq LiOH, 7 eq KOH, 75° C. for 4 days, then acidified with 1 M aqueous HCl and extracted with EtOAc.

[0602] Preparation 174 (1S,2S)-2-(4-(3,3-difluorocyclobutane-1-carboxamido)phenyl)cyclopropane-1-carboxylic acid

[0603] [ka] A mixture of 3,3-difluorocyclobutane-1-carboxamide (4.48 g, 33.2 mmol), (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (prepared as described in U.S. Patent Application Publication No. 2011 / 0201623(A1), 4.00 g, 16.6 mmol), XantPhos Pd G4 (CAS No. 1621274-19-8, 798 mg, 0.830 mmol), and Cs2CO3 (16.2 g, 49.8 mmol) was prepared. The reaction flask was purged with N2 (×2) and NMP (33.2 mL) was added. The reaction mixture was sparged with N2 for 10 min, briefly warmed to 45 °C, and then stirred at 80 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL), and extracted with EtOAc (2 x 100 mL). The aqueous layer was acidified to pH 2 with 1 M aqueous HCl (100 mL) and extracted with EtOAc (4 x 100 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-90% (10% EtOH / EtOAc) in heptane (containing 0.05% HOAc) to afford the title compound (2.14 g, 44%) as a white solid. ES-MS m / z 296.2 (M+H).

[0604] Preparation 175 (1S,2S)-2-(4-(4,4-difluorocyclohexane-1-carboxamido)phenyl)cyclopropane-1-carboxylic acid

[0605] [ka] A mixture of 4,4-difluorocyclohexane-1-carboxamide (2.88 g, 17.6 mmol), XantPhos-Pd-G4 (CAS no. 1621274-19-8, 736 mg, 0.764 mmol), and CsCO3 (11.5 g, 35.3 mmol) was purged with N2. NMP (23.5 mL) and methyl (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylate (3.00 g, 11.8 mmol) were added, and the resulting mixture was sparged with N2 for 10 min, briefly warmed to 50 °C, and then stirred at 83 °C for 40 h. The reaction mixture was cooled to room temperature and diluted with water (350 mL) and EtOAc (70 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl (1S,2S)-2-(4-(4,4-difluorocyclohexane-1-carboxamido)phenyl)cyclopropane-1-carboxylate. ES-MS m / z 338.2 (M+H). The residue was suspended in THF (40 mL), water (10 mL), and 2 M aqueous LiOH (17.6 mL), and the resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with EtOAc (100 mL), 1.0 M aqueous HCl (100 mL), and water (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 75 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-90% (10% EtOH / EtOAc) in heptane (containing 0.05% HOAc) to give the title compound (1.83 g, 48%) as an off-white solid. ES-MS m / z 324.2 (M+H).

[0606] Preparation 176 (1S,2S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylic acid

[0607] [ka] A mixture of methyl (1S,2S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate (1.00 g, 3.31 mmol) and trimethylstannanol (1.80 g, 9.93 mmol) in DCE (10 mL) was stirred at 80 °C overnight and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water, and the organic layer was washed with 1 N aqueous HCl, dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound in quantitative yield. ES-MS m / z 287.2 (M−H).

[0608] Preparation 177 tert-Butyl 2-(4-bromophenyl)-2-methylcyclopropane-1-carboxylate (mixture of cis / trans enantiomers)

[0609] [ka] A mixture of 1-bromo-4-(prop-1-en-2-yl)benzene (1.0 g, 5.1 mmol) and rhodium(II) acetate (0.22 g, 0.51 mmol) in THF (20 mL) was treated with tert-butyl 2-diazoacetate (0.87 g, 6.1 mmol). The resulting mixture was stirred at 18 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 8% EtOAc in PE to give the title compound (1.6 g, 19%, 75% purity) as a white solid. ES-MS m / z 255, 257 (Mt-Bu+H).

[0610] Preparation 178 tert-Butyl 2-methyl-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylate (mixture of cis / trans enantiomers)

[0611] [ka] To a mixture of tert-butyl-2-(4-bromophenyl)-2-methylcyclopropane-1-carboxylate (a mixture of cis / trans enantiomers, 395 mg, 952 μmol, 75% purity) and (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (168 mg, 952 μmol) in 1,4-dioxane (6 mL) and water (0.6 mL) was added NaCO (0.14 mL, 1.90 mmol) and Pd(dppf)Cl (104 mg, 143 μmol). After stirring at 90 °C under N for 16 h, the reaction mixture was cooled, diluted with EtOAc (8 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0–6% MeOH in DCM to afford the title compound (371 mg, 95%, 89% purity) as a brown oil. ES-MS m / z 364.3 (M+H).

[0612] Preparation 179 2-Methyl-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylic acid (mixture of cis / trans enantiomers)

[0613] [ka] A solution of tert-butyl 2-methyl-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylate (mixture of cis / trans enantiomers, 365 mg, 894 μmol, 89% purity) in DCM (3 mL) was treated with TFA (1.00 mL, 13.0 mmol), and the resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (278 mg, 91%, 90% purity) as a brown oil. ES-MS m / z 308.2 (M+H).

[0614] Preparation 180 Methyl (R)-2-amino-3-(1-methyl-1H-pyrazol-4-yl)propanoate hydrochloride

[0615] [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 (0.14 MPa) 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).

[0616] Preparation 181 Methyl (R)-2-((1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxamido)-3-(1-methyl-1H-pyrazol-4-yl)propanoate

[0617] [ka] To a mixture of HATU (5.13 g, 13.5 mmol) and (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (2.50 g, 10.4 mmol, prepared as described in U.S. Patent Application Publication No. 2011 / 0201623(A1)), DMF (40 mL), methyl (R)-2-amino-3-(1-methyl-1H-pyrazol-4-yl)propanoate HCl (2.9 g, 11.4 mmol), and DIEA (11 mL, 62 mmol) were added under N. The resulting mixture was stirred at room temperature for 15 hours and then poured into saturated aqueous NaHCO (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with water (2 x 30 mL), then saturated aqueous NaCl (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-5% MeOH in DCM to give a quantitative yield of the title compound (5.0 g, 76% purity) as a white solid. ES-MS m / z 406, 408 (M+H).

[0618] Preparation 182 (R)-3-(1-methyl-1H-pyrazol-4-yl)-2-((1S,2S)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamido)propanoic acid

[0619] [ka] A mixture of 1,4-dioxane (70 mL) and water (23 mL) was sparged with N for 10 min and then added to a mixture of methyl (R)-2-((1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxamido)-3-(1-methyl-1H-pyrazol-4-yl)propanoate (3.80 g, 9.35 mmol), (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (2.65 g, 15.0 mmol), Pd(dppf)Cl·CHCl (764 mg, 935 μmol), and CsCO (9.75 g, 29.9 mmol) under N. The resulting mixture was stirred at 90 °C for 27 h, then cooled to room temperature, acidified to pH 3 with 1 M aqueous HCl, and concentrated under reduced pressure. The residue was azeotroped with toluene and then purified by silica gel chromatography using a gradient of 0-38% (20% MeOH / DCM with 2% HOAc) in DCM. Repeated azeotropy with MeOH / toluene gave the title compound (1.9 g, 45%) as a tan solid. ES-MS m / z 445.2 (M+H).

[0620] Preparation 183 1-(4-Bromobenzyl)tetrahydro-1H-thiophen-1-ium bromide

[0621] [ka] A mixture of p-bromobenzyl bromide (200 g, 784 mmol), acetone (2 L), and tetrahydrothiophene (104 g, 1.18 mol) was stirred at 25° C. for 32 h. The resulting precipitate was filtered, rinsed with acetone (2×1 L), and triturated by stirring with acetone (1 L) at 25° C. for 16 h. Filtration afforded the title compound (182 g, 66%) as a white solid. ES-MS m / z 257, 259 (M + ).

[0622] Preparation 184 rac-(trans)-1-(4-bromophenyl)-5-oxaspiro[2.4]heptan-4-one

[0623] [ka] To a mixture of 3-methylenedihydrofuran-2(3H)-one (30.0 g, 291 mmol), DCM (600 mL), and 1-(4-bromobenzyl)tetrahydro-1H-thiophen-1-ium bromide (102 g, 291 mmol) at 0 °C, 1 M lithium bis(trimethylsilyl)amide (262 mL, 262 mmol) in THF was added dropwise over 30 minutes (until the mixture became clear). The resulting mixture was stirred at 35 °C (internal temperature) for 2 hours, then cooled and treated with saturated aqueous NH4Cl (60 mL). Water (300 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (3 × 300 mL). The organic layers were combined, washed with saturated aqueous NaCl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (152 mL) by stirring at 25° C. for 8 hours. Filtration afforded the title compound (63 g, 79%) as a white solid. ES-MS m / z 267, 269 (M+H). Analytical SFC 1:1 mixture, Rt=2.10, 2.29 min (Chiralpak® AD-3, 4.6×150 mm, 3 μm, column temperature 35° C., 220 nm, flow rate 2.5 mL / min, isocratic 20% EtOH (with 0.2% 7M NH3 / MeOH):80% CO2; Waters® ACQUITY UPC with PDA). 2 (registered trademark).

[0624] Preparation 185 rac-(trans)-2-(4-bromophenyl)-1-(2-hydroxyethyl)cyclopropane-1-carboxylic acid

[0625] [ka] A mixture of rac-(trans)-1-(4-bromophenyl)-5-oxaspiro[2.4]heptan-4-one (45.1 g, 167 mmol) in THF (300 mL) and water (150 mL) was treated with LiOH (12.0 g, 501 mmol) and then stirred at 25 °C for 2 h. The reaction mixture was partially concentrated to remove THF, and 1 N HCl was added until pH = 3. The resulting suspension was filtered, and the filter cake was washed with water (400 mL) and then triturated with water (225 mL) at 25 °C. The suspension was filtered, and the filter cake was dried under reduced pressure to give the title compound (41 g, 86% yield) as a white solid. ES-MS m / z 285, 287 (M+H). Analytical SFC 1:1 mixture, Rt = 2.59, 3.36 min (Chiralpak® AD-3, 4.6 × 150 mm, 3 μm, column temperature 35 °C, 220 nm, flow rate 2.5 mL / min, isocratic 20% EtOH (with 0.2% 7 M NH3 / MeOH): 80% CO2; Waters® ACQUITY UPC with PDA) 2 (registered trademark).

[0626] Preparation 186 (S)-1-(Naphthalen-1-yl)ethan-1-amine (1R,2R)-2-(4-bromophenyl)-1-(2-hydroxyethyl)cyclopropane-1-carboxylate

[0627] [ka] A mixture of rac-(trans)-2-(4-bromophenyl)-1-(2-hydroxyethyl)cyclopropane-1-carboxylic acid (31.0 g, 108 mmol) in methyl acetate (930 mL) was stirred at 25° C. for 10 minutes. (S)-1-(1-naphthyl)ethylamine (9.59 mL, 59.5 mmol) was added, and the resulting mixture was stirred at 27° C. (internal temperature) for 16 hours. The resulting precipitate was filtered and then triturated with MTBE (210 mL) by stirring at 25° C. for 6 hours. Filtration afforded the title compound (19.7 g, 40%) as a white solid.

[0628] A sample of the title compound (5 mg) was dissolved in water (1 mL) and adjusted to pH = 3 with 1 N aqueous HCl. The resulting solid was filtered and used for analytical SFC. Approximately 98% ee, Rt = 3.31 min, isomer 2 (Chiralpak® AD-3, 4.6 × 150 mm, 3 μm, column temperature 35 °C, 220 nm, flow rate 2.5 mL / min, isocratic 20% EtOH (with 0.2% 7 M NH3 / MeOH): 80% CO2; Waters® ACQUITY UPC with PDA). 2 (registered trademark).

