PHD inhibitor compounds, compositions and uses

Abstract

The present invention provides, in part, novel small molecule PHD inhibitors having a structure according to Formula (A) or its subformulas: or a pharmaceutically acceptable salt thereof. The compounds provided herein are useful for treating diseases including heart disease (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung disease (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver disease (e.g., acute liver failure and liver fibrosis and cirrhosis), and kidney disease (e.g., acute kidney injury and chronic kidney disease). #imgabs0#

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 992,606, filed on March 20, 2020, which is hereby incorporated by reference in its entirety. Background Art

[0003] Hypoxia is a condition or state in which the oxygen supply is insufficient for normal life functions, for example, where there is a low arterial oxygen supply. Hypoxia may lead to functional impairment and structural tissue damage of cells. The activation of cellular defense mechanisms during hypoxia is mediated by HIF (hypoxia inducible factor) proteins. In response to hypoxic conditions, due to a reduction in HIFα prolyl hydroxylation, the level of HIFα in most cells increases. The prolyl hydroxylation of HIFα is accomplished by a family of proteins, variously referred to as proteins containing prolyl hydroxylase domains (PHD1, 2, and 3), also known as HIF prolyl hydroxylases (HPH-3, 2, and 1) or EGLN-2, 1, and 3. PHD proteins are oxygen sensors and regulate the stability of HIF in an oxygen-dependent manner. The three PHD isoforms play different roles in their regulation of HIF and may have other non-HIF-related regulatory effects.

[0004] Indeed, numerous studies have shown that stabilizing HIF can reduce tissue inflammation and promote repair. Therefore, compounds that can inhibit the activity of PHD proteins could be particularly beneficial in new therapeutic approaches (Lee et al. (2019) Exp. Mol. Med. 51:68).

[0005] Described herein are novel small molecule PHD inhibitors for the treatment of diseases including heart disease (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung disease (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver disease (e.g., acute liver failure and liver fibrosis and cirrhosis), and kidney disease (e.g., acute kidney injury and chronic kidney disease). Summary of the Invention

[0006] The present invention provides, among other things, novel small molecule PHD inhibitors and is useful for treating diseases including, but not limited to, heart disease (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung disease (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver disease (e.g., acute liver failure and liver fibrosis and cirrhosis), and kidney disease (e.g., acute kidney injury and chronic kidney disease).

[0007] In one aspect, provided herein are compounds having a structure according to Formula (A),

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] A is C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0011] Ar 1 is aryl or heteroaryl optionally substituted by one or more groups selected from halogen, CN, OH, C optionally substituted by CN or one or more halogens 1-3 Alkyl and C 1-3 alkoxy; and

[0012] Ar 2 is pyridin-2-yl optionally substituted by one or more groups selected from the group consisting of halogen; amino; amide; OH; sulfonyl; sulfinyl; carbonyl; phosphoryl; C 3-6 Cycloalkyl; C optionally substituted by sulfonyl or =O 3-6 Heterocycloalkyl; C optionally substituted by carbonyl or one or more halogen 1-3 Alkyl; and optionally C 1-3 Heteroaryl substituted with alkyl or phenyl.

[0013] In an embodiment, A is C 1-3 alkyl.

[0014] In an embodiment, A is C 3-6 Cycloalkyl.

[0015] In the embodiment, Ar 1 yes

[0016] in

[0017] X is N or CR 1a ;

[0018] Y and Z are independently CH or N;

[0019] R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 alkyl;

[0020] Each time R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 alkoxy; and

[0021] m is 1, 2, 3, or 4.

[0022] In the embodiment, Ar 1 yes

[0023]

[0024] In the embodiment, Ar 1 yes

[0025] where R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 alkyl.

[0026] In an embodiment, R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 alkyl.

[0027] In the embodiment, each time R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy.

[0028] In the embodiment, Ar 2 yes

[0029] in

[0030] Each time R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0031] R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R 14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted with alkyl or phenyl, or C 1-3 alkyl;

[0032] R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl;

[0033] R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ;

[0034] R 8 is NH, NCN or NCH3;

[0035] R 10 It is C 1-3 Alkyl or NHSO2R 20 ;

[0036] R 11 It's COR 21 or SO2R 22 ;

[0037] R 9 、R 12 、R 13 、R 14 、R 15 and R 20 Each is independently C 1-3 alkyl;

[0038] R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 alkyl;

[0039] R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl;

[0040] R 4 、R 5 、R 18 、R 19 、R 23 and R 24 are each independently H or C 1-3 alkyl;

[0041] R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 together with the carbon to which it is attached, form a heterocycloalkyl group;

[0042] p is 1, 2, or 3; and

[0043] n is 0, 1, 2 or 3.

[0044] In the embodiment, Ar 2 yes where R 3 Selected from the group consisting of: F, Cl, Br and I.

[0045] In the embodiment, Ar 2 yes where R 11 It's COR 21 or SO2R 22 ; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl; and R 23 and R 24 are independently H or C 1-3 alkyl.

[0046] In the embodiment, Ar 2 yes where R 3 is cycloalkyl or optionally SO2R 14 or =O substituted heterocycloalkyl; and R 14 It is C 1-3 alkyl.

[0047] In the embodiment, Ar 2 yes where R 3 is optionally C 1-3 Heteroaryl substituted with alkyl or phenyl.

[0048] In an embodiment, the cycloalkyl or optionally substituted heterocycloalkyl is selected from the group consisting of:

[0049] In an embodiment, the optionally substituted heteroaryl is selected from the group consisting of:

[0050] In the embodiment, each time R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C3-6 Cycloalkyl, where R 4 and R 5 are each independently H or C 1-3 alkyl.

[0051] In an embodiment, R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R 14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted by alkyl or phenyl or C optionally substituted by one or more halogen 1-3 Alkyl, where R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 11 It's COR 21 or SO2R 22 ; R 9 、R 12 、R 13 、R 14 、R 15 and R 20 Each is independently C 1-3 Alkyl; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 Alkyl; R 4 、R 5 、R 18 、R 19 、R 23 and R 24 are each independently H or C1-3 Alkyl; R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 together with the carbon to which it is attached form a heterocycloalkyl; and p is 1, 2 or 3.

[0052] In an embodiment, the compound of formula (A) has the following structure,

[0053] or a pharmaceutically acceptable salt thereof.

[0054] In embodiments of formula (I), X is N or CR 1a ; Y and Z are independently CH or N; A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R 14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted by alkyl or phenyl or C optionally substituted by one or more halogen 1-3 Alkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; R7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 9 It is C 1-3 Alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 11 It's COR 21 or SO2R 22 ; R 12 and R 13 Each is independently C 1-3 Alkyl; R 14 It is C 1-3 Alkyl; R 15 It is C 1-3 Alkyl; R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 Together with the carbon to which it is attached, it forms a heterocycloalkyl group; R 18 and R 19 are each independently H or C 1-3 Alkyl; R 20 It is C 1-3 Alkyl; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 Alkyl; R 23 and R 24 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

[0055] In an embodiment, the compound of formula (A) or formula (I) has the following structure,

[0056] or a pharmaceutically acceptable salt thereof.

[0057] In the embodiment of formula (II), X is N or CR 1a ; Z is CH or N; A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens,1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R 14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted by alkyl or phenyl or C optionally substituted by one or more halogen 1-3 Alkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 9 It is C 1-3 Alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 11 It's COR 21 or SO2R 22 ; R 12 and R 13 Each is independently C 1-3 Alkyl; R 14 It is C 1-3 Alkyl; R 15 It is C 1-3 Alkyl; R 16 and R17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 Together with the carbon to which it is attached, it forms a heterocycloalkyl group; R 18 and R 19 are independently H or C 1-3 Alkyl; R 20 It is C 1-3 Alkyl; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 Alkyl; R 23 and R 24 are independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

[0058] In embodiments, the compound of formula (A), formula (I) or formula (II) has the structure,

[0059] or a pharmaceutically acceptable salt thereof.

[0060] In the embodiment of formula (III), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted by alkyl or phenyl or C optionally substituted by one or more halogen 1-3 Alkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 9 It is C 1-3 Alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 11 It's COR 21 or SO2R 22 ; R 12 and R 13 Each is independently C 1-3 Alkyl; R 14 It is C 1-3 Alkyl; R 15 It is C 1-3 Alkyl; R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 Together with the carbon atom to which it is attached, it forms a heterocycloalkyl ring; R 18 and R 19 are independently H or C 1-3 Alkyl; R 20 It is C 1-3 Alkyl; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 Alkyl; R 23 and R 24 are independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

[0061] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0062] or a pharmaceutically acceptable salt thereof.

[0063] In the embodiment of formula (IV), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 18 and R 19 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0064] In the embodiment. 1 It is C 1-3 In an embodiment, R 1 It is CH3.

[0065] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (IV) has the structure,

[0066] or a pharmaceutically acceptable salt thereof.

[0067] In an embodiment, A is C 1-3 Alkyl; R 1a is CN or halogen; R 2 Selected from hydrogen or C 1-3 A group consisting of an alkyl group; R 7 It is C1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; and R 18 and R 19 are each independently H or C 1-3 alkyl.

[0068] In an embodiment, R 1a It is CN.

[0069] In an embodiment, R 1a is halogen. In an embodiment, R 1a It's Cl.

[0070] In an embodiment, A is C 1-3 In an embodiment, A is CH3.

[0071] In an embodiment, R 2 It is C 1-3 alkyl.

[0072] In an embodiment, R 2 It is CH3.

[0073] In an embodiment, R 7 It is C 1-3 In an embodiment, R 7 is CH3. In an embodiment, R 7 is CH2CH3. In an embodiment, R 7 is CH(CH3)2. In an embodiment, R 7 It is C 3-5 In an embodiment, R 7 In an embodiment, R 7 In an embodiment, R 7 In an embodiment, R 7 It is NR 18 R 19 , and where R 18 and R 19 are each independently H or C 1-3 alkyl.

[0074] In an embodiment, R 18 and R 19 are independently H. In an embodiment, R 18 is H and R 19 It is C 1-3 In an embodiment, R 19 is CH3. In an embodiment, R 18 and R 19is independently CH3.

[0075] In an embodiment, R 8 is NH. In an embodiment, R 8 is NCN. In an embodiment, R 8 It is NCH3.

[0076] In embodiments, the compound of formula (A), formula (I) or formula (II) has the structure,

[0077] or a pharmaceutically acceptable salt thereof.

[0078] In embodiments of formula (V), X is N or CR 1a ; Z is N or CH; A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; and R 15 It is C 1-3 Alkyl; R 16 and R 17 Independently H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 together with the carbon to which it is attached to form a heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.

[0079] In an embodiment, X is N. In an embodiment, X is CR 1a .

[0080] In an embodiment, A is C 1-3In an embodiment, A is CH3. In an embodiment, A is CH2CH3. In an embodiment, A is cycloalkyl. In an embodiment, A is cyclopropyl.

[0081] In an embodiment, R 1a is CN. In an embodiment, R 1a is halogen. In an embodiment, R 1a Is Cl. In an embodiment, R 1a is F. In an embodiment, R 1a is Br. In an embodiment, R 1a It is C 1-3 Alkoxy.

[0082] In an embodiment, R 1a In an embodiment, R 1a is H. In an embodiment, R 1a is C optionally substituted by CN 1-3 In an embodiment, R 1a is CH2CN. In an embodiment, R 1a It's OH.

[0083] In an embodiment, Z is CH. In an embodiment, Z is N.

[0084] In an embodiment, R 1 is H. In an embodiment, R 1 It is C 1-3 In an embodiment, R 1 is CH3. In an embodiment, R 1 It is C 1-3 In an embodiment, R 1 In an embodiment, R 1 It is CN.

[0085] In an embodiment, R 2 is H. In an embodiment, R 2 It is C 1-3 In an embodiment, R 2 It is CH3.

[0086] In an embodiment, R 6 It is C 1-3 In an embodiment, R 6 is CH3. In an embodiment, R 6 NHCOR 15 , and where R 15 It is C 1-3 In an embodiment, R 15 is CH3. In an embodiment, R 6 It is NR 16 R17 , and where R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 Together with the carbon to which it is attached, it forms a heterocycloalkyl group. 6 is NH2. In an embodiment, R 6 It is phenyl.

[0087] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0088] or a pharmaceutically acceptable salt thereof, wherein R 3 is cycloalkyl or optionally SO2R 14 or heterocycloalkyl substituted with =O.

[0089] In the embodiment of formula (VI), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 14 It is C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0090] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (VI) has the following structure,

[0091] or a pharmaceutically acceptable salt thereof, wherein R 3 is cycloalkyl or optionally SO2R 14 or heterocycloalkyl substituted with =O.

[0092] In an embodiment, A is C 1-3Alkyl; R 2 is hydrogen or C 1-3 alkyl; and R 14 It is C 1-3 alkyl.

[0093] In an embodiment, A is C 1-3 In an embodiment, A is CH3.

[0094] In an embodiment, R 2 is H. In an embodiment, R 2 It is C 1-3 In an embodiment, R 2 It is CH3.

[0095] In an embodiment, R 3 It is a cycloalkyl group.

[0096] In an embodiment, R 3 It is cyclopropyl.

[0097] In an embodiment, R 3 is optionally SO2R 14 or =O substituted heterocycloalkyl, and wherein R 14 It is C 1-3 alkyl.

[0098] In an embodiment, R 3 yes

[0099] In an embodiment, R 3 yes

[0100] In an embodiment, R 3 yes

[0101] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0102] or a pharmaceutically acceptable salt thereof.

[0103] In the embodiment of formula (VII), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a is H, CN, halogen, C1-3 alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 11 It's COR 21 or SO2R 22 ; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 Alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 Alkyl; R 23 and R 24 are independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0104] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (VII) has the structure,

[0105] or a pharmaceutically acceptable salt thereof.

[0106] In an embodiment, A is C 1-3 Alkyl or cycloalkyl; R 2 is hydrogen or C 3-6 Cycloalkyl; R 11 It's COR 21 or SO2R 22 ; R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 alkyl; and R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl, and wherein R 23 and R 24 are independently H or C 1-3 alkyl.

[0107] In an embodiment, A is C 1-3 In an embodiment, A is CH3.

[0108] In an embodiment, R 2 is H. In an embodiment, R 2 It is C 1-3 In an embodiment, R 2 It is CH3.

[0109] In an embodiment, R 11 It's COR 21 , and where R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 alkyl.

[0110] In an embodiment, R 21 In an embodiment, R 21 yes In an embodiment, R 21 yes In an embodiment, R 21 In an embodiment, R 21 In an embodiment, R 21 It is C 1-3 In an embodiment, R 21 It is CH2CH3.

[0111] In an embodiment, R 11 It is SO2R 22 , where R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl, and wherein R 23 and R 24 are independently H or C 1-3 alkyl.

[0112] In an embodiment, R 22 is C optionally substituted by carboxyl 1-3 In an embodiment, R 22 is CH3. In an embodiment, R 22 is CH2CH3. In an embodiment, R 22 is CH2COOH. In an embodiment, R 22 It is NR 23 R 24 , and where R 23 and R 24 are each independently H or C 1-3 In an embodiment, R 22 is NHCH3. In an embodiment, R 22 It is N(CH3)2.

[0113] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0114] or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally C 1-3Heteroaryl substituted with alkyl or phenyl.

[0115] In an embodiment, A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl and C 1-3 Alkoxy; R 1a is H, CN, halogen, C1-3 alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0116] In an embodiment, the compound of formula (A), formula (I), formula (II), formula (III), or formula (VIII) has the following structure,

[0117] or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally C 1-3 Heteroaryl substituted with alkyl or phenyl.

[0118] In an embodiment, A is C 1-3 Alkyl or cycloalkyl.

[0119] In an embodiment, A is C 1-3 alkyl.

[0120] In an embodiment, A is CH3.

[0121] In an embodiment, R 3 In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 is optionally C1-3 In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes In an embodiment, R 3 yes

[0122] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0123] or a pharmaceutically acceptable salt thereof.

[0124] In an embodiment, A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a is H, CN, halogen, C1-3 alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 20 It is C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0125] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (IX) has the structure,

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In embodiments of Formula (IXa), A is C 1-3 Alkyl; R 1a is CN or halogen; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; and R 20 It is C 1-3 alkyl.

[0128] In an embodiment, R 1a is CN. In an embodiment, R 1a is halogen. In an embodiment, R 1a It's Cl.

[0129] In an embodiment, R 10 It is C 1-3 In an embodiment, R 10 is CH3. In an embodiment, R 10 is CH(CH3)2. In an embodiment, R 10 is CH2CH3. In an embodiment, R 10 It is NHSO2R 20 , and where R 20 It is C 1-3 In an embodiment, R 20 It is CH3.

[0130] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0131] or a pharmaceutically acceptable salt thereof.

[0132] In an embodiment, A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a is H, CN, halogen, C1-3 alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 9 It is C 1-3alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0133] In an embodiment, R 1a It is CN.

[0134] In an embodiment, R 1 It’s H.

[0135] In an embodiment, A is C 1-3 In an embodiment, A is CH3.

[0136] In an embodiment, R 2 It’s H.

[0137] In an embodiment, R 9 It is C 1-3 In an embodiment, R 9 It is CH3.

[0138] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In embodiments of formula (XI), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a is H, CN, halogen, C1-3 alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

[0141] In an embodiment, R 1a It is CN.

[0142] In an embodiment, R 1 It’s H.

[0143] In an embodiment, A is C 1-3In an embodiment, A is CH3.

[0144] In an embodiment, R 2 It’s H.

[0145] In an embodiment, p is 1.

[0146] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0147] or a pharmaceutically acceptable salt thereof, wherein R 3 It's a halogen.

[0148] In the embodiment of formula (XII), A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, or 3.

[0149] In an embodiment, R 1a It is CN.

[0150] In an embodiment, R 1 It’s H.

[0151] In an embodiment, R 2 It’s H.

[0152] In an embodiment, R 3 Is Cl. In an embodiment, R 3 is Br. In an embodiment, R 3 It's F.

[0153] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0154] or a pharmaceutically acceptable salt thereof.

[0155] In an embodiment, A is C 1-3 Alkyl or cycloalkyl; each time taken, R 1 are independently selected from the group consisting of hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens, 1-3 Alkyl and C 1-3 Alkoxy; R 1a It is H, CN, halogen, C 1-3 Alkoxy, OH or C optionally substituted by CN 1-3 Alkyl; and each time taken, R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 Alkyl; R 12 It is C 1-3 Alkyl; R 13 It is C 1-3 alkyl; and m is 1, 2, 3 or 4.

[0156] In an embodiment, R 1a It is CN.

[0157] In an embodiment, R 1 It’s H.

[0158] In an embodiment, A is C 1-3 In an embodiment, A is CH3.

[0159] In an embodiment, R 2 It is C 1-3 In an embodiment, R 2 It is CH3.

[0160] In an embodiment, R 12 It is C 1-3 In an embodiment, R 12 It is CH3.

[0161] In an embodiment, R 13 It is C 1-3 In an embodiment, R 13 It is CH3.

[0162] In an embodiment, a compound is any one of Compounds 1 to 83:

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] In embodiments, at least one hydrogen atom of the compound of formula (A) and (I) to (XIII), such as any one of compounds 1 to 83, is replaced by a deuterium atom.

[0170] In another aspect, the invention features a pharmaceutical composition comprising any compound described herein (e.g., a compound of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0171] In another aspect, the invention features a method for treating a disease mediated by PHD activity, the method comprising administering to a subject any compound described herein (e.g., a compound of Formulas (A) and (I) to (XIII), such as any one of compounds 1 to 83) or a pharmaceutically acceptable salt thereof.

[0172] In embodiments, the disease mediated by PHD activity is ischemia-reperfusion injury (eg, stroke, myocardial infarction, or acute kidney injury).

[0173] In embodiments, the disease mediated by PHD activity is inflammatory bowel disease (eg, ulcerative colitis or Crohn's disease).

[0174] In embodiments, the disease mediated by PHD activity is cancer (eg, colorectal cancer).

[0175] In embodiments, the disease mediated by PHD activity is a liver disease.

[0176] In embodiments, the disease mediated by PHD activity is atherosclerosis.

[0177] In embodiments, the disease mediated by PHD activity is cardiovascular disease.

[0178] In embodiments, the disease mediated by PHD activity is a disease or condition of the eye (e.g., radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia).

[0179] In embodiments, the disease mediated by PHD activity is anemia (eg, anemia associated with chronic kidney disease).

[0180] In embodiments, the disease mediated by PHD activity is hyperoxia.

[0181] In embodiments, the disease mediated by PHD activity is retinopathy of prematurity.

[0182] In embodiments, the disease mediated by PHD activity is bronchopulmonary dysplasia (BPD).

[0183] In embodiments, the disease mediated by PHD activity is ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis, or cirrhosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0184] Figure 1 This is an exemplary demonstration of the TR-FRET assay principle for PHD enzymes (PHD1, PHD2, and PHD3). In the presence of 2-oxoglutarate and O2, the PHD enzyme hydroxylates proline 564 of the biotinylated HIF-1α peptide, generating biotinylated HIF-1α-hydroxyproline, succinate, and CO2. The resulting proximity of a donor fluorophore complex (i.e., monoclonal antibody anti-6His-Terbium (Tb)-cryptate Gold) bound to the His-tagged VHL protein / EloB / EloC complex (His-VBC) and an acceptor fluorophore bound to HIF-1α-hydroxyproline (i.e., SA-D2 complex) generates a fluorescence resonance energy transfer signal that can be detected and quantified. DETAILED DESCRIPTION

[0185] definition

[0186] In order to make the present invention more easily understood, certain terms are first defined below. The following terms and other definitions of other terms are set forth throughout this specification. The publications and other reference materials cited herein that describe the background technology of the present invention and provide additional details about its implementation are incorporated herein by reference.

[0187] Animal: As used herein, the term "animal" refers to any member of the kingdom Animalia. In some embodiments, "animal" refers to a human at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal, and / or a clone.

[0188] Approximately or approximately: As used herein, when applied to one or more values ​​of interest, the term "approximately" or "about" refers to a value similar to the reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the range in either direction (greater than or less than) of the value, unless otherwise specified or otherwise apparent from the context (unless the number exceeds 100% of the possible values).

[0189] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a mixture of two or more such compositions.

[0190] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising and comprises", means "including but not limited to", and is not intended to exclude, for example, other additives, components, integers or steps.

[0191] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0192] Improve, increase, or decrease: As used herein, the terms "improve," "increase," or "decrease," or their grammatical equivalents, refer to values ​​relative to a baseline measurement, such as that measured in the same individual prior to starting a treatment described herein, or in a control subject (or multiple control subjects) in the absence of a treatment described herein. A "control subject" is a subject having the same form of disease as the subject being treated and who is about the same age as the subject being treated.

[0193] In vitro: As used herein, the term "in vitro" refers to events that occur in an artificial environment, such as in a test tube or reaction vessel, in cell culture, etc., rather than in a multicellular organism.

[0194] In vivo: As used herein, the term "in vivo" refers to events that occur within multicellular organisms such as humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events that occur within living cells (as opposed to, for example, in vitro systems).

[0195] Patient: As used herein, the term "patient" or "subject" refers to any organism to which the provided compositions can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include both prenatal and postnatal forms.

[0196] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to substances that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0197] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates and arylsulfonates. Additional pharmaceutically acceptable salts include salts formed by quaternization of amines using appropriate electrophilic reagents (e.g., alkyl halides) to form quaternized alkylated amino salts.

[0198] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Humans include prenatal and postnatal forms. In many embodiments, the subject is a human. The subject can be a patient, which refers to a human being presented to a medical provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may have or be susceptible to a disease or condition, but may or may not exhibit symptoms of the disease or condition.

[0199] Substantially: As used herein, the term "substantially" refers to the qualitative condition of exhibiting the full or nearly full extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, reach completion and / or proceed to completion or achieve or avoid an absolute result. Thus, the term "substantially" is used herein to capture the inherent completeness that is potentially lacking in many biological and chemical phenomena.

[0200] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent refers to an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of the disease, disorder, and / or condition. One of ordinary skill in the art will recognize that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0201] Treatment: As used herein, the term "treatment" refers to any method used to partially or completely alleviate, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment can be administered to subjects who do not exhibit signs of disease and / or who exhibit only early signs of disease in order to reduce the risk of developing pathology associated with the disease.

[0202] Aliphatic: As used herein, the term aliphatic refers to a C1-C 40 Hydrocarbons, and include saturated hydrocarbons and unsaturated hydrocarbons. Aliphatic can be straight chain, branched or cyclic. For example, C1-C 20 Aliphatic can contain C1-C 20 Alkyl (e.g., straight or branched C1-C 20 saturated alkyl), C2-C 20 Alkenyl (e.g., straight or branched C4-C 20 Dienyl, straight chain or branched C6-C 20 triene, etc.) and C2-C 20 Alkynyl (e.g., straight or branched C2-C 20 C1-C 20 Aliphatic can contain C3-C 20 Cyclic aliphatic (e.g., C3-C 20 Cycloalkyl, C4-C 20 Cycloalkenyl or C8-C 20In certain embodiments, an aliphatic group may include one or more cyclic aliphatic groups and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halogen, alkoxy, hydroxy, amino, aryl, ether, ester, or amide. An aliphatic group is unsubstituted or substituted with one or more substituents as described herein. For example, an aliphatic group may be substituted with one or more of (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) halogen, -COR', -C02H, -C02R', -CN, -OH, -OR', -OCOR', -OC02R', -NH2, -NHR', -N(R')2, -SR', or -S02R', wherein each instance of R' is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the aliphatic is unsubstituted. In some embodiments, the aliphatic does not contain any heteroatoms.

[0203] Alkyl: As used herein, the term "alkyl" refers to non-cyclic straight-chain and branched hydrocarbon groups, such as "C1-C 20 "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms. The alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The term "lower alkyl" means an alkyl group having 1 to 6 carbon atoms, straight or branched. Other alkyl groups will be apparent to those skilled in the art given the benefit of this disclosure. The alkyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkyl group can be substituted with one or more of the following: (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) halogen, -COR', -C02H, -C02R', -CN, -OH, -OR', -OCOR', -OC02R', -NH2, -NHR', -N(R')2, -SR', or -S02R', wherein each instance of R' is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently an unsubstituted C1-C3 alkyl. In some embodiments, the alkyl group is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkyl," where the prefix represents an -OH group and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with an -OR' group and may also be referred to herein as an "alkoxy."

[0204] Appending the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0205] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight or branched hydrocarbon radical, and is exemplified by methylene, ethylene, isopropylene, and the like. Similarly, as used herein, the term "alkenylene" refers to an unsaturated divalent straight or branched hydrocarbon radical having one or more unsaturated carbon-carbon double bonds, which may be present at any stable point along the chain, and the term "alkynylene" refers herein to an unsaturated divalent straight or branched hydrocarbon radical having one or more unsaturated carbon-carbon triple bonds, which may be present at any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene radical may include one or more cyclic aliphatic groups and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halogen, alkoxy, hydroxy, amino, aryl, ether, ester, or amide. For example, the alkylene, alkenylene, or alkynylene group may be substituted with one or more of (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', wherein each instance of R' is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10In some embodiments, R′ is independently unsubstituted C1-C3 alkyl. In some embodiments, the alkylene, alkenylene, or alkynylene group is unsubstituted. In some embodiments, the alkylene, alkenylene, or alkynylene group does not contain any heteroatoms.

[0206] Alkenyl: As used herein, "alkenyl" means any straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds, which may be present at any stable point along the chain, for example, "C2-C 20 "Alkenyl" refers to an alkenyl group having 2 to 20 carbons. For example, alkenyl includes prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, etc. In some embodiments, the alkenyl includes 1, 2, or 3 carbon-carbon double bonds. In some embodiments, the alkenyl includes a single carbon-carbon double bond. In some embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group can be unbound. substituted or substituted with one or more substituents described herein. For example, alkenyl may be substituted with one or more of the following: (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', wherein each instance of R' is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted C1-C3 alkyl. In some embodiments, alkenyl is unsubstituted. In some embodiments, alkenyl is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, alkenyl is substituted with an -OH group and may also be referred to herein as "hydroxyalkenyl," where the prefix indicates an -OH group and "alkenyl" is as described herein.

[0207] Alkynyl: As used herein, "alkynyl" means any hydrocarbon chain in a straight or branched configuration having one or more carbon-carbon triple bonds at any stable point along the chain, for example, "C2-C 20"Alkynyl" refers to an alkynyl group having 2 to 20 carbons. Examples of alkynyl include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In some embodiments, the alkynyl group includes one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group can be substituted with one or more of the following: (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', or -SO2R', wherein each instance of R' is independently C1-C 20 Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In some embodiments, R' is independently unsubstituted C1-C3 alkyl. In some embodiments, the alkynyl group is unsubstituted. In some embodiments, the alkynyl group is substituted (e.g., 1, 2, 3, 4, 5, or 6 substituents as described herein).

[0208] Aryl: The term "aryl" used alone or as part of a larger moiety as in "aralkyl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and wherein each ring in the system contains 4 to 7 ring members. In some embodiments, aryl has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, and in such a case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Exemplary aryl groups include phenyl, naphthyl, and anthracene.

[0209] Arylene: As used herein, the term "arylene" refers to a divalent aromatic group (ie, having two points of attachment to the molecule). Exemplary arylene groups include phenylene (eg, unsubstituted phenylene or substituted phenylene).

[0210] Halogen or halo: As used herein, the term "halogen" or "halo" means fluoro, chloro, bromo, or iodo.

[0211] Amide: The term "amide" or "amido" refers to a chemical moiety having the formula -C(O)N(R')2, -C(O)N(R')-, -NR'C(O)R', -NR'C(O)N(R')2-, or -NR'C(O)-, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, aralkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein, or two R's can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0212] Amino: The term "amino" or "amine" refers to a -N(R')2 radical, where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, aralkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), sulfonyl, amide, or carbonyl, unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein, or two R's can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In embodiments, amino is -NHR', where R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), amide, or alkyl ("alkylamino").

[0213] Sulfonyl: The term "sulfonyl" refers to a -S(=O)2R' or -S(=O)2- group, where R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), amino, cycloalkyl, aryl, aralkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein. For example, in one embodiment, a sulfonyl group is -SO2R', where R' is alkyl substituted with a carbonyl group.