[0629] Preparation 187 (1R,3R)-1-(4-bromophenyl)-5-oxaspiro[2.4]heptan-4-one

[0630] [ka] A mixture of (S)-1-(naphthalen-1-yl)ethan-1-amine (1R,2R)-2-(4-bromophenyl)-1-(2-hydroxyethyl)cyclopropane-1-carboxylate (80.0 g, 175 mmol) in ACN (400 mL) was treated dropwise with 12 M HCl (161 mL), and the resulting mixture was stirred at 25° C. for 2 h. Water (1.2 L) was added, and stirring was continued at 25° C. for 3 h. The resulting suspension was filtered to give the title compound (42.8 g, 91%) as a white solid. ES-MS m / z 267, 269 (M+H). Analytical SFC ca. 97% ee, Rt = 2.12 min, isomer 1 (Chiralpak® AD-3, 4.6 x 150 mm, 3 μm, column temperature 35 °C, 220 nm, flow rate 2.5 mL / min; 20% EtOH (with 0.2% 7 M NH3 in MeOH): 80% CO2; Waters® ACQUITY UPC with PDA) 2 (registered trademark).

[0631] Preparation 188 (1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-5-oxaspiro[2.4]heptan-4-one

[0632] [ka] To a mixture of (1R,3R)-1-(4-bromophenyl)-5-oxaspiro[2.4]heptan-4-one (663 mg, 3.74 mmol), Pd(dppf)Cl CHCl (411 mg, 0.562 mmol), CsCO (2.44 g, 7.49 mmol), and (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (663 mg, 3.7 mmol) in 1,4-dioxane (34 mL) and water (3.4 mL) was sparged with N for 5 min. After stirring at 80 °C for 1.5 h, the reaction mixture was cooled to room temperature, diluted with DCM, and washed with water. The organic layer was dried over MgSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-3% MeOH in DCM and recrystallized from EtOAc to give the title compound (855 mg, 72%) as a tan solid. ES-MS m / z 320.0 (M+H).

[0633] Preparation 189 1-(4-Bromo-2-fluorobenzyl)tetrahydro-1H-thiophen-1-ium bromide

[0634] [ka] A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (20 g, 75 mmol), acetone (200 mL), and tetrahydrothiophene (9.9 g, 0.11 mol) was stirred at room temperature for 24 hours. The resulting precipitate was filtered and rinsed with acetone (200 mL). The collected solid was stirred in acetone (300 mL) at room temperature for 1 hour. The mixture was filtered, and the solid was dried under reduced pressure at room temperature. All filtrates were combined, concentrated to approximately 50 mL, and stirred for 3 days. Acetone (100 mL) was added, and the mixture was stirred for 10 minutes and then filtered. The collected solid was rinsed with acetone (50 mL) and dried under reduced pressure at room temperature overnight. The two portions of the white solid were combined to give the title compound (23.6 g, 89%). ES / MS m / z 275 / 277 (M + ).

[0635] Preparation 190 rac-(trans)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one

[0636] [ka] A mixture of 3-methylenedihydrofuran-2(3H)-one (7.7 g, 78 mmol), DCM (148 mL), DMSO (50 mL), and 1-(4-bromo-2-fluorobenzyl)tetrahydro-1H-thiophen-1-ium bromide (18.46 g, 51.84 mmol) was stirred at 0 °C under N and treated dropwise with 1 M LiHMDS in THF (78 mL, 78 mmol) while maintaining the internal reaction temperature below 7 °C. After the addition was complete, stirring was continued at 0 °C for 30 min. The cold reaction mixture was poured into a stirred mixture of ice / water (200 mL) and DCM (200 mL). The biphasic mixture was stirred for 1 h, during which time it was allowed to warm to 12 °C. The layers were separated, and the aqueous layer was extracted with DCM (200 mL). The organic layers were combined and washed with water (200 mL), then saturated aqueous NaCl (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in cyclohexane to give the title compound (8.33 g, 56%) as a white solid. ES-MS m / z 2845, 287 (M+H).

[0637] Preparation 191 (1S,3R)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one

[0638] [ka] Chiral separation of rac-(trans)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one (3.77 g) was purified by SFC (CHIRALPAK® IG, 30 × 250 mm, 5 μm, column temperature 40 °C, flow rate 100 mL / min, 20% MeOH in CO for 6.5 min) to give the first eluting isomer as the title compound (1.68 g, white solid). 97.8% ee. ES-MS m / z 285, 287 (M+H).

[0639] Preparation 192 (1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-5-oxaspiro[2.4]heptan-4-one

[0640] [ka] To a mixture of (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (2.22 g, 12.5 mmol), (1S,3R)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one (isomer 1, 2.38 g, 8.35 mmol), and CsCO (5.44 g, 16.7 mmol) in 1,4-dioxane (75 mL) and water (7.5 mL) was sparged with N for 5 min. Pd(dppf)Cl·CHCl (916 mg, 1.25 mmol) was added, and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL) and EtOAc (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 200 mL). The organic layers were combined, filtered through a plug of NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-50% (10% MeOH / EtOAc) in cyclohexane, then switched to 0-40% (10% MeOH / EtOAc) in EtOAc to give the title compound (2.55 g, 91%) as a brown solid. ES-MS m / z 338.0 (M+H).

[0641] Example 1 (1S,2S)-N-((R)-1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamide

[0642] [ka] A mixture of (1S,2S)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxylic acid (805 mg, 2.74 mmol) and (R)-2-amino-N-(1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide (1.20 g, 2.74 mmol) in DMF (5 mL) was treated with DIEA (1.43 mL, 8.23 ​​mmol) and HATU (1.25 g, 3.29 mmol). After 3 h at room temperature, the reaction mixture was quenched with water and concentrated to dryness. The residue was purified by silica gel chromatography using a gradient of 20-100% (3:1 EtOAc:EtOH) in DCM to give the title compound (1.25 g, 64%) as a white solid. ES-MS m / z 712, 714 (M+H).

[0643] The compounds in the following table were prepared using the appropriate carboxylic acid or carboxylic acid Li salt and the appropriate amine or amine salt as described in Example 1. (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid was prepared as described in U.S. Patent Application Publication No. 2011 / 0201623(A1). The reactants can be added in different orders or in different equivalent amounts. DMA is a suitable alternative to DMF. Reaction times can vary (from 30 minutes to overnight), and different methods can be used to work up or purify the compounds (normal phase, or reverse phase at high, neutral, or low pH). Such variations will be apparent to those skilled in the art.

[0644] [Table 14-1]

[0645] [Table 14-2]

[0646] [Table 14-3]

[0647] Preparation 200 (1S,2S)-2-(4-bromophenyl)-N-((R)-1-((1-(4-fluorophenyl)-2-methylpropan-2-yl)amino)-3-(imidazo[1,2-a]pyrimidin-3-yl)-1-oxopropan-2-yl)cyclopropane-1-carboxamide

[0648] [ka] A mixture of (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (prepared as described in U.S. Patent Application Publication No. 2011 / 0201623(A1), 250 mg, 1.0 mmol) and propanephosphonic anhydride (50% in EtOAc, 0.76 mL, 1.3 mmol) in THF (7 mL) was treated with DIEA (1.1 mL, 6.2 mmol). After stirring for 1 minute, (R)-2-amino-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-3-(imidazo[1,2-a]pyrimidin-3-yl)propanamide (531 mg, 1.24 mmol) was added. The reaction mixture was stirred for 2 days and then diluted with saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc (2×10 mL), and the organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (472 mg, 79%) as a yellow foam. ES-MS m / z 578, 580 (M+H).

[0649] Preparation 201 (1S,2S)-N-((R)-3-(imidazo[1,2-a]pyrimidin-3-yl)-1-((2-methyl-1-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamide

[0650] [ka] A mixture of PdCl(dppf) (DCM adduct, 102 mg, 125 μmol), bis(pinacolato)diboron (790 mg, 3.11 mmol), KOAc (489 mg, 4.98 mmol), and (1S,2S)-2-(4-bromophenyl)-N—((R)-3-(imidazo[1,2-a]pyrimidin-3-yl)-1-((2-methyl-1-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-1-oxopropan-2-yl)cyclopropane-1-carboxamide (770 mg, 1.25 mmol) in 1,4-dioxane (8.3 mL) was sparged with N for 5 min and then heated to 80° C. for 2 h. The reaction mixture was filtered and carried forward as a solution of the title compound (approximately 0.15M, quantitative yield): ES-MS m / z 666 (M+H).

[0651] The compounds in the following table were prepared as described in Preparation 200 using the appropriate aryl bromide.

[0652] [Table 15]

[0653] Example 7 (trans)-N-((R)-1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-2-(5-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)thiophen-2-yl)cyclopropane-1-carboxamide, isomer 2

[0654] [ka] (2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (76 mg, 0.43 mmol) and (trans)-N-((R)-1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-2-(5-bromo) To a mixture of (thiophen-2-yl)cyclopropane-1-carboxamide (a mixture of two diastereomers, 280 mg, 420 μmol), Pd(dppf)Cl₂·CHCl₂ (18 mg, 25 μmol), and CsCO₃ (250 mg, 767 μmol) was added 3:1 1,4-dioxane / water (5 mL), and the resulting mixture was stirred at room temperature for 5 minutes and then at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with 1,4-dioxane (6 mL) and EtOAc (6 mL), and stirred. The layers were separated, and the aqueous layer was acidified to pH 3 with 1 N aqueous HCl (ca. 0.7 mL) and then extracted with EtOAc (3 × 30 mL). All organic layers were combined, dried over NaSO₄, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (Waters® XSelect® CSH C18, 30 × 150 mm, 5 μm, 60 mL / min) eluting with 25–50% ACN in 10 mM aqueous NH4HCO3, pH = 10 (containing 5% MeOH) for 20 min to give the second eluting isomer as the title compound (100 mg, 31%). ES-MS m / z 718, 720 (M+H).

[0655] Example 8 (1S,2S)-2-(4-(7-methyl-1,8-naphthyridin-3-yl)phenyl)-N-((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)cyclopropane-1-carboxamide

[0656] [ka] 6-Bromo-2-methyl-1,8-naphthyridine (15 mg, 67 μmol), (1S,2S)-N-((R)-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 To a mixture of )-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamide (40 mg, 45 μmol, 87% pure), CsCO (44 mg, 0.14 mmol), and Pd(dppf)Cl (10 mg, 14 μmol) was added 4:1 1,4-dioxane / water (1 mL) sparged with N under N, and the resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water, and then extracted with EA. The layers were separated, and the organic extract was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (100 mg, 31%) as a dark brown oil. ES-MS m / z 718.2 / 720.1 (M+H).

[0657] Preparation 205 (1S,2S)-2-(4-aminophenyl)-N-((R)-1-((1-(4-fluorophenyl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)cyclopropane-1-carboxamide hydrochloride

[0658] [ka] A solution of tert-butyl (4-((1S,2S)-2-(((R)-1-((1-(4-fluorophenyl)-2-methylpropan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamoyl)cyclopropyl)phenyl)carbamate (380 mg, 559 μmol, 85% purity) in MeOH (1 mL) and 1,4-dioxane (2 mL) was treated with 4 M HCl in 1,4-dioxane (1.40 mL, 5.59 mmol). The resulting mixture was stirred at 25° C. for 4 h and then concentrated under reduced pressure to give a quantitative yield of the title compound (390 mg, 75% purity) as a yellow solid. ES-MS m / z 478.1 (M+H).

[0659] Preparation 206 (1R,2S)-1-(2-chloroethyl)-N-((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)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamide

[0660] [ka] A mixture of (1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-5-oxaspiro[2.4]heptan-4-one (200 mg, 593 μmol) and benzyltriethylammonium chloride (270 mg, 1.19 mmol) in DCE (5 mL) was treated with SOCl (176 μL, 2.39 mmol) followed by BF EtO (148 μL, 1.18 mmol). After stirring at 80 °C overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. DCE (5 mL) was added, and the mixture was concentrated under reduced pressure to give a quantitative yield of (1R,2R)-1-(2-chloroethyl)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonyl chloride as a light brown solid. In a separate vessel, a mixture of (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 (350 mg, 591 μmol) in DCM (10 mL) was stirred at 0 °C and treated with TEA (579 μL, 4.15 mmol). A suspension of (1R,2R)-1-(2-chloroethyl)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonyl chloride (593 μmol) in DCM (10 mL) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 min. EtOAc (100 mL) and cold water (100 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL), and the organic layers were combined, washed with water (3 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a quantitative yield of the title compound as a light brown solid. ES-MS m / z 875 (M+H).

[0661] The compounds in the following table were prepared as described in Preparation 206 using the appropriate lactone and the appropriate amine or amine salt. DIEA is a suitable substitute for TEA. Minor modifications to the reaction conditions and purification methods will be apparent to those skilled in the art.