[0214] Sulfinyl: The term "sulfinyl" refers to a chemical moiety having the formula -S(=O)R', -S(=O)-, or -S(=O)(=NR')-, where R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, aralkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein.

[0215] Carbonyl: The term "carbonyl" refers to a -C(=O)R' or -C(=O)- group, where R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a carbon chain), cycloalkyl, aryl, aralkyl, amino, hydroxy, heteroaryl (bonded through a ring carbon), heteroarylalkyl, heterocycloalkyl (bonded through a ring carbon), unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein.

[0216] Phosphoryl: The term "phosphoryl" refers to a -P(=O)(R')2 or -P(=O)(R')- group, wherein each R' is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon or heteroatom), cycloalkyl, aryl, aralkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon) group, unless stated otherwise in the specification, each of which moieties can itself be optionally substituted as described herein, or two R's can be combined with a nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0217] Assorted alkyl: the term "assorted alkyl" means, in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of: N, O, S and P, a branched or unbranched alkyl, alkenyl or alkynyl group having from 1 to 14 carbon atoms. Assorted alkyl includes tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiester, phosphoramidates, sulfonamides and disulfides. Assorted alkyl groups can optionally include monocycles, dicycles or tricycles, wherein each ring ideally has three to six members. Examples of assorted alkyl include polyethers, such as methoxymethyl and ethoxyethyl.

[0218] Heteroalkylene: As used herein, the term "heteroalkylene" refers to a divalent form of a heteroalkyl group as described herein.

[0219] Heteroaryl: As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single point of attachment to the rest of the molecule, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 4 to 7 ring members, and wherein at least one ring atom is a heteroatom such as, but not limited to, nitrogen and oxygen.

[0220] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" is a non-aromatic ring in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Heterocycloalkyl groups may be substituted or unsubstituted.

[0221] Deuterium: The term "deuterium" ("D" or " 2 H") is also called heavy hydrogen. Deuterium is an isotope of hydrogen in which the nucleus consists of one proton and one neutron and is twice as massive as the nucleus of ordinary hydrogen (one proton).

[0222] Isotope: The term "isotope" refers to a variant of a particular chemical element that has a different number of protons and, therefore, a different number of nucleons. All isotopes of a given element have the same number of protons but a different number of neutrons in each atom.

[0223] The term "substituted" means that a particular group or moiety bears one or more substituents. The term "unsubstituted" means that a specified group bears no substituents. The term "optionally substituted" means that a specified group is unsubstituted or substituted with one or more substituents. Where the term "substituted" is used to describe a structural system, substitution is intended to occur at any valence-allowed position on the system, e.g., a substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Where a specified moiety or group is not explicitly noted as being optionally substituted or substituted with any specified substituent, it is understood that such moiety or group is intended to be unsubstituted.

[0224] When a ring system (e.g., a cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with a plurality of substituents that vary within well-defined limits, it is understood that the total number of substituents does not exceed the normally available valences under the prevailing conditions. It is also understood that hydrogen atoms are assumed to be present to fill the remaining valences of the ring system. Substituted groups encompass only those combinations of substituents and variables that result in stable or chemically feasible compounds. A stable compound or chemically feasible compound is one that possesses stability sufficient to allow its preparation and testing, among other factors.

[0225] A variety of substituents are well known, and methods for forming and introducing substituents into a variety of parent groups are also well known. Representative substituents include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, alkaryl, aryl, arylalkoxy, arylamino, heteroarylamino, heteroaryl, heteroarylalkoxy, heterocycloalkyl, hydroxyalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolidinyl, indolealkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkyl, amino, alkylamino, dialkylamino, amide, cyano, alkoxy, hydroxyl, sulfonamide, halo (e.g., -Cl and -Br), nitro, oxime, -COOR 50 、-COR 50 、-SO 0-2 R 50 、-SO2NR 50 R 51 NR 52 SO2R 50 ,═C(R 50 R 51 ),═N-OR 50 ,═N-CN,═C(halogen)2,═S,═O,-CON(R 50 R 51 ),-OCOR 50 、-OCON(R 50 R 51 )、-N(R 52 )CO(R 50 )、-N(R 52 )COOR 50 and -N(R 52 )CON(R 50 (R 51 ), wherein R, with or without substituents, 50 、R 51 and R 52 can be independently selected from the following: hydrogen atoms and branched or linear C 1-6 -alkyl, C 3-6 -cycloalkyl, C 4-6 - heterocycloalkyl, heteroaryl and aryl. Where permitted, R 50 and R 51 They can be linked together to form carbocyclic or heterocyclic ring systems.

[0226] In preferred embodiments, the substituents are selected from halogen, -COR', -CO2H, -CO2R', -CN, -OH, -OR', -OCOR', -OCO2R', -NH2, -NHR', -N(R')2, -SR', and -SO2R', wherein each instance of R' is independently C1-C 20Aliphatic (e.g., C1-C 20 Alkyl, C1-C 15 Alkyl, C1-C 10 In certain embodiments thereof, R' is independently unsubstituted alkyl (e.g., unsubstituted C1-C3 alkyl). 20 Alkyl, C1-C 15 Alkyl, C1-C 10 Preferably, R' is independently unsubstituted C1-C3 alkyl.

[0227] Any formula given herein is intended to represent a compound with the structure described by the structural formula and some modifications or forms. Specifically, the compound of any formula given herein can have an asymmetric center and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compound of the general formula and mixtures thereof are considered to be within the scope of the formula. Therefore, any formula given herein is intended to represent racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomer forms and mixtures thereof. In addition, some structures can exist as geometric isomers (i.e., cis and trans isomers), as tautomers or as atropisomers. In addition, any formula given herein is intended to include hydrates, solvates and polymorphs of such compounds and mixtures thereof.

[0228] Compounds of the present invention

[0229] Disclosed herein are compounds that are effective inhibitors of PHD. In some embodiments, the compounds of the present invention have an enzymatic half-maximal inhibitory concentration (IC) of less than 100 μM for any of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 50 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 25 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 20 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 15 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 10 μM for any one of PHD1, PHD2, and PHD3. 50In some embodiments, the compounds of the present invention have an IC value of less than 5 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC value of less than 1 μM for any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 3 nM to about 5 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 5 nM to about 10 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 10 nM to about 20 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 20 nM to about 50 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 50 nM to about 100 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 100 nM to about 200 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 200 nM to about 500 nM against any one of PHD1, PHD2, and PHD3. 50 In some embodiments, the compounds of the present invention have an IC of about 500 nM to about 1000 nM against any one of PHD1, PHD2, and PHD3. 50 value.

[0230] Representative examples of this class showed inhibitory activity against PHD1, PHD2, and PHD3 in vitro.

[0231] Exemplary compounds are described herein. Specifically, these selective inhibitors can have a pyrazole moiety connecting two aromatic moieties (eg, a 5-hydroxy substituted pyrazole).

[0232] Compounds of formula (A) and (I)-(XIII)

[0233] In one aspect, provided herein are compounds having a structure according to Formula (A):

[0234]

[0235] or a pharmaceutically acceptable salt thereof, wherein:

[0236] A is C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0237] Ar 1 is aryl or heteroaryl optionally substituted by one or more groups selected from halogen, CN, OH, C optionally substituted by CN or one or more halogens 1-3 Alkyl and C 1-3 alkoxy; and

[0238] Ar 2 is pyridin-2-yl optionally substituted by one or more groups selected from the group consisting of halogen; amino; amide; OH; sulfonyl; sulfinyl; carbonyl; phosphoryl; C 3-6 Cycloalkyl; C optionally substituted by sulfonyl or =O 3-6 Heterocycloalkyl; C optionally substituted by carbonyl or one or more halogen 1-3 Alkyl; and optionally C 1-3 Heteroaryl substituted with alkyl or phenyl.

[0239] In an embodiment, A is C 1-3 Alkyl. In embodiments, A is CH3. In embodiments, A is CH2CH3. In embodiments, A is CH2CH2CH3. In embodiments, A is CH(CH3)2.

[0240] In an embodiment, A is C 3-6 In an embodiment, A is cycloalkyl. In an embodiment, A is cyclopropyl. In an embodiment, A is cyclobutyl. In an embodiment, A is cyclopentyl. In an embodiment, A is cyclohexyl.

[0241] In the embodiment, Ar 1 is an unsubstituted aryl group. 1 is a substituted aryl group. 1 is a substituted phenyl group.

[0242] In the embodiment, Ar 1 is an unsubstituted 6-membered heteroaryl. 1 is a substituted 6-membered heteroaryl.

[0243] In the embodiment, Ar 1 is substituted by one or more groups selected from the group consisting of halogen, CN, OH, C optionally substituted by CN or one or more halogens 1-3 Alkyl and C 1-3 In some embodiments, Ar 1 In some embodiments, Ar 1In some embodiments, Ar 1 In some embodiments, Ar 1 Substituted with 4 substituents.

[0244] In the embodiment, Ar 1 Include one or more R 1 group, where each R 1 are independently selected from hydrogen, halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl and C 1-3 In the embodiment, Ar 1 Includes a certain number of R represented by m 1 group, wherein m is 1, 2, 3 or 4. When R 1 When present, R 1 Can replace the hydrogen in the parent molecular structure. In the embodiment, when R 1 When present and non-hydrogen moiety, R 1 In the embodiment, R 1 independently selected from halogen, CN, OH, C optionally substituted with one or more halogens 1-3 Alkyl and C 1-3 Alkoxy.

[0245] Thus, it is also understood that for any value of m described herein, hydrogen is present where appropriate to form the Ar 1 The valence requirements are fulfilled at the constituent atoms of the molecule such that the molecule is a stable compound (e.g., one that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). 1 、R 1 and exemplary embodiments of m.

[0246] In the embodiment, Ar 1 yes

[0247] in

[0248] X is N or CR 1a ;

[0249] Y and Z are independently CH or N; and

[0250] m is 1, 2, 3, or 4.

[0251] In an embodiment, R 1 In an embodiment, when R 1 When present and non-hydrogen moiety, R 1 represents a substituent.

[0252] In embodiments, the value of m is based on the number of nitrogen atoms present in the ring. In embodiments, when only one of Y and Z is N, m is 1, 2, or 3. In embodiments, when each of Y and Z is N, m is 1 or 2.

[0253] In an embodiment, X is N. In an embodiment, X is CR 1a .

[0254] In an embodiment, Y is CH. In an embodiment, Z is N.

[0255] In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4.

[0256] In an embodiment, Y and Z are both N, and m is 1 or 2. In an embodiment, m is 1, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valence. In an embodiment, m is 2.

[0257] In an embodiment, Y and Z are both CH, and m is 1, 2, 3, or 4. In an embodiment, m is 1, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 2, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 3, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 4.

[0258] In an embodiment, one of Y and Z is CH and the other is N, and m is 1, 2, or 3. In an embodiment, m is 1, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 2, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 3.

[0259] In the embodiment, Ar 1 yes

[0260] in

[0261] X is N or CR 1a ;

[0262] Z is CH or N; and

[0263] m is 1, 2, 3, or 4.

[0264] In an embodiment, Z is N, and m is 1, 2, or 3. In an embodiment, m is 1, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 2, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 3.

[0265] In embodiments, Z is CH, and m is 1, 2, 3, or 4. In embodiments, m is 1, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In embodiments, m is 2, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In embodiments, m is 3, and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In embodiments, m is 4.

[0266] In an embodiment, X is N. In an embodiment, X is CR 1a .

[0267] In the embodiment, Ar 1 yes

[0268] in

[0269] m is 1, 2, 3, or 4.

[0270] In an embodiment, m is 1 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 2 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 3 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, m is 4.

[0271] In an embodiment, R 1a It’s H.

[0272] In an embodiment, R 1a It is CN.

[0273] In an embodiment, R 1a It's OH.

[0274] In an embodiment, R 1a is halogen. In an embodiment, R 1a is F. In an embodiment, R 1a Is Cl. In an embodiment, R 1a is Br. In an embodiment, R 1a It's I.

[0275] In an embodiment, R 1a It is C 1-3 In an embodiment, R 1aIn an embodiment, R 1a In an embodiment, R 1a It is a propoxy group.

[0276] In an embodiment, R 1a It is C 1-3 alkyl.

[0277] In an embodiment, R 1a is unsubstituted C 1-3 In an embodiment, R 1a It is CH3.

[0278] In an embodiment, R 1a is substituted C 1-3 In an embodiment, R 1a is C substituted by a CN group 1-3 In an embodiment, R 1a It is CH2CN.

[0279] In the embodiment, each time R 1 It's hydrogen.

[0280] In the embodiment, each time R 1 It is CN.

[0281] In the embodiment, each time R 1 It's OH.

[0282] In the embodiment, each time R 1 is halogen. In an embodiment, halogen is Cl. In an embodiment, halogen is Br. In an embodiment, halogen is I.

[0283] In the embodiment, each time R 1 It is C 1-3 alkyl.

[0284] In the embodiment, each time R 1 is unsubstituted C 1-3 In the embodiment, each time R 1 It is CH3.

[0285] In the embodiment, each time R 1 is substituted C 1-3 In the embodiment, each time R 1 is a C substituted by one or more halogens 1-3 In an embodiment, halogen is F. In an embodiment, halogen is Cl. In an embodiment, halogen is Br. In an embodiment, halogen is I.

[0286] In the embodiment, each time R 1 It's CF3.

[0287] In the embodiment, each time R 1 It is C 1-3 In the embodiment, each time R 1 It's OMe.

[0288] In the embodiment, Ar 2 is pyridin-2-yl optionally substituted with one or more groups selected from: halogen; amino; amide; OH; sulfonyl (e.g., SO2R 6 ); sulfinyl; (e.g., SOR 7 R 8 or SOR 9 ); carbonyl; (e.g., COR 10 ); phosphoryl; (e.g., POR 12 R 13 );C 3-6 Cycloalkyl; C optionally substituted by sulfonyl or =O 3-6 Heterocycloalkyl or C optionally substituted by carbonyl or one or more halogen 1-3 Alkyl; and optionally C 1-3 In the embodiment, Ar 2 is an unsubstituted pyridin-2-yl. In an embodiment, Ar 2 is a substituted pyridin-2-yl. In an embodiment, Ar 2 is pyridin-2-yl substituted with 1 or 2 substituents as described herein. In embodiments, Ar 2 is pyridin-2-yl substituted with 3 substituents as described herein.

[0289] In the embodiment, Ar 2 yes

[0290] in

[0291] Each time R 2 independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0292] R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2)p COOH、NHR 11 、POR 12 R 13 , halogen, cycloalkyl, optionally SO2R 14 or =O substituted heterocycloalkyl, optionally C 1-3 Heteroaryl substituted with alkyl or phenyl, or C 1-3 alkyl;

[0293] R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl;

[0294] R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ;

[0295] R 8 is NH, NCN or NCH3;

[0296] R 10 It is C 1-3 Alkyl or NHSO2R 20 ;

[0297] R 11 It's COR 21 or SO2R 22 ;

[0298] R 9 、R 12 、R 13 、R 14 、R 15 and R 20 Each is independently C 1-3 alkyl;

[0299] R 21 is a heterocycloalkyl, cycloalkyl or C 1-3 alkyl;

[0300] R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl;

[0301] R 4 、R 5 、R 18 、R 19 、R 23 and R24 are each independently H or C 1-3 alkyl;

[0302] R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 together with the carbon to which it is attached, form a heterocycloalkyl group;

[0303] p is 1, 2, or 3; and

[0304] n is 0, 1, 2 or 3.

[0305] In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3.

[0306] In an embodiment, n is 0 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, n is 1 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, n is 2 and any remaining unsubstituted carbon ring atoms are assumed to be bonded to hydrogen to fill the valences. In an embodiment, n is 3.

[0307] In the embodiment, each time R 2 It's hydrogen.

[0308] In the embodiment, each time R 2 It's OH.

[0309] In the embodiment, each time R 2 is halogen. In an embodiment, halogen is Cl. In an embodiment, halogen is Br. In an embodiment, halogen is I.

[0310] In the embodiment, each time R 2 It is NR 4 R 5 , where R 4 and R 5 are each independently H or C 1-3 alkyl.

[0311] In an embodiment, R 4 and R 5 All are H.

[0312] In an embodiment, R 4 and R 5 One of them is H and the other is C 1-3 In the embodiment, C 1-3 Alkyl is CH3.

[0313] In the embodiment, each time R 2 It is C 1-3 alkyl.

[0314] In the embodiment, each time R 2 It is C 3-6 Cycloalkyl.

[0315] In an embodiment, R 3 It is SO2R 6 , where R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl.

[0316] In an embodiment, R 3 It's SOR 7 R 8 , where R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 , and where R 8 is NH, NCN or NCH3.

[0317] In an embodiment, R 3 It's SOR 9 , where R 9 It is C 1-3 alkyl.

[0318] In an embodiment, R 3 It's COR 10 , where R 10 It is C 1-3 Alkyl or NHSO2R 20 .

[0319] In an embodiment, R 3 Yes (CH2) p COOH.

[0320] In an embodiment, p is 1, 2, or 3. In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, p is 3.

[0321] In an embodiment, R 3 It is NHR 11 , where R 11 It's COR 21 or SO2R 22 .

[0322] In an embodiment, R 3 It is POR12 R 13 , where R 12 and R 13 Each is independently C 1-3 alkyl.

[0323] In an embodiment, R 3 It's a halogen.

[0324] In an embodiment, R 3 is cycloalkyl or heterocycloalkyl. In embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted. In embodiments, the cycloalkyl or heterocycloalkyl is substituted.

[0325] In an embodiment, R 3 is a heteroaryl. In embodiments, the heteroaryl is unsubstituted. In embodiments, the heteroaryl is substituted.

[0326] In an embodiment, R 3 It is C 1-3 In the embodiment, C 1-3 The alkyl group is unsubstituted. In an embodiment, C 1-3 The alkyl group is substituted with one or more halogens.

[0327] In an embodiment, the compound of formula (A) has the following structure,

[0328] or a pharmaceutically acceptable salt thereof, wherein A, X, Y, Z, R 1 、R 2 and R 3 As defined anywhere herein.

[0329] In an embodiment, the compound of formula (A) or formula (I) has the following structure,

[0330] or a pharmaceutically acceptable salt thereof, wherein A, X, Z, R 1 、R 2 and R 3 As defined anywhere herein.

[0331] In embodiments, the compound of formula (A), formula (I) or formula (II) has the structure,

[0332] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 、R 2 and R 3 As defined anywhere herein.

[0333] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0334] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0335] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (IV) has the structure,

[0336] or a pharmaceutically acceptable salt thereof, wherein A, R 1a and R 2 As defined anywhere herein.

[0337] In an embodiment, R 7 It is C 1-3 alkyl.

[0338] In an embodiment, R 7 It is C 3-5 Cycloalkyl.

[0339] In an embodiment, R 7 It is phenyl.

[0340] In an embodiment, R 7 It is NR 18 R 19 , where R 18 and R 19 are each independently H or C 1-3 alkyl.

[0341] In an embodiment, R 18 and R 19 All are H.

[0342] In an embodiment, R 18 and R 19 All are C 1-3 In an embodiment, R 18 and R 19 All are CH3.

[0343] In an embodiment, R 18 is H and R 19 It is C 1-3 In an embodiment, R 19 It is CH3.

[0344] In an embodiment, R 8 It's NH.

[0345] In an embodiment, R 8 It's NCN.

[0346] In an embodiment, R 8 It is NCH3.

[0347] In embodiments, the compound of formula (A), formula (I) or formula (II) has the structure,

[0348] or a pharmaceutically acceptable salt thereof, wherein A, X, Z, R 1 and R 2 As defined anywhere herein.

[0349] In an embodiment, R 6 It is C 1-3 In an embodiment, R 6 It is CH3.

[0350] In an embodiment, R 6 NHCOR 15 , and where R 15 It is C 1-3 In an embodiment, R 6 It is NHCOCH3.

[0351] In an embodiment, R 6 It is NR 16 R 17 , and where R 16 and R 17 Each independently is H, C 1-3 Alkyl, aryl, cycloalkyl, or wherein R 16 and R 17 Together with the carbon to which it is attached, it forms a heterocycloalkyl.

[0352] In an embodiment, R 16 and R 17 All are H.

[0353] In an embodiment, R 16 and R 17 All are C 1-3 In an embodiment, R 16 and R 17 All are CH3.

[0354] In an embodiment, R 16 is H and R 17 It is C 1-3 In an embodiment, R 17 It is CH3.

[0355] In an embodiment, R 16 is H and R 17In an embodiment, R 17 It is phenyl.

[0356] In an embodiment, R 16 is H and R 17 In an embodiment, R 17 It is cyclopropyl.

[0357] In an embodiment, R 16 and R 17 Together with the carbon to which it is attached, it forms a heterocycloalkyl group. 16 and R 17 Together with the carbon to which it is attached,

[0358] In an embodiment, R 6 It is phenyl.

[0359] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0360] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0361] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (VI) has the following structure,

[0362] or a pharmaceutically acceptable salt thereof, wherein A and R 2 As defined anywhere herein.

[0363] In an embodiment, R 3 It is a cycloalkyl group.

[0364] In an embodiment, R 3 is an unsubstituted cycloalkyl group. In an embodiment, R 3 yes

[0365] In an embodiment, R 3 is a substituted cycloalkyl. In an embodiment, R 3 It was SO2R 14 or =O substituted cycloalkyl, and wherein R 14 It is C 1-3 alkyl.

[0366] In an embodiment, R 3 It is a heterocycloalkyl group.

[0367] In an embodiment, R3 is an unsubstituted heterocycloalkyl. 3 yes

[0368] In an embodiment, R 3 is a substituted heterocycloalkyl. 3 It was SO2R 14 or =O substituted heterocycloalkyl, and wherein R 14 It is C 1-3 In an embodiment, R 3 yes

[0369] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0370] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0371] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (VII) has the structure,

[0372] or a pharmaceutically acceptable salt thereof, wherein A and R 2 As defined anywhere herein.

[0373] In an embodiment, R 11 It's COR 21 .

[0374] In an embodiment, R 21 In an embodiment, R 21 yes

[0375] In an embodiment, R 21 In an embodiment, R 21 yes

[0376] In an embodiment, R 21 It is C 1-3 In an embodiment, R 21 It is CH2CH3.

[0377] In an embodiment, R 11 It is SO2R 22 .

[0378] In an embodiment, R 22 It is C 1-3 In an embodiment, R 22 is unsubstituted C 1-3 In an embodiment, R 22 is C substituted by a carboxyl group 1-3 In an embodiment, R 22 It is CH2COOH.

[0379] In an embodiment, R 22 It is NR 23 R 24 , and where R 23 and R 24 are each independently H or C 1-3 alkyl.

[0380] In an embodiment, R 23 and R 24 All are H.

[0381] In an embodiment, R 23 and R 24 All are C 1-3 In an embodiment, R 23 and R 24 All are CH3.

[0382] In an embodiment, R 23 is H and R 24 It is C 1-3 In an embodiment, R 24 It is CH3.

[0383] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0384] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0385] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (VIII) has the structure,

[0386] or a pharmaceutically acceptable salt thereof, wherein A is as defined anywhere herein.

[0387] In an embodiment, R 3 In an embodiment, the heteroaryl group is thiazole, oxazole, pyridine, triazole, tetrazole or pyrazole.

[0388] In an embodiment, R 3 is an unsubstituted heteroaryl. In an embodiment, R 3 yes

[0389] In an embodiment, R 3 Is C 1-3 In an embodiment, R 3 yes

[0390] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0391] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0392] In embodiments, the compound of Formula (A), Formula (I), Formula (II), Formula (III), or Formula (IX) has the structure,

[0393] or a pharmaceutically acceptable salt thereof, wherein A and R 1a As defined anywhere herein.

[0394] In an embodiment, R 10 It is C 1-3 alkyl.

[0395] In an embodiment, R 10 It is NHSO2R 20 , and where R 20 It is C 1-3 In an embodiment, R 10 It is NHSO2CH3.

[0396] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0397] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0398] In an embodiment, R 9 It is C 1-3 alkyl.

[0399] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0400] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0401] In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, p is 3.

[0402] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0403] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0404] In an embodiment, R 3 is halogen. In an embodiment, R 3 is F. In an embodiment, R 3 Is Cl. In an embodiment, R 3 is Br. In an embodiment, R 3 It's I.

[0405] In embodiments, the compound of Formula (A), Formula (I), Formula (II), or Formula (III) has the following structure,

[0406] or a pharmaceutically acceptable salt thereof, wherein A, R 1a 、R 1 and R 2 As defined anywhere herein.

[0407] In an embodiment, R 12 and R 13 All are C 1-3 In an embodiment, R 12 and R 13 All are CH3.

[0408] Exemplary compounds

[0409] In some embodiments, the PHD inhibitor compound is any one of Compounds 1 to 83 or a pharmaceutically acceptable salt thereof.

[0410]

[0411]

[0412]

[0413]

[0414]

[0415] isotope

[0416] It will be understood that in the compounds described herein (e.g., compounds of Formulas (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83), the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds described herein (e.g., compounds of Formulas (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the major isotope of hydrogen found in nature.

[0417] In some embodiments, one or more of the hydrogens in the compounds described herein (e.g., compounds of formula (A) and any of (I) to (XIII), such as any of compounds 1 to 83) are replaced with deuterium. Enrichment with deuterium can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. In some embodiments, one or more of the hydrogens in the compounds described herein (e.g., compounds of formula (A) and any of (I) to (XIII), such as any of compounds 1 to 83) are replaced with tritium. Tritium is radioactive and can therefore provide radiolabeled compounds that can be used as tracers in metabolic or kinetic studies.

[0418] Isotopic enrichment of the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) can be achieved without undue experimentation by conventional techniques well known to those skilled in the art or by methods analogous to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0419] The term "isotopologue" refers to a species having the same chemical structure and formula as a specific compound provided herein, except for the isotopic substitution position and / or isotopic enrichment level at one or more positions, such as hydrogen to deuterium. Thus, as used herein, the term "compound" encompasses a collection of molecules having the same chemical structure but also having isotopic variation between the constituent atoms of the molecule. Thus, it will be clear to those skilled in the art that a compound represented by a specific chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amount of such isotopologues in the provided compound depends on many factors, including but not limited to the isotopic purity of the deuterated reagent used to prepare the compound and the efficiency of deuterium incorporation in the various synthesis steps used to prepare the compound.

[0420] When a position is designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. When a position is designated as "D" or "deuterium," the position is understood to have deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term "D" or "deuterium" indicates at least 50.1% deuterium incorporation).

[0421] In embodiments, the compounds provided herein can have an isotopic enrichment factor for each deuterium present at a site designated as a potential deuteration site on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0422] Synthesis of the compounds of the present invention

[0423] The compounds described herein (e.g., compounds of formula (A) and any one of (I) to (XIII), such as any one of compounds 1 to 83) can be prepared according to methods known in the art, including exemplary syntheses of the examples provided herein.

[0424] Abbreviations and acronyms used in this document include the following:

[0425]

[0426]

[0427] Compositions and methods

[0428] The present invention provides the use of a compound of any one of formulas (A) and (I) to (XIII) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating various conditions or disorders as described herein. In one embodiment, a pharmaceutical composition is provided, comprising at least one compound of any one of formulas (A) and (I) to (XIII) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. In various embodiments, the medicament or pharmaceutical composition may further comprise at least one additional therapeutic agent or be used in combination with at least one additional therapeutic agent.

[0429] The compounds or drugs of the present invention or compositions comprising the compounds can be used to inhibit the activity of PHD. Inhibiting PHD can be particularly beneficial for treating diseases including heart disease (e.g., ischemic heart disease, congestive heart failure, and valvular heart disease), lung disease (e.g., acute lung injury, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease), liver disease (e.g., acute liver failure and liver fibrosis and cirrhosis), and kidney disease (e.g., acute kidney injury and chronic kidney disease).

[0430] In one embodiment, the method of the present invention comprises administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Formula (A) and (I) to (XIII) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of any one of Formula (A) and (I) to (XIII).

[0431] The present invention also relates to a method for inhibiting PHD activity. In one embodiment, the method comprises contacting PHD with an effective amount of one or more compounds selected from the group consisting of a compound of formula (A) and any one of formulas (I) to (XIII) or a pharmaceutically acceptable salt thereof.

[0432] In still other embodiments, the compounds disclosed herein (e.g., compounds of any one of Formulas (A) and (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat or prevent anemia, including treating anemia conditions associated with chronic kidney disease, polycystic kidney disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplant anemia, Churg-Strauss syndrome, Diamond Blackfan anemia, Fanconi's anemia, Felty syndrome, and the like. syndrome), graft-versus-host disease, hematopoietic stem cell transplantation, hemolytic uremic syndrome, myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria, myelofibroma, pancytopenia, pure red cell aplasia, Henoch-Schonlein purpura, refractory anemia with excess blasts, rheumatoid arthritis, Shwachman syndrome, sickle cell disease, thalassemia major, thalassemia minor, thrombocytopenic purpura, anemic or non-anemic patients undergoing surgery, anemia associated with or secondary to trauma, sideroblastic anemia, anemia secondary to other treatments, including: reverse transcriptase inhibitors used to treat HIV, corticosteroids, chemotherapy drugs with or without cisplatin, vinca alkaloids, mitotic inhibitors, topoisomerase II inhibitors, anthracyclines, alkylating agents, especially anemia secondary to inflammatory, aging and / or chronic diseases. PHD1 inhibition could also be used to treat symptoms of anemia, including chronic fatigue, paleness, and dizziness.

[0433] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat or prevent metabolic disorders, including but not limited to diabetes and obesity.

[0434] In yet other embodiments, the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat or prevent vascular diseases. These include, but are not limited to, diseases associated with hypoxia or wound healing, which require pro-angiogenic mediators for angiogenesis, vasculogenesis, and arteriogenesis.

[0435] In still other embodiments, the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat or prevent ischemia-reperfusion injury. These include, but are not limited to, stroke, myocardial infarction, and acute kidney injury.

[0436] In other embodiments, the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat inflammatory bowel diseases. These include, but are not limited to, ulcerative colitis and Crohn's disease.

[0437] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat cancers such as colorectal cancer.

[0438] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat atherosclerosis.

[0439] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat cardiovascular disease.

[0440] In other embodiments, the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat diseases or conditions of the eye. These include, but are not limited to, radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and ocular ischemia.

[0441] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat diseases associated with hyperoxia.