[0662] [Table 16] a. Purified on silica using 0-15% MeOH in EtOAc. b. Purified on silica using 0-5% MeOH in DCM. c. DIEA was used instead of TEA, and purified on silica using 0-40% MeOH in DCM.

[0663] Example 9 (2R)-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)-2-((1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanamide

[0664] [ka] A mixture of (1R,2R)-1-(2-chloroethyl)-N-((2R)-1-((2-methyl-1-(5-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1-oxopropan-2-yl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamide (338 mg, 399 μmol) and CsCO (520 mg, 1.60 mmol) in NMP (8 mL) was stirred at room temperature for 18 hours. The reaction mixture was slowly added dropwise to rapidly stirring water (150 mL). The resulting mixture was filtered under suction to give a quantitative yield of the title compound (340 mg) as a white solid: ES-MS m / z 811.2 (M+H).

[0665] Example 10 (R)—N-(1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanamide

[0666] [ka] The title compound was prepared as described in Example 9 using (1R,2R)—N—((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)-1-(2-chloroethyl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamide, stirring for 5 days, followed by reverse-phase flash purification (150 g, C18 using a gradient of 50-100% ACN in water (containing 0.1% FA)). ES-MS m / z 774, 776 (M+H).

[0667] Preparation 210 N-(2,2-dimethoxyethyl)-N-methyl-1H-pyrazole-5-carboxamide

[0668] [ka] To a solution of 1H-pyrazole-5-carboxylic acid (7.00 g, 62.4 mmol), 2,2-dimethoxy-N-methylethan-1-amine (8.19 g, 68.7 mmol), and HATU (30.9 g, 81.2 mmol) in DMA (70.0 mL) was added DIEA (43.0 mL, 250 mmol) at 0 °C. The reaction was stirred at 26 °C for 16 h and then diluted with water (300 mL). The reaction mixture was extracted with EtOAc (3 × 300 mL), and the combined organic layers were washed with saturated aqueous NaCl (3 × 300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0–60% EtOAc in heptane to give the title compound (14.5 g, 54%, 50% purity) as a yellow oil. ES-MS m / z 214 (M+H).

[0669] Preparation 211 5-Methylpyrazolo[1,5-a]pyrazin-4(5H)-one

[0670] [ka] A mixture of N-(2,2-dimethoxyethyl)-N-methyl-1H-pyrazole-5-carboxamide (14.5 g, 33.9 mmol, 50 wt%) and p-toluenesulfonic acid (6.45 g, 33.9 mmol) in toluene (100 mL) was stirred at 130 °C for 16 h. Upon conversion, the pH of the mixture was adjusted to approximately 8 with saturated aqueous NaHCO, and the mixture was then diluted with water (150 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 57% EtOAc in heptane to afford the title compound (6.00 g, 95%, 80% purity) as a white solid. ES-MS m / z 150.0 (M+H).

[0671] Preparation 212 7-Bromo-5-methylpyrazolo[1,5-a]pyrazin-4(5H)-one

[0672] [ka] To a mixture of 5-methylpyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 80 wt%, 10.7 mmol) in DMF (20.0 mL) was added NBS (2.10 g, 11.8 mmol). The reaction mixture was degassed and refilled with N2 three times, cooled to 0 °C, and then stirred under N2 at 0 °C for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 32% EtOAc in heptane to give the title compound (1.31 g, 50%) as a white solid. ES-MS m / z 228, 230 (M+H).

[0673] Preparation 213 tert-Butyl (1-(5-(1,3,6,2-dioxyazaborocan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0674] [ka] A mixture of 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (9.3 g, 24 mmol) in 2-MeTHF (25 mL) was stirred at room temperature under nitrogen, and a solution of 2,2′-azanediylbis(ethan-1-ol) (2.47 g, 23.5 mmol) in IPA (2.5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was triturated with MTBE (50 mL) and 2-MeTHF (10 mL) at room temperature for 1 hour, filtered, and dried under reduced pressure to give the title compound (6.8 g, 66%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.42(br s,1H), 7.28(br s,1H), 6.56(s,1H), 4.25(s,2H), 3.88(td,J=9.2,5.6Hz,2H), 3.76(ddd,J=9.6, 6.4,3.6Hz,2H), 3.12-3.26(m,2H), 2.84-3.02(m,2H), 1.34(s,9H), 1.25(s,6H).

[0675] Preparation 214 3-Fluoro-1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

[0676] [ka] To a stirred suspension of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (193 mg, 807 μmol) and potassium carbonate (277 mg, 2.00 mmol) in DMF (1 mL) was added iodomethane-d3 (233 mg, 1.61 mmol). The resulting mixture was stirred under air at room temperature for 18 hours, diluted with water (10 mL), and extracted with EtOAc (10 mL). The organic layer was washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (35 mg, 17%) as a beige solid. ES-MS m / z 257.2 (M+H).

[0677] Preparation 215 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

[0678] [ka] In a glovebox filled with N2, bis(pinacolato)diborane (5.5 g, 22 mmol), [Ir(OMe)(1,5-cod)]2 (0.36 g, 0.55 mmol), and 4,4'-bis(tert-butyl)-2,2'-bipyridine (0.29 g, 1.1 mmol) were added to a dry reaction vial. Degassed 2-MeTHF (40 mL) was added, and the reaction mixture was stirred at 25 °C for 30 min. Then, a solution of tert-butyl (2-methyl-1-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (5.7 g, 18 mmol) in 2-MeTHF (60 mL) was added to the catalyst solution. The resulting reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-1% MeOH in DCM to give the title compound (7.1 g, 86%) as a white solid. ES-MS m / z 434.3 (M+H).

[0679] Preparation 216 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

[0680] [ka] The title compound was prepared as described in Preparation 15 using tert-butyl (1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate, 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.95 eq), Na2CO3 (3 eq), and Pd(dppf)Cl2 (0.2 eq) at 90 °C for 12 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-40% EtOAc in PE. The residue was purified by silica gel chromatography using a gradient of 0-45% EtOAc in DCM to give the title compound (7.1 g, 86%) as a white solid. ES-MS m / z 433.0 (M+H).

[0681] Preparation 217 tert-Butyl (1-(5-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0682] [ka] To a solution of (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (75 mg, 88 wt%, 0.19 mmol), 2-(3-bromo-2-oxopyridin-1(2H)-yl)acetonitrile (81 mg, 0.38 mmol), and Pd(dppf)Cl (18 mg, 28 μmol) in 1,4-dioxane (1.3 mL) was added KPO (2.5 M aqueous solution, 0.26 mL, 0.66 mmol). The resulting mixture was sparged with argon for 2 min and then stirred at 90 °C for 1.5 h. The reaction mixture was concentrated under a stream of nitrogen and then diluted with DCM (5 mL). To the resulting mixture were added both SiliaMetS-thiol (60 mg) and SiliaMetS-thiourea (60 mg) palladium scavengers. The mixture was shaken at 40 °C for 30 min and then filtered through a 3 g diatomaceous earth SPE cartridge. The cartridge was rinsed with DCM (20 mL) and EtOAc (5 mL). The filtrate was concentrated under a stream of nitrogen. The residue was purified by reverse-phase prep-HPLC (Phenomenex Kinetex EVO C18, 30 × 100 mm, 5 μm) eluting with 33–67% ACN in water (containing 0.1% FA) over 6 min to give the title compound (59 mg, 68%) as a brown solid. ES-MS m / z 340.2 (M+H-Boc).

[0683] The compounds in the following table were prepared as described in Preparation 217 using the appropriate aryl halide coupling partner. The reactants can be added in a different order or in different equivalent amounts. K2CO3 is a suitable substitute for K3PO4. Reaction times can be varied, and different methods can be used to work up or purify the compounds (normal phase, high pH, ​​or low pH prep-HPLC). Such variations will be apparent to those skilled in the art.

[0684] [Table 17-1]

[0685] [Table 17-2] a. 2.5 eq of aryl halide was used. b. The product was purified by reverse-phase prep-HPLC (Phenomenex Kinetex EVO C18, 30 x 100 mm, 5 μm) eluting with a gradient of ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH). c. 1.5 eq of aryl halide was used, XPhos Pd G4 (0.1 eq) was used as catalyst, K2CO3 (3.0 eq) was used as base, MeOH / H2O (10:1) was used as solvent and the reaction was heated to 70 °C for 2 h. d.3 eq of K3PO4 (2.5 M in water) was used as base and the reaction was heated to 90°C for 3.5 hours.

[0686] Preparation 228 tert-Butyl (1-(5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0687] [ka] A mixture of 6-bromo-8-fluoroimidazo[1,2-a]pyridine (39 mg, 0.18 mmol) and BrettPhos Pd G3 (17 mg, 19 μmol) in 1,4-dioxane (1.1 mL), IPA (300 μL), and Na2CO3 (1 M aqueous solution, 0.50 mL, 0.50 mmol) was stirred at room temperature for 5 minutes. The mixture was purged with N2, and tert-butyl (1-(5-(1,3,6,2-dioxyazaborocan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (70 mg, 0.17 mmol) was added. The mixture was heated at 65 °C for 16 hours. Saturated aqueous NaCl was added, and the mixture was then extracted with EtOAc (3 mL). The organic layer was separated, filtered through diatomaceous earth, and concentrated under a stream of N2 to give the title compound (74 mg, quantitative yield). ES-MS m / z 442 (M+H).

[0688] Preparation 229 tert-Butyl (1-(5-(6-cyano-2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate

[0689] [ka] The title compound was prepared using 5-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile as described in Preparation 228. ES-MS m / z 352 (M+H-Boc).

[0690] Preparation 230 tert-Butyl (2-methyl-1-(5-(1-(methyl-d3)-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0691] [ka] A mixture of XPhos Pd G4 (18 mg, 0.021 mmol), 5-bromo-1-(methyl-d3)pyridin-2(1H)-one, and an aqueous solution of K3PO4 (2.0 M, 0.38 mL, 0.76 mmol) was then flushed with argon into the vial. An argon-purged solution of (1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (75 mg, 0.21 mmol) in 1,4-dioxane (1.9 mL) and EtOH (0.21 mL) was added to the reaction mixture. The resulting mixture was purged with argon for 10 minutes, then the reaction vessel was sealed and the mixture was heated to 80 °C for 7 hours. The reaction mixture was concentrated under a stream of nitrogen, and the residue was purified by silica gel chromatography eluting with 0-35% 3:1 EtOAc / EtOH in heptane to give the title compound (54 mg, 60%) as a white solid. ES-MS m / z 362 (M+H).

[0692] Preparation 231 tert-Butyl (2-methyl-1-(5-(5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-7-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate

[0693] [ka] The title compound was prepared as described in Preparation 230 using 7-bromo-5-methylpyrazolo[1,5-a]pyrazin-4(5H)-one, 0.2 eq XPhos Pd G3 as catalyst, and 1,4-dioxane / HO (10:1) as solvent; the reaction was heated at 70 °C for 16 h. The product was purified by silica gel chromatography eluting with 0-50% EtOAc in hexanes. ES-MS m / z 355 (M+H-Boc).

[0694] Preparation 232 5-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-fluoro-1-methylpyridin-2(1H)-one hydrochloride

[0695] [ka] A solution of 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 (23.5 g, 51.6 mmol) in 1,4-dioxane (50 mL) and MeOH (50 mL) was treated with 2 M HCl in 1,4-dioxane (129 mL, 258 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated to give the title compound (19.0 g, quantitative yield) as a white solid. ES-MS (m / z) 333 (M+H).

[0696] The compounds in the following table were prepared as described in Preparation 232 using the appropriate tert-butyl carbamate. 4M HCl in 1,4-dioxane could be substituted for 2M HCl in 1,4-dioxane. Various reaction times, equivalents of HCl, and solvents (DCM, MeOH) could be used and would be apparent to one skilled in the art. The deprotected amines were isolated as the corresponding hydrochloride salts. The compounds may be used without determining the number of equivalents of HCl.

[0697] [Table 18-1]

[0698] [Table 18-2]

[0699] [Table 18-3] a. The volatiles were removed under a stream of nitrogen to give the product. b. 4M HCl in 1,4-dioxane (8 eq) was used, DCM was used as solvent and the reaction time was 1 h. c. 4M HCl in 1,4-dioxane (30 eq) was used, DCM was used as solvent, reaction time was 2 h. d. 4M HCl in 1,4-dioxane (12 eq) was used, DCM was used as solvent, reaction time was 2 h. e. 2M HCl (30 eq) in 1,4-dioxane was used, MeOH was used as the solvent, and the reaction time was 1 h. DCM was added to the residue, and the mixture was stirred at 25 °C for 10 min. Then, the mixture was filtered, and the filter cake was washed with DCM (2 × 5 mL). The filter cake was dried in vacuo to obtain the product. f. 4M HCl in 1,4-dioxane (9 eq) was used, DCM was used as solvent, reaction time was 1.5 h. g. 4M HCl (18 eq) in 1,4-dioxane was used, DCM was the solvent, and the reaction time was 4 days. Volatiles were removed under a stream of nitrogen, and the residue was dissolved in MeOH and loaded onto a strong cation exchange SPE cartridge. The cartridge was eluted with MeOH, then 7M NH3 in MeOH. The product-containing fractions were combined and concentrated under reduced pressure. h. 4M HCl in 1,4-dioxane (8 eq) was used, MeOH was used as solvent, reaction time was 5.5 h. i. Nitriles were converted to primary amides under these reaction conditions.

[0700] Preparation 246 2-(3-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-oxopyridin-1(2H)-yl)acetonitrile

[0701] [ka] A solution of tert-butyl (1-(5-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (59 mg, 0.13 mmol) in DCM (4 mL) was treated with TFA (25 mL, 0.32 mmol), and the resulting mixture was stirred at room temperature for 2 h. TFA (1 portion) was added, and the mixture was stirred at room temperature for 22 h. TFA (1 portion) was added, and the mixture was stirred at room temperature for 2 h. The reaction was then quenched with NaHCO3 (1 M), and the layers were separated. The aqueous layer was extracted twice with DCM (2.5 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was placed in a vacuum oven at 50 °C for 30 min to give the title compound (37 mg, 41% yield) as a white foam. ES-MS m / z 340 (M+H).

[0702] The compounds in the following table were prepared from the appropriate tert-butyl carbamate as described in Preparation 246. Various reaction times and equivalents of TFA may be used and will be apparent to one skilled in the art.

[0703] [Table 19] a. A strong cation exchange was performed instead of aqueous workup using 10 eq TFA for a reaction time of 16 h. b. tert-Butyl (1-(5-(6-cyano-2-oxo-1,2-dihydropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate was used as the starting material. The nitrile was converted to a primary amide under these reaction conditions.

[0704] Preparation 249 2-(6-bromo-1,8-naphthyridin-2-yl)propan-2-ol

[0705] [ka] A mixture of 3-hydroxy-3-methylbutan-2-one (1.1 mL, 10 mmol) and 2-amino-5-bromonicotinaldehyde (2.0 g, 10 mmol) in EtOH (50 mL) was treated with NaOH (5.0 M aqueous solution, 1.9 mL, 9.5 mmol). The mixture was heated to reflux and stirred for 1 hour. The mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The resulting solid was washed with water and dried under reduced pressure overnight to give the title compound (2.3 g, 87%) as a yellow solid. ES-MS m / z 267, 269 (M+H).

[0706] Preparation 250 6-Bromo-3-methoxy-2-methyl-1,8-naphthyridine

[0707] [ka] The title compound was prepared using 1-methoxypropan-2-one and 2-amino-5-bromonicotinaldehyde as described in Preparation 249. ES-MS m / z 253, 255 (M+H).

[0708] Preparation 251 tert-Butyl 3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)azetidine-1-carboxylate

[0709] [ka] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (1.00 g, 5.05 mmol) in THF (15 mL) was added dropwise with sodium bis(trimethylsilyl)amide solution (7.0 mL, 6.06 mmol, 1 M in THF) at 0° C., followed by treatment with tert-butyl 3-bromoazetidine-1-carboxylate (2.38 g, 10.1 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature for 3 days. NaI (757 mg, 5.05 mmol) was added, followed by DMF (10 mL), and the resulting reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then heated at 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 20-50% EtOAc in cyclohexane to give the title compound (second eluting minor isomer, 410 mg, 23%) as an off-white solid. ES-MS m / z 353, 355 (M+H).

[0710] Preparation 252 2-(azetidin-3-yl)-5-bromo-2H-pyrazolo[3,4-b]pyridine

[0711] [ka] A mixture of tert-butyl 3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)azetidine-1-carboxylate (360 mg, 1.02 mmol) in DCM (6 mL) was cooled at 0 °C, and TFA (2 mL) was added dropwise at 0 °C. The resulting mixture was warmed to room temperature, stirred at room temperature for 2 hours, and concentrated under reduced pressure. The residue was diluted with DCM, cooled in an ice bath, and basified with saturated aqueous NaHCO to approximately pH 8. The layers were separated, and the aqueous layer was washed with water. The aqueous layer was extracted once more with DCM and three times with 3:1 CHCl / IPA. The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (160 mg, 62%) as a white solid. ES-MS m / z 253, 255 (M+H).

[0712] Preparation 253 5-Bromo-2-(1-methylazetidin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[0713] [ka] A mixture of 2-(azetidin-3-yl)-5-bromo-2H-pyrazolo[3,4-b]pyridine (160 mg, 632 μmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 0° C. Formaldehyde (500 μL, 6.53 mmol, 36% in water) was added dropwise, followed by the addition of HOAc (0.1 mL, 2 mmol). The resulting mixture was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was then cooled in an ice bath, and sodium triacetoxyborohydride (268 mg, 1.26 mmol) was added in small portions. After 10 min, the reaction mixture was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was diluted with 50% MeOH in DCM, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was dissolved in MeOH and loaded onto 5 g of strong cation exchange resin. The resin was eluted with MeOH, then 7M NH3 in MeOH. The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound (169 mg, quantitative yield) as a white solid. ES-MS m / z 267, 269 (M+H).

[0714] Preparation 254 2-(5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)ethan-1-ol

[0715] [ka] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (200 mg, 1.01 mmol), 2-bromoethan-1-ol (252 mg, 2.02 mmol), NaI (151 mg, 1.01 mmol), and potassium tert-butoxide (170 mg, 1.52 mmol) in DMF (2 mL) was stirred at 140 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (Kinetex® EVO C18, 30 × 100 mm, 5 μm, 85 mL / min) using a gradient of 5–39% ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH) to give the title compound (71 mg, 29%) as a white solid. ES-MS m / z 242, 244 (M+H).

[0716] Preparation 255 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyrimidine

[0717] [ka] To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyrimidine (0.300 g, 1.42 mmol), bis(pinacolato)diboron (1.46 g, 5.76 mmol), Pd(dppf)Cl₂·CHCl₂ (0.172 g, 0.210 mmol), and KOAc (0.422 g, 4.30 mmol), 1,4-dioxane (5.00 mL) was added and purged with N₂ for 5 minutes. The resulting mixture was then stirred at 90 °C overnight under N₂. The reaction mixture was cooled to room temperature to give the title compound, which was used as a solution. ES-MS m / z 260 (M+H).

[0718] Preparation 256 5-(5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0719] [ka] 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4-b]pyridine (700 mg, 2.70 mmol), Pd(dppf)Cl CHCl (221 mg, 270 μmol), 2-bromo-5-chloro-4-(trifluoromethyl)pyrimidine (1.06 g, 4.05 mmol), and cesium carbonate (3.87 g, 11.9 mmol) were all combined in 1,4-dioxane / water (3:1) (10 mL). The suspension was sparged with N for 5 min and then heated to 90 °C and held at this temperature for 1.0 h. The reaction was then cooled to room temperature, diluted with 12 mL of EtOAc, and stirred. The organic extract was passed through sodium sulfate and 8 grams of Silicycle SiliMetS® Thiol metal scavenger, then concentrated under reduced pressure to give a quantitative yield of the title compound as a brown oil: ES-MS m / z 314 (M+H).

[0720] Preparation 257 5-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0721] [ka] The title compound was prepared using 6-bromo-3-chloro-2-(difluoromethyl)pyridine (stirring for 2 hours) as described in Preparation 256. ES-MS m / z 295 (M+H).

[0722] Preparation 258 Ethyl (1S,2S)-2-(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carboxylate

[0723] [ka] Catacxium Pd G4 (200 mg, 270 μmol), 5-(5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (847 mg, 2.70 mmol), ethyl (1S,2S)-2-(trifluoro-14-boraneyl)cyclopropane-1-carboxylate, potassium salt (1.19 g, 5.40 mmol), and cesium carbonate (2.64 g, 648 μL, 8.10 mmol) were combined in toluene (8 mL). The mixture was evacuated and backfilled with N, water (0.8 mL) was added, and then evacuated and backfilled with N again. The reaction vessel was sealed and heated to 80 °C for 16 h, then filtered and purified by reverse-phase flash chromatography using a gradient of 30-100% ACN / 10 mM aqueous NH4HCO3 (containing 5% MeOH) to give the title compound (887 mg, 84%) as a brown solid. ES-MS m / z 392 (M+H).

[0724] Preparation 259 Ethyl (1S,2S)-2-(2-(difluoromethyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropane-1-carboxylate

[0725] [ka] Prepared in a similar manner to Preparation 258 using 5-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (stirring for 7 hours) to give the title compound (238 mg, 21%) as a light brown solid. ES-MS m / z 373.0 (M+H).

[0726] Preparation 260 (1S,2S)-2-(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carboxylic acid

[0727] [ka] Ethyl (1S,2S)-2-(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carboxylate (887 mg, 2.27 mmol) and lithium hydroxide hydrate (11.3 mL, 2.0 molar, 22.7 mmol) were combined in MeOH (2 mL) and THF (2 mL) and stirred overnight. Hydrogen chloride in 1,4-dioxane (5.67 mL, 4.0 molar, 22.7 mmol) was added and the reaction mixture was concentrated under a stream of N2 to give a quantitative yield of the title compound as a brown solid. ES-MS m / z 364.0 (M+H).

[0728] Preparation 261 (1S,2S)-2-(2-(difluoromethyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropane-1-carboxylic acid

[0729] [ka] The title compound was prepared from ethyl (1S,2S)-2-(2-(difluoromethyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropane-1-carboxylate (stirring for 3 hours) as described in Preparation 260. ES-MS m / z 345.0 (M+H).

[0730] Preparation 262 rac-Ethyl (trans)-2-(4-bromo-2-fluorophenyl)-2-methylcyclopropane-1-carboxylate

[0731] [ka] To a 40 mL vial containing 4-bromo-2-fluoro-1-(prop-1-en-2-yl)benzene (1.54 g, 65 wt%, 4.65 mmol), a stir bar was added, and rhodium(II) octanoate dimer (39 mg, 50 μmol) and DCM (3 mL) were added. The reaction mixture was stirred under argon at room temperature as a DCM solution (total volume of 6 mL) of ethyl 2-diazoacetate (911 mg, 87 wt%, 6.95 mmol) was added via syringe pump over 26 min. Upon complete addition, the reaction mixture was stirred at room temperature for an additional 1 h and then concentrated under Ar. The residue was purified by silica gel chromatography using a gradient of 0 to 20% MTBE in heptane to give the title compound (50 mg, 3.3%, first eluting diastereomer) as a colorless oil, followed by rac-ethyl (cis)-2-(4-bromo-2-fluorophenyl)-2-methylcyclopropane-1-carboxylate (252 mg, 18.0%, second eluting diastereomer) as an orange oil. ES-MS m / z 301, 303 (M+H) for both diastereomers.

[0732] Preparation 263 rac-Ethyl (trans)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-methylcyclopropane-1-carboxylate

[0733] [ka] A 1-dram vial was charged with rac-ethyl (trans)-2-(4-bromo-2-fluorophenyl)-2-methylcyclopropane-1-carboxylate (50 mg, 92 wt%, 0.15 mmol), sodium carbonate (48 mg, 0.45 mmol), (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (41 mg, 0.23 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.9 mg, 6.9 μmol), and EtOH (1 mL). The headspace of the vial was flushed with Ar, and the vial was sealed with a pressure-relief septum cap. The reaction mixture was then stirred under argon on an aluminum heating block at 80 °C for 21 h and then concentrated under N at 40 °C. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in CH2Cl2 to give the title compound (60.2 mg, 100%) as a yellow oily solid. ES-MS m / z 354.2 (M+H).