[0442] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat bronchopulmonary dysplasia (BPD).

[0443] In yet other embodiments, the compounds disclosed herein (e.g., compounds of any one of Formulas (A) and (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat heart disease. Such conditions include, but are not limited to, myocardial ischemia after pancreatic surgery, myocardial injury after percutaneous coronary intervention (PCI), myocardial injury after non-cardiac surgery, perioperative myocardial ischemia during elective abdominal aortic aneurysm surgery, myocardial injury after PCI, myocardial injury in patients undergoing coronary artery bypass grafting (CABG) surgery, minimally invasive mitral valve (MIMV) repair or replacement, adult patients undergoing open heart surgery, chronic heart failure, NYHA class II-IV.

[0444] In other embodiments, the compounds disclosed herein (e.g., compounds of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat lung diseases. Such conditions include, but are not limited to, lung injury during elective lobectomy, lung injury during CABG surgery, and lung transplantation.

[0445] In other embodiments, the compounds disclosed herein (e.g., compounds of Formula (A) and any one of (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat liver diseases. Such conditions include, but are not limited to, non-alcoholic steatohepatitis (NASH).

[0446] In other embodiments, the compounds disclosed herein (e.g., compounds of any one of Formulas (A) and (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used to treat kidney disease. Such conditions include, but are not limited to, contrast-induced acute kidney injury, stage III to IV chronic kidney disease undergoing planned coronary angiography, acute kidney injury in patients undergoing heart valve surgery, non-dialysis-dependent chronic kidney disease, chronic kidney disease patients starting dialysis, and non-dialysis-dependent chronic kidney disease.

[0447] In addition, the compounds disclosed herein (e.g., compounds of any one of Formulas (A) and (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof can be used in combination with additional active ingredients to treat the above-mentioned conditions. The additional compound can be co-administered alone with the compounds disclosed herein (e.g., compounds of any one of Formulas (A) and (I) to (XIII), such as any one of Compounds 1 to 83) or pharmaceutically acceptable salts thereof, or included in a pharmaceutical composition according to the present invention together with the additional active ingredient. In exemplary embodiments, the additional active ingredient is one that is known or discovered to be effective in treating a condition or disorder mediated by a PHD enzyme or has activity against another target associated with a particular condition, disorder, or disease, such as an alternative PHD modulator. The combination can be used to increase efficacy (e.g., by including a compound in the combination that enhances the potency or effectiveness of a compound according to the present invention), reduce one or more side effects, or reduce the required dose of a compound according to the present invention.

[0448] The compounds of the present invention are used alone or in combination with one or more other active ingredients to formulate the pharmaceutical compositions of the present invention. The pharmaceutical compositions of the present invention include: (a) an effective amount of a compound disclosed herein (e.g., a compound of any of Formulas (A) and (I) to (XIII), such as any of Compounds 1 to 83) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

[0449] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a medicament and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Suitable excipients may also include antioxidants. Such antioxidants may be used in pharmaceutical compositions or storage media to extend the shelf life of the drug product.

[0450] Drug formulations and routes of administration

[0451] As is well known in the art, the compounds and compositions of the present invention can be delivered directly or in a pharmaceutical composition or medicine together with a suitable carrier or excipient. The therapeutic methods of the present invention may include administering an effective amount of the compounds of the present invention to a subject in need thereof. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.

[0452] The effective amount of such a compound, composition or drug can be readily determined by routine experimentation, such as the most effective and convenient route of administration and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences, supra.

[0453] Suitable routes of administration can for example comprise oral, rectal, topical, nasal, pulmonary, ocular, intestinal and parenteral administration. The primary route of parenteral administration comprises intravenous, intramuscular and subcutaneous administration. Minor routes of administration comprise intraperitoneal, intraarterial, intraarticular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine and intraventricular administration. The physical, chemical and biological properties of the indication to be treated and the drug determine the type of formulation to be used and the route of administration, and whether preferably local or systemic delivery.

[0454] The pharmaceutical dosage form of the compound of the present invention can be provided in the form of quick release, controlled release, sustained release or targeted drug delivery system. Common dosage forms include, for example, solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried formulations. Depending on the route of administration used, special devices may be needed to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms are generally composed of drugs, excipients and containers / closed systems. One or more excipients, also referred to as inactive ingredients, can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and a method for achieving a desired drug release profile can be provided. Therefore, the type of excipient to be added to the drug can depend on various factors, such as the physical and chemical properties, route of administration and manufacturing procedures of the drug. Pharmaceutically acceptable excipients are available in the art and are included in those listed in various pharmacopoeias. See, for example, US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopeia (BP); U.S. Food and Drug Administration

[0455] (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Ash and Ash, eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott, NY; etc.). Pharmaceutical dosage forms of the compounds of the invention can be prepared by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee preparation, tableting, suspending, extruding, spray drying, milling, emulsifying, (nano / micro)encapsulation, embedding, or lyophilization methods. As described above, the compositions of the invention may contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.

[0456] Appropriate formulations depend on the desired route of administration. For example, for intravenous injection, the composition can be formulated in an aqueous solution, using physiologically compatible buffers, such as phosphates, histidine or citrate, to adjust the pH of the formulation, and tonicity agents, such as sodium chloride or glucose, if necessary. For transmucosal or nasal administration, semisolid, liquid formulations or patches may be preferred and may contain penetration enhancers. Such penetrants are known in the art. For oral administration, the compound can be formulated into liquid or solid dosage forms, as well as quick-release or controlled-release / sustained-release formulations. Suitable dosage forms for oral administration include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. These compounds can also be formulated into rectal compositions (such as suppositories or retention enemas) containing, for example, conventional suppository bases (such as cocoa butter or other glycerides).

[0457] Excipients can be used to obtain solid oral dosage forms, which can include fillers, disintegrants, binding agents (dry and wet), dissolution delay agents, lubricants, glidants, antiadhesives, cation exchange resins, wetting agents, antioxidants, preservatives, coloring agents and flavorings. These excipients can be synthetic or natural origin. The example of this type of excipient includes cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicate, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salt, sugar (that is, glucose, sucrose, lactose etc.), talcum powder, mucilage of tragacanth, vegetable oil (hydrogenation) and wax. Ethanol and water can be used as granulation aids. In some cases, it is desirable to coat tablet with, for example, a taste masking film, a gastric acid resistant film or a release-retarding film. Natural and synthetic polymers in combination with colorants, sugars, and organic solvents or water are commonly used to coat tablets to produce dragees. When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof can be delivered in compatible hard or soft shell capsules.

[0458] In one embodiment, the compounds of the present invention can be topically applied, such as by a skin patch, a semisolid or liquid formulation, such as a gel, (micro) emulsion, an ointment, a solution, a (nano / micro) suspension, or a foam. The penetration of the drug into the skin and subcutaneous tissue can be regulated, for example, by the following: using a penetration enhancer; appropriately selecting and combining lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; adjusting pH; and using a complexing agent. Other techniques such as iontophoresis can be used to regulate the skin penetration of the compounds of the present invention. For example, in the case of desiring local delivery with minimal systemic exposure, transdermal or topical application is preferred.

[0459] For inhalation administration or being applied to nose, the compound used according to the present invention is easily sent with the form of solution, suspension, emulsion or semisolid aerosol from pressurized packaging or atomizer, usually using propellant, for example derived from halocarbons, carbon dioxide or any other suitable gas of methane and ethane.For local aerosol, hydrocarbons such as butane, isobutane and pentane are useful. In the case of pressurized aerosol, suitable dosage unit can be determined by providing the valve for delivering the metered amount. Capsules and cartridges such as gelatin that can be deployed for inhaler or insufflator. These contain compound and powder mixes such as suitable powder bases such as lactose or starch usually.

[0460] Compounds and compositions for parenteral administration are typically sterile and can be present in unit dosage form, for example, in ampoules, syringes, injection pens or multidose containers, the latter usually containing preservatives. Compositions can be in such forms as suspensions, solutions or emulsions in oily or aqueous media, and can contain formulations such as buffers, tension agents, viscosity enhancers, surfactants, suspending agents and dispersants, antioxidants, biocompatible polymers, chelating agents and preservatives. Depending on the injection site, the vehicle can contain water, synthetic oils or vegetable oils and / or organic cosolvents. In some cases, such as using lyophilized products or concentrates, parenteral formulations will be reconstructed or diluted before administration. The controlled release or sustained release reservoir formulations of the compounds of the present invention are provided and can include injectable suspensions of nanometer / micrometer particles or nanometer / micrometer or non-micronized crystals. In addition to other well-known in the art, polymers such as poly (lactic acid), poly (glycolic acid) or its copolymers can be used as controlled release / sustained release matrices. Other depot delivery systems are available in the form of implants and pumps that require an incision.

[0461] Suitable carriers for intravenous injection of the compounds of the present invention are well known in the art and include aqueous solutions containing a base such as sodium hydroxide to form an ionized compound; sucrose or sodium chloride as a tonicity agent; and a buffer, such as a buffer containing phosphate or histidine. Cosolvents such as polyethylene glycol may be added. These aqueous systems are effective in dissolving the compounds of the present invention and produce low toxicity when administered systemically. The proportions of the components of the solution system can vary widely without compromising solubility and toxicity characteristics. In addition, the properties of the components can be varied. For example, low toxicity surfactants such as polysorbates or poloxamers may be used, as may polyethylene glycol or other cosolvents, biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may be substituted for glucose.

[0462] The therapeutically effective dose can be initially estimated using various techniques well known in the art. The initial dose used in animal studies can be based on the effective concentration established in cell culture assays. For example, the data obtained from animal studies and cell culture assays can be used to determine a dosage range suitable for human subjects. In certain embodiments, the compounds of the present invention are formulated for oral administration. An exemplary dose of the compounds of the present invention in a pharmaceutical formulation for oral administration is about 0.5 to about 10 mg / kg subject body weight. In certain embodiments, the pharmaceutical formulation includes about 0.7 to about 5.0 mg / kg subject body weight, or alternatively, about 1.0 to about 2.5 mg / kg subject body weight. A typical dosing regimen for oral administration is three times a week, twice a week, once a week, or daily administration of a pharmaceutical formulation for oral administration.

[0463] An effective amount or therapeutically effective amount or dose of an agent, such as a compound of the present invention, refers to the amount of the agent or compound that results in an improvement in symptoms or a prolonged survival rate in a subject. The toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective to 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Agents that exhibit a high therapeutic index are preferred.

[0464] An effective dose or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal, or human that a researcher, veterinarian, physician, or other clinician is seeking. The dosage specifically falls within a circulating concentration range that includes an ED50 with minimal toxicity or no toxicity. The dosage can vary within this range depending on the dosage form employed and / or the route of administration utilized. In view of the specific circumstances of the subject's condition, the precise formulation, route of administration, dosage, and dosage interval should be selected according to methods known in the art.

[0465] Dosage and interval can be adjusted individually to provide a plasma level of the active moiety sufficient to achieve the desired effect; that is, the minimum effective concentration (MEC). The MEC will vary for each compound, but can be estimated from, for example, in vitro data and animal studies. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

[0466] The amount of compound or composition administered may depend on a variety of factors, including the sex, age, and weight of the subject to be treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0467] If desired, the compounds and compositions of the present invention may be presented in a package or dispenser device containing one or more unit dosage forms of the active ingredient. Such a package or device may, for example, comprise metal or plastic foil, such as a blister pack or glass, and a rubber stopper, such as in a vial. The package or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0468] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein and are specifically contemplated.

[0469] Example

[0470] Purity determination using HPLC

[0471] The purity of the compounds and their synthetic intermediates was determined by reverse phase HPLC using any of the methods described below:

[0472] Method A: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B to 95% B over 1.4 minutes, 95% B over 1.6 minutes (total run time: 3 minutes); Flow rate: 2.3 ml / min. Column: SunFire C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 50°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0473] Method B: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; Gradient: 5% B to 95% B in 1.5 minutes, 95% B in 1.5 minutes (total run time: 3 minutes); Flow rate: 2.0 ml / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 40°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0474] Synthesis of exemplary compounds

[0475] Example 1: Preparation of Compound 1

[0476] Ethyl 2-(4-chlorophenyl)-3-oxobutanoate

[0477]

[0478] To a solution of ethyl 2-(4-chlorophenyl)acetate (1.98 g, 10.0 mmol) in anhydrous tetrahydrofuran (15.0 mL) at -78 ° C was added bis(trimethylsilyl)lithium amide (25.0 mL, 25.0 mmol, 1.0 M in tetrahydrofuran) under nitrogen. The mixture was stirred at -78 ° C for 10 minutes and anhydrous tetrahydrofuran (5.0 mL) containing acetyl chloride (1.17 g, 15.0 mmol) was added. The mixture was warmed to 0 ° C and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain ethyl 2-(4-chlorophenyl)-3-oxobutanoate (800 mg, 3.3 mmol, 33.3% yield) as a yellow solid. LCMS: m / z=241.1 (M+H) + , retention time 2.12 minutes (Method A).

[0479] 2-Bromo-5-(methylsulfonyl)pyridine:

[0480]

[0481] To a solution of 3,6-dibromopyridine (2.5 g, 12.7 mmol) in anhydrous tetrahydrofuran (10.0 mL) at 0 ° C. was added isopropylmagnesium chloride (8.25 mL, 16.5 mmol, 2.0 M in hexane) under nitrogen. The mixture was stirred at 0 ° C. for 45 minutes, and then a solution of methanesulfonyl chloride (1.89 g, 16.5 mmol) in anhydrous tetrahydrofuran (5.0 mL) was added. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain 2-bromo-5-(methylsulfonyl)pyridine (1.4 g, 5.98 mmol, 47.1% yield) as a yellow solid. LC-MS: m / z=236.0 (M+H) + , retention time 1.54 minutes (Method A).

[0482] 2-Hydrazino-5-(methylsulfonyl)pyridine

[0483]

[0484] To a solution of 2-bromo-5-(methylsulfonyl)-pyridine (1.0 g, 4.25 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (1.0 g, 17.0 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-hydrazino-5-(methylsulfonyl)pyridine (1.2 g, 6.4 mmol, 75% yield) as a white solid. LC-MS: m / z = 188.0 (M + H) +, retention time of 0.43 minutes (method A).

[0485] 4-(4-Chlorophenyl)-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-5-ol

[0486]

[0487] To a solution of ethyl 2-(4-chlorophenyl)-3-oxobutanoate (0.24 g, 1.0 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine (0.20 g, 1.0 mmol) in ethanol (3.0 mL) was added p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol). The mixture was stirred at reflux for 12 hours and cooled. The insoluble solid was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparative HPLC to provide 4-(4-chlorophenyl)-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-5-ol (45 mg, 0.12 mmol, 12.3% yield) as a white solid. LCMS: m / z=364.0[M+H] + , retention time 4.49 minutes (Method A). 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),8.91(s,1H),8.72(m,1H),8.43-8.46(d,J=7. 5Hz,1H),7.65-7.67(d,J=7.5Hz,1H),7.44-7.49(m,2H),3.25(s,3H),2.54(s,3H).