[0734] Preparation 264 rac-(trans)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-methylcyclopropane-1-carboxylic acid

[0735] [ka] A solution of rac-ethyl (trans)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-methylcyclopropane-1-carboxylate (60.2 mg, 91 wt%, 155 μmol) in MeOH (1 mL) was treated with aqueous lithium hydroxide (200 μL, 2 molar, 400 μmol). The reaction vial was flushed with Ar, sealed with a pressure-relief septum cap, and stirred at 65 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with aqueous HCl (300 μL, 1 molar, 300 μmol), and then concentrated under N at 40 °C. The residue was further dried in a vacuum oven at 50 °C overnight to give the title compound (assumed quantitative) as an off-white solid. ES-MS m / z 326.2 (M+H).

[0736] Preparation 265 1-(methyl-d3)-1H-pyrazole-4-carbaldehyde

[0737] [ka] 1H-Pyrazole-4-carbaldehyde (10.1 g, 105 mmol) and cesium carbonate (33.6 g, 0.981 Eq, 103 mmol) were added to a 500 mL flask containing a stir bar. DMF (200 mL) was added, the flask was sealed, and purged with N2. Iodomethane-d3 (7.73 mL, 124 mmol) was added. The reaction mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature, diluted with water (400 mL), and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with saturated aqueous NaCl (3 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 20–80% EtOAc in hexanes to afford the title compound (4.06 g, 34% yield) as a colorless liquid. 1 H NMR (400MHz, DMSO) δ 9.79 (s, 1H), 8.42 (d, J = 0.7 Hz, 1 H), 7.97 (d, J = 0.7 Hz, 1 H).

[0738] Preparation 266 Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)acrylate

[0739] [ka] Methyl 2-{[(tert-butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (12.0 g, 40.4 mmol) was added to a 100 mL flask containing 1-(methyl-d3)-1H-pyrazole-4-carbaldehyde (4.0 g, 35 mmol) and purged with N2. DCM (48 mL) was added, and the resulting clear solution was stirred at room temperature. DBU (6.1 g, 6.0 mL, 40 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30 mL) and washed with water (50 mL), saturated aqueous ammonium sulfate (50 mL), and then saturated aqueous K2CO3 (50 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 50-100% EtOAc in hexanes to give the title compound (7.56 g, 75%) as a white solid. ES-MS m / z 285.4 (M+H).

[0740] Preparation 267 Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)propanoate

[0741] [ka] In a glovebox under N2, methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)acrylate (5.71 g, 20.1 mmol) and Rh-COD-[(R)-MaxPhos]-BF4 (612 mg, 1.09 mmol) were added to a Parr stirred autoclave. 2,2,2-Trifluoroethanol (80 mL) was added. The autoclave was sealed and removed from the glovebox. The autoclave was purged with H2, pressurized to 200 psi, and stirred at 40 °C overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 75% to 100% EtOAc in hexanes to give the title compound (4.82 g, 84%, 92% ee) as a colorless viscous liquid. Chiral analysis was performed using a Lux 5um i-Amylose-3, 4.6 x 100 mm column containing 15% IPA (0.2% IPAm) / CO2 at 5 mL / min with detection at 225 nm. Rt = 1.24 min. ES-MS m / z 287.4 (M+H).

[0742] Preparation 268 tert-Butyl (R)-(1-((1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0743] [ka] Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(methyl-d3)-1H-pyrazol-4-yl)propanoate (1.29 g, 4.50 mmol) and a stir bar were placed in a 40 mL vial, and tert-butyl alcohol (8 mL) was added. The mixture was sonicated until homogeneous, and then water (1 mL) was added. The reaction mixture was stirred on an ice-water bath, and lithium hydroxide (3 mL, 2 molar, 6 mmol) was added dropwise at 0°C. Upon complete addition, the reaction mixture was stirred at 0°C for 2 h, quenched at 0°C by the slow addition of concentrated aqueous HCl (200 μL, 2.40 mmol, 12 M), and lyophilized. The resulting white foam was combined with 1-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropan-2-amine hydrochloride (1.88 g, 5.83 mmol) and DMSO (5 mL), vortexed until homogeneous, and TEA (2 mL, 0.01 mol) was added, followed by HATU (2.5 g, 6.6 mmol). The reaction mixture was stirred at room temperature for 20 min, quenched with water (5 mL), and purified by reverse-phase flash chromatography (275 g C18) using a gradient of 30-100% ACN in 0.1% aqueous FA to give the title compound (3 g, 100%, 80% pure) as an oily solid. ES-MS m / z 540, 542 (M+H).

[0744] Preparation 269 Methyl (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate hydrochloride

[0745] [ka] A solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (6.00 g, 19.5 mmol) in 2 M HCl in MeOH (58.4 mL, 117 mmol) was stirred at room temperature for 22 hours. The reaction mixture was then concentrated under reduced pressure to give the title compound (5.01 g, 91%, 90% pure) as a white solid. ES-MS m / z 220 (M+H).

[0746] Preparation 270 Methyl-d3(R)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0747] [ka] To a 40 mL vial was added a stir bar, (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (1.533 g, 5.022 mmol), and silver oxide (4.2 g, 18 mmol). The solid was suspended in anhydrous DMF (10 mL) under argon, and iodomethane-d3 (3.0 g, 1.3 mL, 21 mmol) was added. The reaction vial was wrapped in aluminum foil, stirred at room temperature for 5 days, diluted with MTBE to a total volume of 40 mL, filtered through diatomaceous earth, and rinsed with additional MTBE (3 × 10 mL). The filtrate was washed with water (40 mL) and concentrated under reduced pressure at 25 °C. The residue was purified by silica gel column chromatography using a gradient of 0–100% EtOAc in heptane (ELSD detection, TLC visualization with ninhydrin, product R f 0.3 (30% EtOAc-heptane)) to give the title compound (1.65 g, 96.8%) as a colorless oil. ES-MS m / z 340 (M+H).

[0748] Preparation 271 Lithium (R)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0749] [ka] A 40 mL vial was charged with methyl-d3(R)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (1.65 g, 4.86 mmol) and a stir bar. 1,4-Dioxane (6 mL) and water (1 mL) were added, and the reaction mixture was stirred under air at 0 °C to give a homogeneous solution. Aqueous lithium hydroxide (0.14 g, 3.0 mL, 2 molar, 6.0 mmol) was added dropwise, and the resulting cloudy solution was stirred at 0 °C for 5 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with aqueous HCl (1.5 mL, 1 molar, 1.5 mmol) and lyophilized to give the title compound (assumed quantitative) as a white solid. ES-MS m / z 323 (M+H).

[0750] Preparation 272 tert-Butyl (1-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropyl)carbamate

[0751] [ka] A mixture of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (6.11 g, 28.4 mmol), tert-butyl 6-oxa-5-thia-4-azaspiro[2.4]heptane-4-carboxylate 5,5-dioxide (4.72 g, 18.9 mmol), and CsCO (12.3 g, 37.9 mmol) in anhydrous DMA (50 mL) was stirred at 90 °C under nitrogen for 3 h. The reaction mixture was cooled to room temperature and poured into a stirred mixture of 1 M aqueous hydrochloric acid (20 mL) and EtOAc (50 mL). Additional water and EtOAc were added until all solids dissolved. The aqueous layer was then acidified to a pH of approximately 2-3 by the addition of 1 M aqueous hydrochloric acid (approximately 25-30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% MTBE in cyclohexane to give the second eluting isomer as the title compound (2.08 g, 29%) as a white solid. ES-MS m / z 328, 330 (M-tBu+H).

[0752] Preparation 273 1-((5-Bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropan-1-amine hydrochloride

[0753] [ka] A solution of tert-butyl (1-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropyl)carbamate (2.07 g, 5.39 mmol) in MeOH (5 mL) was treated with a 4.0 M solution of hydrogen chloride in 1,4-dioxane (15 mL, 60 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give the title compound (1.73 g, 100%) as a white solid. ES-MS m / z 284, 286 (M+H).

[0754] Preparation 274 tert-Butyl (R)-(1-((1-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate

[0755] [ka] A stirred mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoic acid (1.74 g, 5.70 mmol), 1-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropan-1-amine hydrochloride (1.73 g, 5.40 mmol), and HATU (3.19 g, 8.39 mmol) in DMF (10 mL) was treated with DIEA (4.7 mL, 27 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution and further diluted with water until all solids dissolved. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was first purified on silica using a gradient of 0-20% 1:1 MTBE / DCM in DCM. Impure fractions were purified by high pH reverse-phase flash chromatography (40-65% ACN in 10 mM aqueous NH4HCO3). Pure fractions from each purification were isolated to give the title compound (1.54 g, 50%) as a white solid. ES-MS m / z 515, 517 (M-tBu+H).

[0756] Preparation 275 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)(methyl-d3)carbamate

[0757] [ka] A 20 mL vial was charged with a stir bar and 5-(1-(2-amino-2-methylpropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-fluoro-1-methylpyridin-2(1H)-one hydrochloride (608 mg, 1.65 mmol). Lithium (R)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (500 mg, 1.52 mmol) was added as a solution in DMSO (5 mL), and the reaction mixture was stirred at room temperature until homogeneous. TEA (800 μL, 5.74 mmol) was then added, resulting in a colorless, biphasic mixture. HATU (778 mg, 2.05 mmol) was added, and the reaction mixture was stirred under air at room temperature for 45 min, quenched with water (1 mL), and loaded directly onto diatomaceous earth using minimal MeOH. Reverse-phase flash column chromatography (100 g C18) eluted with a gradient of 40–100% ACN in 0.1% aqueous FA afforded the title compound (0.89 g, 92%) as a white solid. ES-MS m / z 637.4 (M+H).

[0758] Preparation 276 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

[0759] [ka] In a 1 L round-bottom flask 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) A mixture of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-oxopropan-2-yl)carbamate (50.0 g, 87.2 mmol), Pd(dppf)-dichloride adduct (5.5 g, 6.7 mmol), and K2CO3 (36.2 g, 262 mmol) was added, followed by 1,4-dioxane (279 mL) and water (69.8 mL). The mixture was degassed under high vacuum, purged with N2 (three times), 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 chromatography using a gradient of 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).

[0760] The compounds in the following table were prepared using the appropriate aryl bromide and the appropriate boronic ester or boronic acid as described in Preparation 276. The reactants may be added in different orders or in different equivalent amounts, reaction times and temperatures 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.

[0761] [Table 20] a. Purified by silica gel chromatography eluting with EtOAc:EtOH (3:1) in heptane. b. Purified by silica gel chromatography eluting with DCM:MeOH (4:1) (0-20%) in EtOAc.

[0762] Preparation 282 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-thioxopropan-2-yl)carbamate

[0763] [ka] A mixture 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 (500 mg, 807 μmol) and Lawesson's reagent (CAS number 19172-47-5, 560 mg, 1.38 mmol) in THF (5 mL) was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, and Lawesson's reagent (560 mg, 1.38 mmol) was added. The resulting mixture was stirred at 70° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30-100% EtOAc in cyclohexane to give the title compound (241 mg, 47%) as a yellow solid. ES-MS m / z 636.2 (M+H).

[0764] Preparation 283 (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

[0765] [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. 4 M hydrogen chloride in 1,4-dioxane (140 mL, 560 mmol) was added over 15 minutes and stirred overnight, resulting in a thick oil at the bottom of the flask. The mixture was cooled to ambient temperature and 100 mL of MeOH was added to dissolve the thick oil. 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, 110%) as a light tan foamy solid. ES-MS (m / z) 502.2 (M+H).

[0766] The compounds in the following table were prepared from the appropriate tert-butyl carbamate as described in Preparation 283. Various reaction times and equivalents of HCl may be used and will be apparent to those skilled in the art. The deprotected amine was isolated as the corresponding hydrochloride salt. The compounds may be used without determining the number of equivalents of HCl.

[0767] [Table 21-1]

[0768] [Table 21-2] a. Room temperature, 2.5 hours, 10.5 eq HCl. b. At room temperature, the crude reaction mixture was concentrated under reduced pressure to give the title compound.

[0769] Preparation 291 (6-chloro-2-(trifluoromethyl)pyridin-3-yl)methanol

[0770] [ka] 6-Chloro-2-(trifluoromethyl)nicotinic acid (25 g, 0.11 mol) was dissolved in THF (100 mL) under Ar. Borane dimethyl sulfide (19 mL, 0.22 mol) was added dropwise. The reaction was stirred for 3 days, then cooled to 0 °C, and MeOH (30 mL, 0.74 mol) was added dropwise. Upon complete addition, the mixture was concentrated under reduced pressure and chased with additional MeOH (3 × 100 mL). The residue was resuspended in MTBE (200 mL) and filtered. The filtrate was treated with 1 M aqueous NaOH (200 mL), and the aqueous layer was extracted with MTBE (100 mL). The combined organics were dried over NaSO, filtered, and concentrated to give the title compound (25.7 g, 100%) as a pale yellow to orange oil. ES-MS m / z 212.0 / 214.0 (M+H).

[0771] Preparation 292 (6-chloro-2-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate

[0772] [ka] (6-Chloro-2-(trifluoromethyl)pyridin-3-yl)methanol (24.7 g, 110 mmol) was dissolved in DCM (250 mL) and TEA (24 mL, 0.17 mol) was added under argon. The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (10 mL, 0.13 mol) was added dropwise over 5 minutes. The reaction was stirred for 20 minutes, then diluted with water (200 mL) and warmed to room temperature. The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were concentrated under reduced pressure to give the title compound (32.72 g, 100%) as an orange-yellow oil. ES-MS m / z 290.0 (M+H).

[0773] Preparation 293 1-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)methyl)tetrahydro-1H-thiophen-1-ium methanesulfonate

[0774] [ka] (6-Chloro-2-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate (31.3 g, 100 mmol) was dissolved in 2,2,2-trifluoroethanol (100 mL), and tetrahydrothiophene (10 mL, 0.11 mol) was added. The flask was sealed with a septum, and the reaction mixture was mixed by swirling and then left under air overnight. The reaction mixture was combined with the 1.0 g scale reaction mixture and concentrated under reduced pressure to give a thick oil. The residue was suspended in MTBE (500 mL) and filtered. The precipitate was washed with MTBE (3 x 200 mL) and air-dried on the filter to give the title compound (34 g, 86%) as a white solid. ES-MS m / z 282 (M + ).

[0775] Preparation 294 1-((6-bromo-2-methylpyridin-3-yl)methyl)tetrahydro-1H-thiophen-1-ium tetrafluoroborate

[0776] [ka] To 6-bromo-3-(bromomethyl)-2-methylpyridine (2 g, 8 mmol) and tetrahydrothiophene (0.7 mL, 8 mmol) in ACN (10 mL) was added silver tetrafluoroborate (1 g, 8 mmol). The reaction was stirred for 6 h, then combined with 1.5 g of the reaction mixture and partially concentrated (2 mL). The mixture was filtered through diatomaceous earth, concentrated to dryness, resuspended in ACN (5 mL), and filtered. The filtrate was concentrated to give the title compound (4.46 g, 50% purity, 45%) as a gray solid. ES / MS m / z 274 (M + ).

[0777] Preparation 295 1-(4-Bromo-2-chlorobenzyl)tetrahydro-1H-thiophen-1-ium bromide

[0778] [ka] 4-Bromo-1-(bromomethyl)-2-chlorobenzene (10 g, 34 mmol) was dissolved in 2,2,2-trifluoroethanol (50 mL) and tetrahydrothiophene (4.0 mL, 45 mmol) was added. The resulting suspension was stirred under air at room temperature for 3 hours and then concentrated under reduced pressure at 25°C. The residue was suspended in MTBE (100 mL) and filtered. The precipitate was rinsed with MTBE (2 x 50 mL) and air-dried to give the title compound (13.45 g, 100%) as a white powder. ES / MS m / z 291 (M + ).

[0779] Preparation 296 1-(4-Bromo-2-(difluoromethyl)benzyl)tetrahydro-1H-thiophen-1-ium bromide

[0780] [ka] The title compound was prepared from 4-bromo-1-(bromomethyl)-2-(difluoromethyl)benzene by stirring overnight as described in Preparation 295. ES-MS m / z 307 (M + ).

[0781] Preparation 297 (trans)-1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-5-oxaspiro[2.4]heptan-4-one, isomer 1

[0782] [ka] 1-((6-Chloro-2-(trifluoromethyl)pyridin-3-yl)methyl)tetrahydro-1H-thiophen-1-ium methanesulfonate (31.97 g, 83.77 mmol) and 3-methylenedihydrofuran-2(3H)-one (9.2 g, 94 mmol) were dissolved in DCM (120 mL) under Ar. The reaction mixture was cooled to 0 °C and LiHMDS (1 M in THF, 90 mL, 90 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, followed by the dropwise addition of LiHMDS (1 M in THF, 12.5 mL, 12.5 mmol). The mixture was stirred at 0 °C for an additional 30 min, then quenched with saturated aqueous NH4Cl (200 mL), warmed to room temperature, and transferred to a 500 mL separatory funnel. The organic layer was collected, and the aqueous layer was diluted with HO (50 mL) and extracted with additional DCM (2 × 100 mL). The combined extracts were concentrated under reduced pressure. The residue was suspended in MTBE (200 mL) with stirring for 5 minutes, then filtered and rinsed with MTBE (3 × 20 mL). The filtrate was concentrated, dry-loaded onto silica, and purified by column chromatography using 30–100% EtOAc in heptane, followed by chiral SFC purification (Chiralpak IG 30 × 250 mm × 5 μM, 85 mL / min) eluting with 5% MeOH in 10 mM NHOAc in MeOH to give the title compound (2 g, 7%) as the first-eluting trans enantiomer.

[0783] Preparation 298 (1S,3R)-1-(4-bromo-2-chlorophenyl)-5-oxaspiro[2.4]heptan-4-one

[0784] [ka] The title compound was prepared using 1-(4-bromo-2-chlorobenzyl)tetrahydro-1H-thiophen-1-ium bromide as described in Preparation 297. Purification by silica using a gradient of 10-40% EtOAc / heptane, followed by chiral SFC purification (Chiralpak IG 50 mm x 250 x 5 μm, 80 mL / min) eluting with MeOH afforded the title compound (1.43 g, 14%) as the first eluting enantiomer. ES-MS m / z 301.0, 303.0 (M+H).

[0785] Preparation 299 rac-(trans)-1-(4-bromo-2-(difluoromethyl)phenyl)-5-oxaspiro[2.4]heptan-4-one

[0786] [ka] 3-Methylenedihydrofuran-2(3H)-one (0.50 g, 5.1 mmol) and 1-(4-bromo-2-(difluoromethyl)benzyl)tetrahydro-1H-thiophen-1-ium bromide (1.4 g, 3.6 mmol) were combined in DCM (12 mL) and cooled to 0° C. LiHMDS (1 M in toluene, 4.7 mL, 4.7 mmol) was added dropwise to the flask. The reaction was stirred at 0° C. for 1 h, then LiHMDS (1 M in toluene, 2.35 mL, 2.35 mmol) was added and the reaction was stirred for 15 min. The reaction mixture was then diluted with water and DCM and allowed to warm to room temperature. The aqueous layer was extracted with DCM (3×), and the organic layers were combined, dried over sodium sulfate, and concentrated. The reaction mixture was combined with the 500 mg scale reaction mixture and purified by UPLC CSH (XSelect, C18, 50 mm x 250 mm x 5 μm, 100 mL / min) using a gradient of 40-95% ACN / water (containing 10 mM NHOAc) to give the title compound (721 mg, 48%) as a white solid. ES-MS m / z 317.0 / 319.0 (M+H).

[0787] Preparation 300 Rac-(trans)-1-(6-bromo-2-methylpyridin-3-yl)-5-oxaspiro[2.4]heptan-4-one

[0788] [ka] The title compound was prepared by the reaction of tetrafluoro-λ as described in Preparation 299. 4 -borane, 1-((6-bromo-2-methylpyridin-3-yl)methyl)tetrahydro-1H-thiophen-1-ium salt. The product was purified on silica using a gradient of 0-40% MeOH in DCM to give the title compound (430 mg, 32%). ES-MS m / z 282, 284 (M+H).

[0789] Preparation 301 Methyl (R)-2-((1R,2R)-1-(2-chloroethyl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamido)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0790] [ka] To a mixture of methyl (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate hydrochloride (5.4 g, 90 wt%, 19 mmol) and TEA (26 mL, 0.19 mmol) in THF (120 mL) and DMA (60 mL) was added (1R,2R)-1-(2-chloroethyl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonyl chloride (17.2 g, 47 wt%, 21.6 mmol) at 0° C., and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was poured into water (150 mL), and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaCl (2×200 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc (100 mL) at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude material was purified by silica gel chromatography eluting with 0-3% MeOH / DCM to give the title compound (8.3 g, 74%) as a pale yellow solid. ES-MS m / z 557 (M+H).

[0791] Preparation 302 Methyl (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoate

[0792] [ka] A mixture of methyl (R)-2-((1R,2R)-1-(2-chloroethyl)-2-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamido)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (8.3 g, 14 mmol) and cesium carbonate (9.2 g, 28 mmol) in THF (150 mL) was stirred at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and then poured into water (200 mL). The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with saturated aqueous NaCl (2×300 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH / DCM to give the title compound (6.2 g, 78%) as a yellow solid: ES-MS m / z 521 (M+H).

[0793] Preparation 303 (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoic acid

[0794] [ka] To a solution of methyl (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1R,3R)-1-(4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoate (3.6 g, 6.6 mmol) in t-BuOH (32 mL) and water (16 mL) was added 1 M aqueous lithium hydroxide solution (20 mL, 20 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was then concentrated at 20 °C to remove t-BuOH and obtain a basic aqueous solution. The aqueous mixture was treated with strongly acidic styrene cation exchange resin (18.2 g), and the resin was then filtered and rinsed with water (300 mL). The filtrate was lyophilized to dryness to give the title compound (2.42 g, 71%) as a yellow solid: ES-MS m / z 507 (M+H).

[0795] Preparation 304 Methyl (R)-2-((1R,2S)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carboxamido)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0796] [ka] To a solution of (1S,3R)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one (4.04 g, 13.3 mmol) and benzyl(triethyl)ammonium chloride (6.07 g, 26.6 mmol) in DCE (80 mL) was added boron trifluoride etherate (3.86 g, 3.41 mL, 26.6 mmol) and thionyl chloride (6.34 g, 3.92 mL, 53.3 mmol). The mixture was purged with N2 three times and then stirred under nitrogen at 80 °C for 16 h. The mixture was concentrated under reduced pressure to give (1R,2R)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carbonyl chloride (10.2 g, 45 wt% purity).

[0797] To a mixture of methyl (R)-2-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate hydrochloride (3.6 g, 13 mmol) and TEA (19 mL, 0.13 mmol) in THF (120 mL) and DMA (60 mL) was added a solution of (1R,2R)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carbonyl chloride (10.2 g, 45 wt%, 13.5 mmol) in THF (80 mL) at 0° C., and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was poured into water (150 mL), and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaCl (2×100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-40% EtOAc / PE to give the title compound (7.8 g, 95%, 85% purity) as a yellow oil. ES-MS m / z 522, 524 (M+H).

[0798] Preparation 305 Methyl (R)-2-((1S,3R)-1-(4-bromo-2-fluorophenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate

[0799] [ka] A mixture of methyl (R)-2-((1R,2S)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carboxamido)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (7.8 g, 13 mmol, 85 wt%) and cesium carbonate (5.0 g, 15 mmol) in THF (120 mL) was stirred at 50° C. for 24 hours and then at room temperature for 48 hours. The reaction mixture was poured into water (100 mL). The mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaCl (2×800 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-35% EtOAc in PE to give the title compound (4.1 g, 63%, 65:35 dr) as a yellow oil. ES-MS m / z 486, 488 (M+H).