[0488] Example 2: Preparation of Compound 2

[0489] Ethyl 2-(4-cyano-2-methylphenyl)acetate

[0490]

[0491] A mixture of 4-bromo-3-methylbenzonitrile (5.0 g, 25.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.24 g, 0.26 mmol), tri-tert-butylphosphine tetrafluoroborate (0.08 g, 0.26 mmol), potassium carbonate (5.3 g, 38.4 mmol) and potassium bicarbonate (3.84 g, 38.4 mmol) in diethyl malonate (27 g 168 mmol) was stirred at 160 ° C for 12 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to give ethyl 2-(4-cyano-2-methylphenyl)acetate (2.0 g, 8.11 mmol, 31.7% yield) as a yellow oil. LCMS: m / z=204.1 (M+H) + , retention time 1.87 minutes (Method A).

[0492] Ethyl 2-(4-cyano-2-methylphenyl)-3-oxobutanoate

[0493]

[0494] To a solution of ethyl 2-(4-cyano-2-methylphenyl)acetate (0.2 g, 1.0 mmol) in anhydrous tetrahydrofuran (10.0 mL) at -78 ° C was added bis(trimethylsilyl)lithium amide (2.5 mL, 2.5 mmol, 1.0 M in tetrahydrofuran) under nitrogen. The mixture was stirred at -78 ° C for 10 minutes and anhydrous tetrahydrofuran (2.0 mL) containing acetyl chloride (0.11 g, 1.5 mmol) was added. The mixture was warmed to 0 ° C and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain ethyl 2-(4-cyano-2-methylphenyl)-3-oxobutanoate (0.1 g, 0.4 mmol, 40% yield) as a white solid. LCMS: m / z=246.1 (M+H) + , retention time 2.11 minutes (Method A).

[0495] 4-(5-hydroxy-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-methylbenzonitrile

[0496]

[0497] To a solution of 2-hydrazino-5-(methylsulfonyl)pyridine (0.18 g, 1.0 mmol) and ethyl 2-(4-cyano-2-methylphenyl)-3-oxobutanoate (0.25 g, 1.0 mmol) in ethanol (3.0 mL) was added p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was stirred at reflux for 12 hours and cooled. The insoluble solid was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparative HPLC to provide 4-(5-hydroxy-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)-3-methylbenzonitrile (11.3 mg, 0.03 mmol, 1.98% yield) as a white solid. LCMS: m / z=369.0[M+H] + , retention time 3.83 minutes (Method A). 1H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.88(s,1H),8.62-8.64(d,J=8.5Hz,1H),8.37-8.39(d,J=8.5Hz,1H),8.14(s ,1H),7.72(s,1H),7.37-7.48(d,J=8.5Hz,1H),7.10-7.12(d,J=7.5Hz,1H),3.52(s,3H),2.38(s,3H),2.08(s,3H).

[0498] Example 3: Preparation of Compound 3

[0499] Methyl 2-(4-cyanophenyl)acetate

[0500]

[0501] To a mixture of 2-(4-cyanophenyl)acetic acid (5.0 g, 31.0 mmol) in methanol (10.0 mL) at 0° C. was added methanol (20.0 mL, 3.0 M). The mixture was stirred at 70° C. for 3.0 hours and cooled to precipitate a solid. The solid was filtered, washed with methanol and dried to give methyl 2-(4-cyanophenyl)acetate (5.0 g, 28.4 mmol, 92% yield) as a yellow solid. LC-MS: m / z=176.0 [M+H] + , retention time 1.54 minutes (Method A).

[0502] Methyl 2-(4-cyanophenyl)-3-oxobutanoate:

[0503]

[0504] To a solution of 2- (4- cyanophenyl) methyl acetate (300mg, 1.71mmol) in anhydrous tetrahydrofuran (10.0mL) at -78°C under nitrogen was added bis (trimethylsilyl) lithium amide (4.29mL, 4.29mmol, 1.0M in tetrahydrofuran). The mixture was stirred at -78°C for 10 minutes and anhydrous tetrahydrofuran (2.0mL) containing acetyl chloride (200mg, 2.57mmol) was added. The mixture was warmed to 0°C and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with saline solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain 2- (4- cyanophenyl) -3- oxobutanoic acid methyl ester (300mg, 1.37mmol, 80% yield) as a yellow solid. LC-MS: m / z = 218.1 (M+H) +, retention time 2.08 minutes (Method A).

[0505] 4-(5-Hydroxy-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0506]

[0507] To the suspension of 2- (4- cyanophenyl) -3- oxobutanoic acid methyl ester (0.26g, 1.11mmol) in acetic acid (10ml) is added 2- hydrazino -5- (methylsulfonyl) pyridine (0.21g, 1.11mmol) at once. After the reaction is stirred at 110 DEG C for 2 hours, the suspension is changed into a clear solution. After the completion of the reaction by TLC analysis, the reaction is quenched with ice water (100mL), and a large amount of solids are precipitated. After filtration, the solid is slurried in methanol (2mL), filtered to obtain the desired product (35mg) as a solid. LCMS (ESI+): m / z 355 (M+H + ); 1H NMR (300MHz, DMSO-d6) δ8.90(d,J=1.5Hz,1H),8.66(d,J=8.7Hz,1H),8.44(dd,J=9.0H z,2.1Hz,1H),7.88(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),3.32(s,3H),2.48(s,3H).

[0508] Example 4: Preparation of Compound 4

[0509] Methyl 2-(4-cyanophenyl)-3-oxopentanoate:

[0510]

[0511] To a solution of 2-(4-cyanophenyl)methyl acetate (300mg, 1.71mmol) in anhydrous tetrahydrofuran (10.0mL) at -78°C under nitrogen was added bis(trimethylsilyl)lithium amide (4.29mL, 4.29mmol, 1.0M in tetrahydrofuran). The mixture was stirred at -78°C for 10 minutes and anhydrous tetrahydrofuran (2.0mL) containing propionyl chloride (236.5mg, 2.57mmol) was added. The mixture was warmed to 0°C and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain 2-(4-cyanophenyl)-3-oxopentanoic acid methyl ester (300mg, 1.29mmol, 75.9% yield) as a yellow solid. LCMS: m / z=232.1 (M+H) + , retention time 2.08 minutes (Method A).

[0512] 4-(3-ethyl-5-hydroxy-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0513]

[0514] To a solution of methyl 2-(4-cyanophenyl)-3-oxopentanoate (350.0 mg, 1.52 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine (283.3 mg, 1.52 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (52.1 mg, 0.30 mmol). The mixture was stirred at reflux for 12 hours and cooled. The insoluble solid was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparative HPLC to provide 4-(3-ethyl-5-hydroxy-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (29.8 mg, 0.08 mmol, 5.33%) as a white solid. LCMS: m / z=369.0[M+H] + , retention time 4.12 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ8.91(d,J=1.2Hz,1H),8.67(d,J=4.4Hz,1H),8.45-8.42(m,1H) ,8.14(s,1H),7.86-7.80(m,4H),3.34(s,3H),2.88-2.82(m,2H),1.22(t,J=7.2Hz,3H).

[0515] Example 5: Preparation of Compound 5

[0516] Methyl 2-(4-cyanophenyl)-3-cyclopropyl-3-oxopropanoate

[0517]

[0518] To a solution of 2-(4-cyanophenyl)methyl acetate (400mg, 2.29mmol) in anhydrous tetrahydrofuran (10.0mL) at -78°C under nitrogen was added bis(trimethylsilyl)lithium amide (5.71mL, 5.71mmol, 1.0M in tetrahydrofuran). The mixture was stirred at -78°C for 10 minutes and anhydrous tetrahydrofuran (2.0mL) containing cyclopropanecarbonyl chloride (356.5mg, 3.43mmol) was added. The mixture was warmed to 0°C and stirred for another hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain 2-(4-cyanophenyl)-3-cyclopropyl-3-oxopropanoic acid methyl ester (500mg, 2.04mmol, 89.9% yield) as a white solid. LCMS: m / z=244.1 (M+H) + , retention time 2.12 minutes (Method A).

[0519] 4-(3-cyclopropyl-5-hydroxy-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0520]

[0521] To a solution of 2-(4-cyanophenyl)-3-cyclopropyl-3-oxopropanoate (350.0 mg, 1.44 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine (269.34 mg, 1.44 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (49.5 mg, 0.29 mmol). The mixture was stirred at reflux for 12 hours and cooled. The insoluble solid was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparative HPLC to obtain 4-(3-cyclopropyl-5-hydroxy-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (59.7 mg, 0.16 mmol, 10.9%) as a white solid. LCMS: m / z=369.0[M+H] + , retention time 4.12 minutes (Method A). 1H NMR(400MHz,DMSO-d6)δ8.91(d,J=1.2Hz,1H),8.67(d,J=4.4Hz,1H),8.45-8.42(m,1H) ,8.14(s,1H),7.86-7.80(m,4H),3.34(s,3H),2.88-2.82(m,2H),1.22(t,J=7.2Hz,3H).

[0522] Example 6: Preparation of Compound 6

[0523] N-(6-Fluoropyridin-3-yl)methanesulfonamide

[0524]

[0525] Methanesulfonyl chloride (600 mg, 5.36 mmol) was added to a solution of 6-fluoropyridin-3-amine (500 mg, 4.46 mmol) in pyridine (5.0 mL) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give N-(6-fluoropyridin-3-yl)methanesulfonamide (420 mg, 2.20 mmol, 49.3% yield) as a white solid. LCMS: m / z=191.1 [M+H] + , retention time 1.32 minutes (Method A). The product was sufficiently pure and used directly in the next step.

[0526] N-(6-Hydrazinopyridin-3-yl)methanesulfonamide

[0527]

[0528] To a solution of N-(6-fluoropyridin-3-yl)methanesulfonamide (420 mg, 2.20 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 4 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give N-(6-hydrazinopyridin-3-yl)ethanesulfonamide (210 mg, 1.03 mmol, 46.8% yield) as a yellow solid. LCMS: m / z = 203.0 (M + H) + , retention time 0.34 min (Method A).

[0529] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide

[0530]

[0531] To a solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (217 mg, 1.0 mmol) and N-(6-hydrazinopyridin-3-yl)methanesulfonamide (202 mg, 1.0 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was stirred at reflux for 12 hours and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give N-(6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide (11.3 mg, 0.03 mmol, 3.05% yield) as a white solid. LCMS: m / z=370.0 (M+H) + , retention time 4.75 minutes (Method A). 1 H NMR(400MHz,DMSO-d6)δ12.85(s,1H),9.91(s,1H),8.31-8.38(m,2H),8.15(s, 1H),7.90-7.493(d,J=8.7Hz,1H),7.76-7.81(m,3H),3.05(s,3H),2.45(s,3H).

[0532] Example 7: Preparation of Compound 7

[0533] 1-(6-Bromopyridin-3-yl)pyrrolidin-2-one

[0534]

[0535] A mixture of 2-bromo-5-iodopyridine (2.0 g, 7.07 mmol), pyrrolidin-2-one (3.0 g, 35.3 mmol), cuprous iodide (133 mg, 0.7 mmol), potassium phosphate (4.5 g, 21.2 mmol), ethylene glycol (62 mg, 1.0 mmol) in dry isopropanol (10.0 mL) was stirred at 110 ° C in a sealed tube for 12.0 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane ether / methanol = 20 / 1) to give 1- (6-bromopyridin-3-yl) pyrrolidin-2-one (820 mg, 3.40 mmol, 48.1% yield) as a yellow solid. LC-MS: m / z = 241.0 (M + H) + , retention time 1.65 minutes (Method A).

[0536] 1-(6-Hydrazinopyridin-3-yl)pyrrolidin-2-one

[0537]

[0538] To a solution of 1-(6-bromopyridin-3-yl)pyrrolidin-2-one (400 mg, 1.66 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred overnight at 130 ° C in a sealed tube. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 1-(6-hydrazinopyridin-3-yl)pyrrolidin-2-one (160 mg, 0.83 mmol, 50.2% yield) as a yellow oil. LC-MS: m / z = 193.2 [M + H] + , retention time 0.69 min (Method B).

[0539] 4-(5-Hydroxy-3-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0540]

[0541] To a solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (50 mg, 0.23 mmol) and 1-(6-hydrazinopyridin-3-yl)pyrrolidin-2-one (44 mg, 0.23 mmol) in ethanol (3.0 mL) was added p-toluenesulfonic acid monohydrate (4.0 mg, 0.02 mmol). The mixture was stirred at 90 ° C. in a sealed tube for 12.0 hours and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (8.0 mg, 0.022 mmol, 9.7% yield) as a white solid. LC-MS: m / z = 360.1 (M + H) + , retention time 4.06 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.79(s,1H),8.37(s,1H),8.21-8.19(m,1H),7.92-7.90(m,2H), 7.78-7.76(m,2H),3.90-3.87(m,2H),2.54-2.52(m,2H),2.50(s,3H),2.12-2.09(m,2H).

[0542] Example 8: Preparation of Compound 8

[0543] 2-Chloro-5-(phenylsulfonyl)pyridine

[0544]

[0545] A mixture of 2-chloro-5-iodopyridine (2.38 g, 10.0 mmol), copper (I) iodide (0.19 g, 1.0 mmol) and benzenesulfinate (978 mg, 6.0 mmol) in dimethyl sulfoxide (20.0 mL) was stirred at 60 ° C for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-chloro-5- (phenylsulfonyl) pyridine (400 mg, 1.58 mmol, 15.8% yield) as a yellow oil. LCMS: m / z = 254.0 (M + H) + , retention time 1.92 minutes (Method A).

[0546] 2-Hydrazino-5-(phenylsulfonyl)pyridine

[0547]

[0548] To a solution of 2-chloro-5-(phenylsulfonyl)pyridine (0.4 g, 1.58 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 4 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-hydrazino-5-(phenylsulfonyl)pyridine (150 mg, 0.6 mmol, 37.9% yield) as a yellow solid. LCMS: m / z = 250.0 (M + H) + , retention time 1.38 minutes (Method A).

[0549] 4-(5-Hydroxy-3-methyl-1-(5-(phenylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0550]

[0551] To a solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (217.0 mg, 1.0 mmol) and 2-hydrazino-5-(phenylsulfonyl)pyridine (249.0 mg, 1.0 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (38.0 mg, 0.2 mmol). The mixture was stirred at reflux for 12 hours and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(phenylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (4.5 mg, 0.01 mmol, 1.1% yield) as a white solid. LCMS: m / z=417.0 (M+H) + , retention time 4.75 minutes (Method A). 1 H NMR (400MHz, DMSO-d6) δ2.45(s,1H),8.94(s,1H),8.63-8.65(d,J=8.9Hz,1H),8.37-8.63(d,J=8.9Hz,1H ),8.13(s,1H),8.00-8.02(d,J=8.9Hz,2H),7.89-7.91(d,J=7.5Hz,2H),7.63-7.72(m,5H),2.41(s,3H).

[0552] Example 9: Preparation of Compound 9

[0553] N-(6-Fluoropyridin-3-yl)propionamide

[0554]

[0555] To a solution of 6-fluoropyridin-3-amine (0.5 g, 4.5 mmol) and triethylamine (0.91 g, 9.0 mmol) in dichloromethane (20.0 mL) at 0 ° C., propionyl chloride (0.41 g, 4.5 mmol) was added. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction was quenched with water and extracted twice with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain N-(6-fluoropyridin-3-yl)propionamide (0.6 g, 3.57 mmol, 79.3% yield) as a yellow solid. LCMS: m / z=169.0 (M+H) + , retention time 1.50 min (Method A).