[0800] Preparation 306 Methyl (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoate

[0801] [ka] To a mixture of methyl (R)-2-((1S,3R)-1-(4-bromo-2-fluorophenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)propanoate (4.12 g, 65:35 dr, 7.96 mmol), (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (1.48 g, 8.36 mmol), and sodium carbonate (1.69 g, 15.9 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added XPhos Pd G3 (1.35 g, 1.59 mmol) at room temperature under nitrogen. The mixture was purged with nitrogen (3 times), and then the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature and then poured into water (150 mL). The mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 150 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH / DCM to give the title compound (4.35 g, 65:35 dr, 92%) as a yellow solid. ES-MS m / z 539 (M+H).

[0802] Preparation 307 (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoic acid

[0803] [ka] To a solution of methyl (R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-oxo-5-azaspiro[2.4]heptan-5-yl)propanoate (4.35 g, 2:1 dr, 7.35 mmol) in t-BuOH (60 mL) and water (30 mL) was added 1 M aqueous lithium hydroxide solution (11.0 mL, 11.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was adjusted to approximately pH 7 with 1 M aqueous hydrochloric acid and then concentrated under reduced pressure. The residue was purified by SFC (Daicel IM 250 × 30 mm, 10 μm, 40% CO in ACN / EtOH containing 0.1% NH OH) to give the second eluting isomer as the title compound (2.57 g, 66%) as a white solid. ES-MS m / z 525 (M+H).

[0804] Preparation 308 (1R,2S)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)-N-(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)cyclopropane-1-carboxamide

[0805] [ka] A mixture of (1S,3R)-1-(4-bromo-2-fluorophenyl)-5-oxaspiro[2.4]heptan-4-one (1.49 g, 5.23 mmol) and benzyltriethylammonium chloride (2.38 g, 10.4 mmol) in DCE (9 mL) was treated with SOCl (1.55 mL, 21.2 mmol) followed by BF·EtO (1.3 mL, 11.0 mmol). After stirring at 80 °C overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. DCE (5 mL) was added, and the mixture was concentrated under reduced pressure to give a quantitative yield of (trans)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carbonyl chloride, isomer 1, as a yellow sticky solid. In a separate vessel, a mixture of (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 (3.10 g, 5.58 mmol) in DCM (20 mL) was stirred at 0° C. and treated with TEA (5.2 mL, 37.0 mmol). A suspension of (trans)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)cyclopropane-1-carbonyl chloride (isomer 1, 5.24 mmol) in DCM (5 mL) was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. TEA (1.5 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. EtOAc (500 mL) and cold water (500 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (200 mL), and the organic layers were combined, washed three times with water, then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound in quantitative yield as a light brown solid. ES-MS m / z 822, 824 (M+H).

[0806] The compounds in the following table were prepared as described in Preparation 308 using the appropriate lactone and the appropriate amine or amine salt. DIEA is a suitable substitute for TEA. Minor modifications to the reaction conditions, work-up procedures, and purification methods will be apparent to those skilled in the art.

[0807] [Table 22-1]

[0808] [Table 22-2]

[0809] [Table 22-3] No workup. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-80% EtOAc in heptane. b. Synthesized from rac-(trans)-1-(6-bromo-2-methylpyridin-3-yl)-5-oxaspiro[2.4]heptan-4-one as described above. Bromopyridyl was also converted to chloropyridyl under these reaction conditions. Purified by silica gel flash chromatography eluting with 3:1 EtOAc:EtOH in heptane. c. No workup. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in EtOH in heptane (3 / 1). d. No workup. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in EtOH in DCM (3 / 1).

[0810] Preparation 318 (2R)-2-(1S,3R)-(1-(4-bromo-2-fluorophenyl)-4-oxo-5-azaspiro[2.4]heptan-5-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

[0811] [ka] A mixture of (1R,2S)-2-(4-bromo-2-fluorophenyl)-1-(2-chloroethyl)-N-((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)cyclopropane-1-carboxamide (4.57 g, 5.28 mmol) and CsCO (3.50 g, 11 mmol) in ACN (15 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ACN, filtered, and washed with ACN. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (Luna® C18, 50 × 250 mm, 10 μm, 120 mL / min) using a gradient of 35-65% ACN in 10 mM aqueous NH4HCO3, pH = 10 (containing 5% MeOH) over 22.5 min to give the title compound (2.94 g, 71%) as a pink foam. ES-MS m / z 786, 788 (M+H).

[0812] The compounds in the table below were prepared as described in Preparation 318. NMP and THF are suitable substitutes for ACN. Reaction times and temperatures 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.

[0813] [Table 23-1]

[0814] [Table 23-2]

[0815] [Table 23-3] a. The reaction was quenched with FA (10 eq) as a solution in H2O and the compound purified with ACN / 0.1% FA in water. b. The reaction was quenched with FA (7 eq) as a solution in H2O and the compound purified with ACN / 0.1% FA in water. c. Prepared as described using 0.1 equivalents of TBAI. Purified by reverse-phase flash chromatography using a gradient of 0–100% ACN / 10 mM aqueous NH4HCO3 (5% MeOH). The reaction mixture was partitioned between 20 mL of water and 20 mL of EtOAc and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with 20 mL of water, washed with saturated aqueous NaCl (3 × 20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound without purification. e. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 mL), HO (15 mL), and 1:1 EtOAc:toluene (30 mL), and the organic layer was separated. The aqueous layer was extracted with 1:1 EtOAc:toluene (3 × 40 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound without further purification.

[0816] Preparation 328 (2R)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(1S,3R)-(1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluorophenyl)-4-oxo-5-azaspiro[2.4]heptan-5-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

[0817] [ka] A stirred mixture of (2R)-2-(1S,3R)-(1-(4-bromo-2-fluorophenyl)-4-oxo-5-azaspiro[2.4]heptan-5-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 (2.42 g, 3.08 mmol), bis(neopentylglycolato)diborane (2.08 g, 9.23 mmol), and KOAc (1.21 g, 12.31 mmol) in 1,4-dioxane (31 mL) was sparged with nitrogen for 5 minutes. Pd(dppf)Cl.CH.Cl. (377 mg, 462 μmol) was then added and nitrogen was sparged for an additional 5 min. The reaction vessel was then sealed and heated to 80 °C for 3 h. The reaction mixture was then cooled to room temperature and used directly in the next step. ES-MS m / z 752 (corresponding boronic acid M+H).

[0818] The compounds in the following table were prepared as described in Preparation 328. Bis(pinacolato)diboron is a suitable substitute for bis(neopentylglycolato)diborane. Reaction times (1 hour to overnight) and temperatures (80°C to 100°C) 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.

[0819] [Table 24]

[0820] Preparation 333 (1R,2S)-1-(2-chloroethyl)-N-((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)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carboxamide

[0821] [ka] A mixture of (1S,3R)-1-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-5-oxaspiro[2.4]heptan-4-one (300 mg, 889 μmol) and benzyltriethylammonium chloride (408 mg, 1.78 mmol) in DCE (4.45 mL) was treated with SOCl (260 μL, 3.56 mmol) followed by BF EtO (220 μL, 1.78 mmol). After stirring at 80 °C overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. DCE (5 mL) was added, and the mixture was concentrated under reduced pressure to give a quantitative yield of (1R,2R)-1-(2-chloroethyl)-2-(2-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)cyclopropane-1-carbonyl chloride as a dark, viscous oil. 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 dihydrochloride (512 mg, 891 μmol) in DCM (10 mL) was stirred at 0 °C and treated with TEA (1.12 mL, 8.04 mmol). A suspension of (1R,2R)-1-(2-chloroethyl)-2-(2-fluoro-4-...

Claims

1. formula: 【Chemistry 1】 A compound of the formula: During the ceremony, R １ but, i) 1 or 2 halo or CH ３ C optionally substituted with ３ ~C ４ cycloalkyl, CH ３ a 4-membered heterocycle optionally substituted with C １ ~C ４ Alkoxy, C １ ~C ４ haloalkyl, C １ ~C ４ haloalkoxy, Oxo, C.N., Hello, CD ３ , and OCH ３ , OH or C ３ ~C ４ C optionally substituted with cycloalkyl １ ~C ４ Alkyl (the above C ３ ~C ４ an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from: ･･･)･･ １６ CO2 １２ 、 iii) OH, or iv) C(O)CH ３ , oxo, OCH ３ , C optionally substituted with CN, halo, and OH １ ~C ４ a 5- or 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from alkyl; R １２ However, NHR １３ , pyridyl, phenyl, OCH ３ or C ３ ~C ６ cycloalkyl, and the pyridyl, phenyl or C ３ ~C ６ cycloalkyl is optionally substituted with one or two halo; R １３ But C １ ~C ４ alkyl, or phenyl optionally substituted with one or two halo; R １６ is H or CH ３ and A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein said phenyl, heteroaryl, or thienyl is selected from halo, CF ３ , CHF ２ , C.H. ３ , cyclopropyl, OH, and CN; or R １ is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R ２ But H, CH ３ , Haro, CF ３ or CHF ２ and R ３ is H and R ４ But H, CH ３ or CD ３ or R ３ and R ４ Together, they form -CH ２ -CH ２ - forms, R ５ but, i) oxo, halo and CH ３ an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with one or two substituents selected from ii) CH ３ , CDs ３ , CHF ２ , OH and CH ２ CN; X is O or S; R ６ and R ７ 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 ８ But H, D, OH, CO ２ R １８ , or 【Chemistry 2】 and R １８ is H or OC(O)C １ ~C ４ C optionally substituted with alkyl or morpholine １ ~C ４ alkyl, and R ８’ is H and R ９ is a 5- or 6-membered N-containing heteroaryl or phenyl, and said heteroaryl or phenyl is R １０ Or R １０ and R １１ or said phenyl is optionally substituted with halo, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with Or R ８ is D and R ８’ is D and R ９ is a 5- or 6-membered N-containing heteroaryl or phenyl, and said heteroaryl or phenyl is R １０ Or R １０ and R １１ or said phenyl is optionally substituted with halo, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with Or R ８ and R ９ 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 ８’ is H, R １０ But CF ３ , C.F. ２ H, halo or cyclopropyl; R １１ but, i) Hello, OH, C １ ~C ４ Alkoxy, CD ３ 、 OCHF ２ 、 SO ２ NH ２ 、 C.N., C １ ~C ４ haloalkyl, C ３ ~C ６ cycloalkyl, C(O)NH ２ 、 oxo or CH ３ a 4- to 6-membered heterocycle optionally substituted with Oxo, CR １４ R １５ OP(O)(OH) ２ 、 (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 , C(O)NR １４ R １５ , C.N., N.R. １４ R １５ , 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 4 substituents independently selected from alkyl; ii) CN, CH ３ , halo, oxo, C(O)O(CH ３ ) ３ a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from: iii) C １ ~C ４ Alkoxy, iv) C ３ ~C ５ cycloalkyl, v) halo, vi) (CH ２ ) ｎ C(O)R １９ (wherein n is 0 or 1, and R １９ But OCH ３ , N.R. １４ R １５ or a 4- to 6-membered heterocycle), vii)(CH ２ ) ｍ P (O) (R). １７ ) ２ 、 viii) optionally substituted with a 4- to 6-membered heterocycle or phenyl, wherein the heterocycle or phenyl is CH ３ C optionally substituted by １ ~C ４ Alkyl, ix) CN, or x) Halo, C １ ~C ４ Alkyl, (CH ２ ) ｍ P(O)(R １７ ) ２ , COOH and NR １４ R １５ and wherein said C is optionally substituted with 1 to 3 substituents independently selected from １ ~C ４ alkyl is phenyl optionally substituted with OH; R １４ and R １５ are independently H or CH ３ and Each R １７ But independently, C １ ~C ４ is alkyl, m is 0 or 1; The compound, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

3. R ６ and R ７ are CH ３ 3. The compound of claim 1 or 2, wherein:

4. R ３ is H and R ４ But H, CH ３ or CD ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R ３ and R ４ Together, they form -CH ２ -CH ２ 4. The compound according to claim 1, wherein the compound forms a pharmaceutically acceptable salt thereof.

6. R ２ is H or CH ３ 6. The compound according to any one of claims 1 to 5, wherein:

7. R １ but, i) 【Transformation 3】 is selected from 1 or 2 halo or CH ３ C optionally substituted with ３ ~C ４ cycloalkyl, CH ３ a 4-membered heterocycle optionally substituted with C １ ~C ４ Alkoxy, C １ ~C ４ haloalkyl, Oxo, C.N., Halo, and OCH ３ , OH or C ３ ~C ４ C optionally substituted with cycloalkyl １ ~C ４ Alkyl (the above C ３ ~C ４ 9- or 10-membered N-containing bicyclic heterocycles optionally substituted with 1 to 3 substituents independently selected from: ii) NR １６ COR １２ (In the formula, R １２ However, NHR １３ , OCH ３ or C optionally substituted with 1 or 2 halo ３ ~C ６ is cycloalkyl, and R １３ is phenyl optionally substituted with one or two halo, and R １６ is H or CH ３ is), or iii)C(O)CH ３ piperazine optionally substituted with OCH ３ C optionally substituted with halo and OH １ ~C ４ pyridine optionally substituted with one or two substituents independently selected from alkyl, or OCH ３ , C.H. ３ 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is pyrimidine optionally substituted with one or two substituents independently selected from aryl, aryloxy ...

8. R １ but, 【Chemistry 4】 8. The compound of claim 7, selected from:

9. R １ but, 【Transformation 5】 9. The compound of claim 8, selected from:

10. A is phenyl, pyridyl, pyrimidinyl or thienyl, and the phenyl, pyridyl, pyrimidinyl or thienyl is F, Cl, CF ３ , CHF ２ , C.H. ３ optionally substituted with one or two substituents independently selected from R １ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein A is optionally absent when is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle.

11. A is, 【Transformation 6】 wherein a is selected from R １ and b is the attachment point to cyclopropyl, or A is absent; or a pharmaceutically acceptable salt thereof.

12. A is, 【Transformation 7】 12. The compound of claim 11 selected from: or a pharmaceutically acceptable salt thereof.

13. R ５ but, i) a 9-membered N-containing bicyclic heterocycle, or ii) CH ３ , CDs ３ or CHF ２ is a 5-membered N-containing heteroaryl substituted with 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R ５ but, 【Transformation 8】 That is, 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof.

15. R ５ but, 【Chemistry 9】 That is, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

16. R ８ and R ８’ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein

17. R ９ but, phenyl substituted with F, or R １０ Or R １０ and R １１ 17. The compound of any one of claims 1 to 16, wherein R is a 5- or 6-membered N-containing heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

18. R ９ but, 【Chemistry 10】 or 【Chemistry 11】 is a 5- or 6-membered N-containing heteroaryl selected from 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

19. R ９ but, 【Chemistry 12】 is a 5- or 6-membered N-containing heteroaryl selected from R １０ But CF ３ , C.F. ２ H or F, and R １１ but, i) Hello, OH, CD ３ 、 C １ ~C ４ haloalkoxy, C.N., C １ ~C ４ haloalkyl, C ３ ~C ５ cycloalkyl, C(O)NH ２ 、 a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR １４ R １５ OP(O)(OH) ２ , and C １ ~C ４ alkyl, wherein the C １ ~C ４ Alkyl is OH, OCH ３ , C(O)NR １４ R １５ , C.N., N.R. １４ R １５ , 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 4 substituents independently selected from alkyl; ii) CH ３ , halo, oxo, and C(O)O(CH ３ ) ３ a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from iii) C ３ ~C ５ cycloalkyl, iv) halo, v)C(O)OCH ３ 、 vi) P(O)(CH ３ ) ２ ,or vii) Halo, P(O)(CH ３ ) ２ , and C １ ~C ４ Alkyl (the above C １ ~C ４ alkyl is optionally substituted with OH; R １４ and R １５ are independently H or CH ３ 19. The compound of claim 18, wherein:

20. R ９ but, 【Chemistry 13】 and R １１ but, i) 【Chemistry 14】 【Chemistry 15】 a 5- or 6-membered heterocycle selected from ii) 【Chemistry 16】 a 9- or 10-membered N-containing bicyclic heterocycle selected from iii) cyclopropyl, cyclobutyl, iv) Br, v)C(O)OCH ３ 、 vi) P(O)(CH ３ ) ２ ,or vii) 【Chemistry 17】 20. The compound of claim 19, wherein:

21. R １１ but, [Chemistry 18] 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein:

22. formula: 【Chemistry 19】 And, During the ceremony, R １ but, i) 1 or 2 halo or CH ３ C optionally substituted with ３ ~C ４ cycloalkyl, CH ３ a 4-membered heterocycle optionally substituted with C １ ~C ４ Alkoxy, C １ ~C ４ haloalkyl, Oxo, C.N., Halo, and OCH ３ , OH or C ３ ~C ４ C optionally substituted with cycloalkyl １ ~C ４ Alkyl (the above C ３ ~C ４ an 8-, 9-, or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from: ii) Nhụcọụ １２ 、 iii) OH, or iv) C(O)CH ３ , C １ ~C ４ a 5- or 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from alkyl, oxo, and CN; R １２ However, NHR １３ , pyridyl, phenyl or C ３ ~C ６ cycloalkyl, and the pyridyl, phenyl or C ３ ~C ６ cycloalkyl is optionally substituted with one or two halo; R １３ But C １ ~C ４ alkyl, or phenyl optionally substituted with one or two halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein said phenyl, heteroaryl, or thienyl is selected from halo, CF ３ , CHF ２ , C.H. ３ , cyclopropyl, or CN; or R １ is an optionally substituted 8-, 9- or 10-membered N-containing bicyclic heterocycle, A may be absent; R ２ But H, CH ３ , Haro, CF ３ or CHF ２ and R ３ is H and R ４ But H, CH ３ or CD ３ or R ３ and R ４ Together, they form -CH ２ -CH ２ - forms, R ５ but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) CH ３ , CDs ３ , CHF ２ or 5- or 6-membered N-containing heteroaryl optionally substituted with OH; X is O or S; R ６ and R ７ are CH ３ or together form a cyclopropyl, R ８ But H, CH ３ , CO ２ H or C(O)OCH ３ and R ９ is a 5- or 6-membered N-containing heteroaryl or phenyl, and said heteroaryl or phenyl is R １０ Or R １０ and R １１ or said phenyl is optionally substituted with halo, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with Or R ８ and R ９ 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 R １０ But CF ３ , C.F. ２ H or halo, R １１ but, i) Hello, OH, OCH ３ 、 CD ３ 、 OCHF ２ 、 SO ２ NH ２ 、 C.N., C １ ~C ４ haloalkyl, C ３ ~C ５ cycloalkyl, C(O)NH ２ 、 a 4- to 6-membered heterocycle optionally substituted with oxo; Oxo, CR １４ R １５ OP(O)(OH) ２ , and C １ ~C ４ alkyl, wherein the C １ ~C ４ Alkyl is OH, OCH ３ , C(O)NR １４ R １５ , C.N., N.R. １４ R １５ , 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 4 substituents independently selected from alkyl; ii) CN, CH ３ , halo, oxo, C(O)O(CH ３ ) ３ a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from: iii) C １ ~C ４ Alkoxy, iv) C ３ ~C ５ cycloalkyl, v) halo, vi)C(O)OCH ３ ,or vii) Halo and C １ ~C ４ Alkyl (the above C １ ~C ４ alkyl is optionally substituted with OH; R １４ and R １５ are independently H or CH ３ The compound of claim 1 having the formula: or a pharmaceutically acceptable salt thereof.

23. R １ but, i) 1 or 2 halo or CH ３ C optionally substituted with ３ ~C ４ cycloalkyl, CH ３ a 4-membered heterocycle optionally substituted with C １ ~C ４ Alkoxy, C １ ~C ４ haloalkyl, oxo, and OCH ３ , OH or C ３ ~C ４ C optionally substituted with cycloalkyl １ ~C ４ Alkyl (the above C ３ ~C ４ cycloalkyl optionally substituted with 1 or 2 halo; ii) Nhụcọụ １２ 、 iii) OH, or iv) C(O)CH ３ , C １ ~C ４ a 6-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from alkyl and oxo; R １２ However, NHR １３ , pyridyl, phenyl or C ３ ~C ６ cycloalkyl, and the pyridyl, phenyl or C ３ ~C ６ cycloalkyl is optionally substituted with one or two halo; R １３ But C １ ~C ４ alkyl, or phenyl optionally substituted with one or two halo; A is phenyl, a 6-membered N-containing heteroaryl, or thienyl, wherein said phenyl, heteroaryl, or thienyl is selected from halo, CF ３ , CHF ２ , C.H. ３ and cyclopropyl; R ２ But H, CH ３ , Haro, CF ３ or CHF ２ and R ３ is H and R ４ But H, CH ３ or CD ３ or R ３ and R ４ Together, they form -CH ２ -CH ２ - forms, R ５ but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) CH ３ , CDs ３ , CHF ２ or 5- or 6-membered N-containing heteroaryl optionally substituted with OH; X is O or S; R ６ and R ７ are CH ３ or together form a cyclopropyl, R ８ But H, CH ３ , CO ２ H or C(O)OCH ３ and R ９ is a 5- or 6-membered N-containing heteroaryl or phenyl, and said heteroaryl or phenyl is R １０ Or R １０ and R １１ or said phenyl is optionally substituted with halo, CF ３ , and CF ２ H or OCH ３ pyrazine optionally substituted with Or R ８ and R ９ 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 R １０ But CF ３ , C.F. ２ H or halo, R １１ but, i) Hello, OH, OCH ３ 、 CD ３ 、 OCHF ２ 、 SO ２ NH ２ 、 C.N., C １ ~C ４ haloalkyl, C ３ ~C ５ cycloalkyl, C(O)NH ２ 、 a 4- to 6-membered heterocycle optionally substituted with oxo; oxo, and C １ ~C ４ alkyl, wherein the C １ ~C ４ Alkyl is OH, OCH ３ , C(O)NR １４ R １５ , C.N., N.R. １４ R １５ , 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 4 substituents independently selected from alkyl; ii) CN, CH ３ , halo, oxo, C(O)O(CH ３ ) ３ a 9- or 10-membered N-containing bicyclic heterocycle optionally substituted with 1 or 2 substituents independently selected from: iii) C １ ~C ４ Alkoxy, iv) C ３ ~C ５ cycloalkyl, v) halo, vi)C(O)OCH ３ ,or vii) Halo and C １ ~C ４ Alkyl (the above C １ ~C ４ alkyl is optionally substituted with OH; R １４ and R １５ are independently H or CH ３ The compound of claim 1, or a pharmaceutically acceptable salt thereof.

24. formula: 【Chemistry 20】 And, During the ceremony, R １ but, i) 1 or 2 halo or CH ３ C optionally substituted with ３ ~C ４ cycloalkyl, C １ ~C ４ haloalkyl, oxo, and OCH ３ or C ３ ~C ４ C optionally substituted with cycloalkyl １ ~C ４ Alkyl (the above C ３ ~C ４ cycloalkyl optionally substituted with 1 or 2 halo; ii) NHCOR １２ , or iii) OH, R １２ However, NHR １３ , pyridyl, phenyl or C ３ ~C ６ cycloalkyl, and the pyridyl, phenyl or C ３ ~C ６ cycloalkyl is optionally substituted with one or two halo; R １３ But C １ ~C ４ alkyl, or phenyl optionally substituted with one or two halo; R ２ But H, CH ３ , Haro, CF ３ or CHF ２ and R ３ is H and R ４ is H or CH ３ or R ３ and R ４ Together, they form -CH ２ -CH ２ - forms, R ５ but, i) an 8- or 9-membered N-containing bicyclic heterocycle optionally substituted with halo, or ii) CH ３ , CHF ２ or 5- or 6-membered N-containing heteroaryl optionally substituted with OH; R ６ and R ７ are CH ３ or together form a cyclopropyl, R ８ But H, CH ３ , CO ２ H or C(O)OCH ３ and R ９ but, R １０ Or R １０ and R １１ a 5- or 6-membered N-containing heteroaryl optionally substituted with Haro, CF ３ , and CF ２ H or OCH ３ or phenyl optionally substituted with 1 or 2 substituents selected from pyrazine optionally substituted with Or R ８ and R ９ 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 R １０ But CF ３ , C.F. ２ H or halo, R １１ but, i) Hello, OH, OCH ３ 、 SO ２ NH ２ 、 a 4- to 6-membered heterocycle, oxo or 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 is the formula, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

25. 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 11 to 198.

26. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

27. 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 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

28. 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 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

29. 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in therapy.

30. 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in treating type II diabetes.

31. 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in treating obesity.

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