[0556] N-(6-Hydrazinopyridin-3-yl)propionamide

[0557]

[0558] To a solution of N-(6-fluoropyridin-3-yl)propanamide (0.17 g, 1.0 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 4 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give N-(6-hydrazinopyridin-3-yl)propanamide (147 mg, 0.82 mmol, 82.8% yield) as a yellow solid. LCMS: m / z = 181.0 (M + H) + , retention time 0.34 min (Method A).

[0559] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)propanamide

[0560]

[0561] To a solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (217 mg, 1.0 mmol) and N-(6-hydrazinopyridin-3-yl)propionamide (180 mg, 1.0 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was stirred at reflux for 12 hours and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give N-(6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)propionamide (4.6 mg, 0.01 mmol, 1.3% yield) as a white solid. LCMS: m / z=348.0 (M+H) + , retention time 4.10 minutes (Method A). 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.21(s,2H),7.83-8.00(m,3H),7.54-7.57(m,2H),2.32-2.43(m,5H),1.04-1.12(m,3H).

[0562] Example 10: Preparation of Compound 10

[0563] tert-Butyl 6-chloronicotinate

[0564]

[0565] To a solution of 6-fluoronicotinic acid (5.0 g, 6.37 mmol) and 4-dimethylaminopyridine (0.39 g, 0.64 mmol) in tetrahydrofuran (50.0 mL) was added di-tert-butyl dicarbonate (10.41 g, 47.77 mmol). The reaction mixture was refluxed for 4.0 hours and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to give tert-butyl 6-chloronicotinate (5.5 g, 5.17 mmol, 81.12% yield) as a yellow solid. LC-MS: m / z=214.0 (M+H) + , retention time 1.83 minutes (Method A).

[0566] tert-Butyl 6-hydrazinonicotinate:

[0567]

[0568] To a solution of tert-butyl 6-chloronicotinate (5.5 g, 25.82 mmol) in ethanol (25.0 mL) was added hydrazine hydrate (6.46 g, 129.11 mmol, 85% in water). The mixture was stirred at 100 ° C for 2.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give tert-butyl 6-hydrazinenicotinate (5.0 g, 23.9 mmol, 92.76% yield) as a yellow solid. LC-MS: m / z = 210.0 (M + H) + , retention time 1.19 minutes (Method A).

[0569] tert-Butyl 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate

[0570]

[0571] A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (600 mg, 2.76 mmol) and tert-butyl 6-hydrazinenicotinate (577 mg, 2.76 mmol) in acetic acid (5.0 mL) was stirred at 120 ° C. for 1.0 hour and concentrated to dryness. The residue was purified by flash chromatography (methanol / dichloromethane = 1 / 10) to give tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate (610 mg, 1.62 mmol, 58.7% yield) as a yellow solid. LC-MS: m / z = 377.1 (M + H) + , retention time 2.24 minutes (Method A).

[0572] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid

[0573]

[0574] To a solution of tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate (610 mg 1.62 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at 40 ° C. for 2.0 hours and concentrated. The residue was triturated with ethyl acetate and filtered to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.56 mmol, 96.4% yield) as a yellow solid. LC-MS: m / z = 321.0 (M + H) + , retention time 3.38 minutes (Method A).

[0575] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinoyl chloride

[0576]

[0577] To a solution of 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.56 mmol) in dichloromethane (15.0 mL) was added thionyl chloride (15.0 mL). The mixture was stirred at 40 ° C. for 3.0 hours and concentrated to dryness. The crude product (500 mg) was obtained and used directly in the next step. LC-MS: m / z = 335.1 (M + H) + , retention time 1.99 minutes (Method A).

[0578] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-methoxy-N-methylnicotinamide

[0579]

[0580] To a 0°C solution of N,O-dimethylhydroxylamine hydrochloride (230 mg, 2.33 mmol) and N,N-diisopropylethylamine (0.60 g, 4.65 mmol) in dichloromethane (5.0 mL) was added 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinoyl chloride (500 mg, crude product). The mixture was stirred at 0°C for 3.0 hours and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol = 10 / 1) to afford 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-methoxy-N-methylnicotinamide (450 mg, 1.24 mmol, 79.5% yield) as a yellow solid. LC-MS: m / z = 364.0 [M+H] + , retention time 4.08 minutes (Method A).

[0581] 4-(5-Hydroxy-1-(5-isobutyrylpyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0582]

[0583] To a solution of isopropylmagnesium chloride (3.40 mL, 3.40 mmol, 1 M in tetrahydrofuran) in anhydrous tetrahydrofuran (8.0 mL) at -20°C was added 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-methoxy-N-methylnicotinamide (300 mg, 0.82 mmol). The mixture was allowed to warm to 0°C and stirred for an additional hour. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-1-(5-isobutyrylpyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) (17.3 mg, 0.044 mmol, 5.38% yield) as a white solid. LC-MS: m / z=347.1 (M+H) + , retention time 5.05 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ9.01(d,J=0.8Hz,1H),8.59-8.48(m,2H),8.14(s,1 H),7.91-7.81(m,4H),3.72-3.65(m,1H),2.49(s,3H),1.14(d,J=3.4Hz,6H).

[0584] Example 11: Preparation of Compound 11

[0585] 6-Hydrazinopyridine-3-sulfonamide

[0586]

[0587] To a solution of 6-chloropyridine-3-sulfonamide (1.63 g, 8.5 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 4 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 6-hydrazinopyridine-3-sulfonamide (600 mg, 3.20 mmol, 37.7% yield) as a yellow solid. LCMS: m / z = 189.0 (M + H) + , retention time 0.32 min (Method A).

[0588] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide

[0589]

[0590] To a solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (217 mg, 1.0 mmol) and 6-hydrazinopyridine-3-sulfonamide (188 mg, 1.0 mmol) in ethanol (5.0 mL) was added p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was stirred at reflux for 12 hours and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide (8.8 mg, 0.24 mmol, 2.4% yield) as a white solid. LCMS: m / z=356.0 (M+H) + , retention time 3.50 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ12.95(s,1H),8.80(s,1H),8.60-8.62(d,J=7.9Hz,2H),8.24-8.26(d,J=7.9H z,1H),8.14(s,1H),7.92-7.94(d,J=7.9Hz,2H),7.71-7.73(d,J=7.3Hz,2H),7.51(s,2H),2.43(s,3H).

[0591] Example 12: Preparation of Compound 12

[0592] 2-Chloro-5-(methylthio)pyridine

[0593]

[0594] To a solution of 5-bromo-2-chloropyridine (1.92 g, 10.0 mmol) and N, N, N', N'-tetramethylethylenediamine (1.51 g, 13.0 mmol) in anhydrous tetrahydrofuran (15.0 mL) at -78 ° C was added n-butyllithium (7.5 mL, 12.0 mmol, 1.6 M in hexane) under nitrogen. The mixture was stirred at -78 ° C for 50 minutes and dimethyl disulfide (1.13 g, 12.0 mmol) was added. The mixture was warmed to 20 ° C and stirred for another hour. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=50 / 1) to obtain 2-chloro-5-(methylthio)pyridine (1.0 g, 6.29 mmol, 62.9% yield) as a yellow oil. LC-MS: m / z=160 (M+H) + , retention time 0.85 min (Method A).

[0595] 2-Chloro-5-(methylsulfinyl)pyridine

[0596]

[0597] 3-Chlorobenzoic acid (1.26 g, 6.22 mmol, 85%) was added to a solution of 2-chloro-5-(methylthio)pyridine (900 mg, 5.66 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this room temperature for 1 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(methylsulfinyl)pyridine (700 mg, 4.0 mmol, 70.6% yield) as a white solid. LC-MS: m / z=176.1 (M+H) + , retention time 0.55 min (Method A).

[0598] 2-Hydrazino-5-(methylsulfinyl)pyridine

[0599]

[0600] To a solution of 2-chloro-5-(methylsulfinyl)pyridine (700 mg, 4.0 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (1.23 g, 20.0 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-hydrazino-5-(methylsulfinyl)pyridine (400 mg, 2.34 mmol, 58.5% yield) as a yellow solid. LC-MS: m / z = 172.0 (M + H) +, retention time of 0.38 minutes (method A).

[0601] 4-(5-Hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0602]

[0603] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (400 mg, 2.34 mmol) and 2-hydrazino-5-(methylsulfinyl)pyridine (400 mg, 2.34 mmol) in acetic acid (8.0 mL) was stirred at 120 ° C. for 1 hour and cooled to precipitate a solid. The solid was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (94 mg, 0.28 mmol, 11.8% yield) as a white solid. LC-MS: m / z = 339.0 (M + H) + , retention time 3.32 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.08(s,1H),8.66-8.73(m,2H),8.29-8.31(d,J=10.4Hz,1H ),7.89-7.91(d,J=8.3Hz,2H),7.81-7.83(d,J=8.4Hz,2H),2.88(s,3H),2.50(s,3H).

[0604] Example 13: Preparation of Compound 13

[0605] (6-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfonone

[0606]

[0607] To a mixture of 2-chloro-5-(methylsulfinyl)pyridine (200 mg, 1.14 mmol) (intermediate of Example 12) and sodium azide (223 mg, 3.43 mmol) in chloroform (5.0 mL) at 0° C. was added concentrated sulfuric acid (1.0 mL). The mixture was stirred at 55° C. for 16.0 hours and cooled. The reaction was diluted with ice water and the organic layer was removed. The aqueous phase was made basic by the addition of ammonium hydroxide solution, thereby separating an oil which was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give (6-chloropyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (120 mg, 0.63 mmol, 55.4% yield). LC-MS: m / z=191.0 (M+H) + , retention time 1.3 minutes (Method A).

[0608] (6-Hydrazinopyridin-3-yl)(Imino)(methyl)-λ 6 -sulfonone

[0609]

[0610] To (6-chloropyridin-3-yl)(imino)(methyl)-λ 6 To a solution of -sulfurone (120 mg, 0.63 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (200 mg, 3.15 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain (6-hydrazinopyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (100 mg, 0.54 mmol, 85.3% yield). LC-MS: m / z = 187.0 (M+H) +, retention time 0.36 min (Method A).

[0611] 4-(5-Hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0612]

[0613] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (117 mg, 0.54 mmol) and (6-hydrazinopyridin-3-yl)(imino)(methyl)-λ 6A mixture of 4-(5-hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (37 mg, 0.10 mmol, 19.4% yield) was stirred at 120° C. for 1 hour and concentrated. The residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (37 mg, 0.10 mmol, 19.4% yield) as a white solid. LC-MS: m / z=354.0 (M+H) + , retention time was 3.19 minutes (method A). 1 HNMR(400MHz,DMSO-d6)δ13.15(s,1H),8.90(s,1H),8.63-8.66(d,J=8.7Hz,1H),8.41-8.44(d,J =8.7Hz,1H),7.89-7.92(d,J=8.7Hz,2H),7.81-7.83(d,J=8.7Hz,2H),3.18(s,3H),2.54(s,3H).

[0614] Example 14: Preparation of Compound 14

[0615] (6-Bromopyridin-3-yl)dimethylphosphine oxide

[0616]

[0617] A mixture of 2-bromo-5-iodopyridine (500 mg, 1.76 mmol), dimethylphosphine oxide (275 mg 3.53 mmol), potassium phosphate (1.12 g, 5.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (203 mg, 0.35 mmol) and palladium acetate (156 mg, 0.7 mmol) in 1,4-dioxane (15.0 mL) was stirred overnight at 100 ° C under nitrogen. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain (6-bromopyridin-3-yl)dimethylphosphine oxide (50 mg, 0.21 mmol, 12.1% yield) as a yellow oil. LC-MS: m / z=234[M+H] + , retention time = 1.36 minutes (Method A).

[0618] (6-Hydrazinopyridin-3-yl)dimethylphosphine oxide

[0619]

[0620] To a solution of (6- bromopyridin-3-yl) dimethylphosphine oxide (120 mg, 0.51 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (160 mg, 2.55 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give (6- hydrazinopyridin-3-yl) dimethylphosphine oxide (80 mg, 0.43 mmol, 80% yield) as a yellow solid. LC-MS: m / z = 186.0 (M + H) +, retention time of 0.36 minutes (method A).

[0621] 4-(1-(5-(dimethylphosphoryl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0622]

[0623] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (93 mg, 0.43 mmol) and (6-hydrazinopyridin-3-yl)dimethylphosphine oxide (80 mg, 0.43 mmol) in acetic acid (5.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(dimethylphosphoryl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (68 mg, 0.19 mmol, 44.9% yield) as a white solid. LC-MS: m / z=353.1.0 (M+H) + , retention time 3.17 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.07(s,1H),8.76(s,1H),8.59(s,1H),8.29-8.33(m,1H),7.81-7.91(m,4H),2.50(s,3H),1.72-1.76(d,J=12.9Hz,6H).

[0624] Example 15: Preparation of Compound 15

[0625] (6-Chloropyridin-3-yl)(methyl)(methylimino)-λ 6 -sulfonone

[0626]

[0627] To 0 ℃ (6-chloropyridin-3-yl)(imino)(methyl)-λ 6To a solution of -sulfonone (330 mg, 1.73 mmol) (intermediate of Example 13) in anhydrous tetrahydrofuran (10.0 mL) was added sodium hydride (83 mg, 2.08 mmol, 60% in oil). The mixture was stirred at 0 ° C for 20 minutes and iodomethane (487 mg, 3.46 mmol) was added. The mixture was allowed to warm to room temperature and stirred for another 3.0 hours. The reaction was extracted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain (6-chloropyridin-3-yl)(methyl)(methylimino)-λ 6 -sulfonone (300 mg, 1.47 mmol, 85.1% yield). LC-MS: m / z=205.0 (M+H) + , retention time 1.45 minutes (Method A).

[0628] (6-Hydrazinopyridin-3-yl)(methyl)(methylimino)-λ 6 -sulfonone

[0629]

[0630] To (6-chloropyridin-3-yl)(methyl)(methylimino)-λ 6 To a solution of -sulfurone (300 mg, 1.47 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (460 mg, 7.35 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain (6-hydrazinopyridin-3-yl)(methyl)(methylimino)-λ as a yellow solid. 6 -sulfonone (200 mg, 1.0 mmol, 68% yield). LC-MS: m / z=201.0 (M+H) + , retention time 0.49 min (Method A).

[0631] 4-(1-(5-(N,S-dimethylsulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0632]

[0633] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (217 mg, 1.0 mmol) and (6-hydrazinopyridin-3-yl)(methyl)(methylimino)-λ 6A mixture of 4-(1-(5-(N,S-dimethylsulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (93.7 mg, 0.25 mmol, 25.5% yield) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(N,S-dimethylsulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (93.7 mg, 0.25 mmol, 25.5% yield) as a white solid. LC-MS: m / z=368.1.0 (M+H) + , retention time 4.23 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.15(s,1H),8.80(s,1H),8.68(s,1H),8.32-8.35(d,J=8.8Hz ,1H),7.89-7.91(d,J=7.9Hz,2H),7.81-7.83(d,J=7.9Hz,2H),3.24(s,3H),3.51(s,3H).

[0634] Example 16: Preparation of Compound 16

[0635] (S)-(6-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfonone

[0636]

[0637] To a mixture of 2-chloro-5-(methylsulfinyl)pyridine (2.0 g, 11.4 mmol) (intermediate of Example 12) and sodium azide (2.23 g, 34.3 mmol) in chloroform (50.0 mL) at 0° C. was added concentrated sulfuric acid (5.0 mL). The mixture was stirred at 55° C. for 16 hours and cooled. The reaction was diluted with ice water and the organic layer was removed. The aqueous phase was made basic by the addition of ammonium hydroxide solution, thereby separating an oil which was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give (6-chloropyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (1.0 g, 5.26 mmol, 46.1% yield). LC-MS: m / z=191.0 (M+H) + , retention time 0.55 min (Method A).

[0638] The two chiral isomers were separated by chiral preparative HPLC (Chiralpak AD-H column; mobile phase: A: hexane, B: MeOH (0.2% methanolamine); gradient: B% = 25%; flow rate: 1.0 mL / min; column temperature: 40°C; wavelength: 254 nm).

[0639] (S)-(6-chloropyridin-3-yl)(imino)(methyl)-λ as a yellow solid 6 -sulfonone (247 mg, 1.30 mmol).

[0640] (R)-(6-chloropyridin-3-yl)(imino)(methyl)-λ as a yellow solid 6 -sulfonone (211 mg, 1.11 mmol).

[0641] (S)-(6-Hydrazinopyridin-3-yl)(imino)(methyl)-λ 6 -sulfonone

[0642]

[0643] To (S)-(6-chloropyridin-3-yl)(imino)(methyl)-λ 6 To a solution of -sulfurone (100 mg, 0.53 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (200 mg, 3.15 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to obtain (S)-(6-hydrazinopyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (100 mg, crude product). LC-MS: m / z = 187.0 (M+H) +, retention time 0.37 minutes (Method A).

[0644] (S)-4-(5-Hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0645]

[0646] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (117 mg, 0.54 mmol) and (S)-(6-hydrazinopyridin-3-yl)(imino)(methyl)-λ 6 A mixture of -sulfonone (100 mg, crude product) in acetic acid (8.0 mL) was stirred at 120° C. for 1 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (S)-4-(5-hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (36.7 mg, 0.103 mmol, 19.2% yield) as a white solid. LC-MS: m / z=354.0 (M+H) +, retention time 3.10 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.15(s,1H),8.90(s,1H),8.65(s,1H),8.42-8.44(dd,J=8.8Hz ,1H),7.89-7.91(d,J=7.8Hz,2H),7.82-7.83(d,J=7.8Hz,2H),3.18(s,3H),2.50(s,3H).

[0647] Example 17: Preparation of Compound 17

[0648] (R)-(6-Hydrazinopyridin-3-yl)(imino)(methyl)-λ 6 -sulfonone

[0649]

[0650] To (R)-(6-chloropyridin-3-yl)(imino)(methyl)-λ 6 To a solution of -sulfonone (100 mg, 0.53 mmol) (intermediate of Example 16) in ethanol (5.0 mL) was added hydrazine hydrate (200 mg, 3.15 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to obtain (R)-(6-hydrazinopyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (100 mg, crude product). LC-MS: m / z = 187.0 (M+H) +, retention time 0.37 minutes (Method A).

[0651] (R)-4-(5-Hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0652]

[0653] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (117 mg, 0.54 mmol) and (R)-(6-hydrazinopyridin-3-yl)(imino)(methyl)-λ 6A mixture of 1-sulfonone (100 mg, crude product) in acetic acid (8.0 mL) was stirred at 120° C. for 1 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (R)-4-(5-hydroxy-3-methyl-1-(5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (47.5 mg, 0.134 mmol, 24.8% yield) as a white solid. LC-MS: m / z=354.0 (M+H) + , retention time 3.10 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.15(s,1H),8.90(s,1H),8.64(m,1H),8.42-8.45(dd,J=8.7Hz ,1H),7.89-7.91(d,J=8.7Hz,2H),7.82-7.84(d,J=8.7Hz,2H),3.18(s,3H),2.51(s,3H).

[0654] Example 18: Preparation of Compound 18

[0655] (6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(imino)-(methyl)-λ 6 -sulfonone

[0656]

[0657] Ethyl 2-(4-chlorophenyl)-3-oxobutanoate (250 mg, 1.04 mmol) (intermediate of Example 1) and (6-hydrazinopyridin-3-yl)(imino)(methyl)-λ 6 A mixture of -sulfonone (190 mg, 1.04 mmol) (intermediate of Example 13) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(imino)(methyl)-λ as a white solid. 6 -sulfonone (formate) (27 mg, 0.07 mmol, 7.17% yield). LC-MS: m / z=363.0 (M+H) + , retention time 3.82 minutes (Method A). 1HNMR (400MHz, DMSO-d6) δ12.73(s,1H),8.88(s,1H),8.61-8.64(d,J=10.7Hz,1H),8.39-8.41(d,J=10.7 Hz,1H),7.67-7.68(d,J=8.2Hz,2H),7.42-7.44(d,J=8.2Hz,2H),4.49(s,1H),3.17(s,3H),2.42(s,3H).

[0658] Example 19: Preparation of Compound 19

[0659] 2-Chloro-5-(isopropylthio)pyridine

[0660]

[0661] To a solution of 5-bromo-2-chloropyridine (1.92 g, 10.0 mmol) in anhydrous diethyl ether (15.0 mL) at -78 ° C. was added n-butyl lithium (7.5 mL, 12.0 mmol, 1.6 M in hexane) under nitrogen. The mixture was stirred at -78 ° C. for 30 minutes and 1,2-diisopropyldisulfane (1.80 g, 12.0 mmol) was added. The mixture was warmed to 20 ° C. and stirred for another hour. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain 2-chloro-5- (isopropylthio) pyridine (1.2 g, 6.42 mmol, 64.2% yield) as a yellow oil. LC-MS: m / z = 188.0 (M + H) + , retention time 2.05 minutes (Method A).

[0662] 2-Chloro-5-(isopropylsulfinyl)pyridine

[0663]

[0664] 3-Chlorobenzoic acid (1.43 g, 7.06 mmol, 85%) was added to a solution of 2-chloro-5-(isopropylthio)pyridine (1.2 g, 6.42 mmol) in dichloromethane (20.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(isopropylsulfinyl)pyridine (1.1 g, 5.42 mmol, 84.4% yield) as a white solid. LC-MS: m / z=204.1 (M+H) + , retention time 0.55 min (Method A).

[0665] (6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6 -sulfonone

[0666]

[0667] To a mixture of 2-chloro-5-(isopropylsulfinyl)pyridine (200 mg, 0.91 mmol) and ammonium carbamate (286 mg, 3.67 mmol) in methanol (5.0 mL) was added (diacetoxyiodine)benzene (880 mg, 2.73 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-chloropyridin-3-yl)(imino)(isopropyl)-λ as a yellow solid. 6 -sulfonone (150 mg, 0.69 mmol, 75.6% yield). LC-MS: m / z=219.1 (M+H) + , retention time 1.50 min (Method A).

[0668] (6-Hydrazinopyridin-3-yl)(Imino)(Isopropyl)-λ 6 -sulfonone

[0669]

[0670] To (6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6To a solution of -sulfonone (200 mg, 0.92 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (280 mg, 4.6 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ was obtained as a yellow syrup. 6 -sulfonone (200 mg, crude product). LC-MS: m / z=215.0 (M+H)+, retention time 0.56 min (Method A). The crude product was used in the next step.

[0671] 4-(5-Hydroxy-3-methyl-1-(5-(propan-2-ylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0672]

[0673] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (195 mg, 0.90 mmol) and (6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ 6 A mixture of 4-(5-hydroxy-3-methyl-1-(5-(propan-2-ylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (28.8 mg, 0.08 mmol, 8.4% yield) was stirred at 120° C. for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(propan-2-ylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (28.8 mg, 0.08 mmol, 8.4% yield) as a white solid. LC-MS: m / z=382.0 (M+H) + , retention time 3.51 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.17(s,1H),8.80(s,1H),8.65-8.67(d,J=8.6Hz,1 H),8.32-8.35(dd,J=8.7Hz,4H),4.48(s,1H),2.51(s,3H),1.17-1.23(m,6H).

[0674] Example 20: Preparation of Compound 20

[0675] 2-Chloro-5-(phenylthio)pyridine

[0676]

[0677] A mixture of 2-chloro-5-iodopyridine (2.3 g, 10 mmol), thiophenol (1.32 g, 12 mmol), sodium methoxide (648 mg, 12 mmol), copper (320 mg, 5.0 mmol) in methanol (10.0 mL) was stirred at 80 ° C under nitrogen for 12.0 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 2-chloro-5- (phenylthio) pyridine (1.5 g, 6.79 mmol, 67.9% yield) as a white solid. LC-MS: m / z = 222 [M + H] + , retention time = 2.10 minutes (Method A).

[0678] 2-Chloro-5-(phenylsulfinyl)pyridine

[0679]

[0680] 3-Chlorobenzoic acid (1.65 g, 8.15 mmol, 85%) was added to a solution of 2-chloro-5-(phenylthio)pyridine (1.5 g, 6.79 mmol) in dichloromethane (20.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain 2-chloro-5-(phenylsulfinyl)pyridine (1.0 g, 4.22 mmol, 62.1% yield) as a white solid. LC-MS: m / z=238.1 (M+H) + , retention time 1.75 minutes (Method A).

[0681] (6-Chloropyridin-3-yl)(Imino)(phenyl)-λ 6 -sulfonone

[0682]

[0683] To a mixture of 2-chloro-5-(phenylsulfinyl)pyridine (300 mg, 1.26 mmol) and ammonium carbamate (393 mg, 5.04 mmol) in methanol (8.0 mL) was added (diacetoxyiodine)benzene (1.22 g, 3.78 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain (6-chloropyridin-3-yl)(imino)(phenyl)-λ as a yellow solid. 6 -sulfonone (150 mg, 0.59 mmol, 47.2% yield). LC-MS: m / z=253.0 (M+H) + , retention time 1.69 minutes (Method A).

[0684] (6-Hydrazinopyridin-3-yl)(Imino)(phenyl)-λ 6 -sulfonone

[0685]

[0686] To (6-chloropyridin-3-yl)(imino)(phenyl)-λ 6 To a solution of -sulfonone (150 mg, 0.59 mmol) in ethanol (3.0 mL) was added hydrazine hydrate (180 mg, 2.95 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ was obtained as a yellow syrup. 6 -sulfonone (75 mg, 0.30 mmol, 51.2% yield). LC-MS: m / z=249.0 (M+H)+, retention time 1.22 min (Method A). The crude product was used in the next step.

[0687] 4-(5-Hydroxy-3-methyl-1-(5-(phenylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0688]

[0689] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (65.1 mg, 0.30 mmol) and (6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ 6A mixture of -sulfonone (75 mg, 0.30 mmol) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(phenylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (28.8 mg, 0.08 mmol, 8.4% yield) as a white solid. LC-MS: m / z=416.0 (M+H) + , retention time 4.05 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.95(s,1H),8.58(s,1H),8.37-8.40(d,J=8.3Hz,1H),8.14(s,1H),8.00-8.02(d,J=7. 3Hz, 2H), 7.88-7.90 (d, J = 8.3Hz, 2H), 7.72-7.74 (d, J = 8.3Hz, 2H), 7.58-7.62 (m, 3H), 5.26 (s, 1H), 2.43 (s, 3H).

[0690] Example 21: Preparation of Compound 21

[0691] 2-Chloro-5-(ethylthio)pyridine

[0692]

[0693] To a solution of 5-bromo-2-chloropyridine (3.0 g, 15.6 mmol) in anhydrous diethyl ether (30.0 mL) at -78 ° C. was added n-butyl lithium (11.7 mL, 18.7 mmol, 1.6 M in hexane) under nitrogen. The mixture was stirred at -78 ° C. for 30 minutes and 1,2-diethyldisulfane (2.28 g, 18.7 mmol) was added. The mixture was warmed to 20 ° C. and stirred for another hour. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 2-chloro-5- (ethylthio) pyridine (2.5 g, 14.45 mmol, 92.6% yield) as a yellow oil. LC-MS: m / z = 174.1 (M + H) + , retention time 2.01 minutes (Method A).

[0694] 2-Chloro-5-(ethylsulfinyl)pyridine

[0695]

[0696] 3-Chlorobenzoic acid (3.51 g, 17.34 mmol, 85%) was added to a solution of 2-chloro-5-(ethylthio)pyridine (2.5 g, 14.45 mmol) in dichloromethane (20.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain 2-chloro-5-(ethylsulfinyl)pyridine (2.0 g, 9.80 mmol, 67.8% yield) as a white solid. LC-MS: m / z=190.1 (M+H) + , retention time 1.47 minutes (Method A).

[0697] (6-Chloropyridin-3-yl)(Imino)(ethyl)-λ 6 -sulfonone

[0698]

[0699] To a mixture of 2-chloro-5-(ethylsulfinyl)pyridine (2.0 g, 9.80 mmol) and sodium azide (1.91 g, 29.4 mmol) in chloroform (15.0 mL) at 0° C. was added concentrated sulfuric acid (2.0 mL). The mixture was stirred at 55° C. for 16.0 hours and cooled. The reaction was diluted with ice water and the organic layer was removed. The aqueous phase was made basic by the addition of ammonium hydroxide solution, thereby separating an oil which was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give (6-chloropyridin-3-yl)(imino)(ethyl)-λ as a yellow solid. 6 -sulfonone (1.82 g, 9.1 mmol, 92.8% yield). LC-MS: m / z=205.1 (M+H) + , retention time 1.40 minutes (Method A).

[0700] (6-Hydrazinopyridin-3-yl)(Imino)(ethyl)-λ 6 -sulfonone

[0701]

[0702] To 6-chloropyridin-3-yl)(imino)(ethyl)-λ 6To a solution of -sulfurone (1.82 g, 9.1 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (2.89 g, 45.5 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain (6-hydrazinopyridin-3-yl)(imino)(ethyl)-λ as a yellow solid. 6 -sulfonone (2.0 g, crude product). LC-MS: m / z=201.1 (M+H)+, retention time 0.39 min (Method A). The crude product was used in the next step.

[0703] 4-(5-Hydroxy-3-methyl-1-(5-(S-ethylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0704]

[0705] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (651 mg, 3.0 mmol) and (6-hydrazinopyridin-3-yl)(imino)(ethyl)-λ 6 A mixture of 4-(5-hydroxy-3-methyl-1-(5-(S-ethylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (115.3 mg, 0.31 mmol, 10.5% yield) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(S-ethylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) as a white solid (115.3 mg, 0.31 mmol, 10.5% yield). LC-MS: m / z=368.1 (M+H) + , retention time 3.36 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.82(s,1H),8.65-8.63(m,1H),8.35-8.32(m,1H),7.92- 7.89(m,2H),7.80-7.78(m,2H),3.25-3.19(m,2H),2.50(s,3H),1.13-1.09(m,3H).

[0706] Example 22: Preparation of Compound 22

[0707] (S)-2-Chloro-5-(methylsulfinyl)pyridine

[0708]

[0709] 3-Chlorobenzoic acid (3.84 g, 19.0 mmol, 85%) was added to a solution of 2-chloro-5-(methylthio)pyridine (2.5 g, 15.82 mmol) (intermediate of Example 12) in dichloromethane (20.0 mL) at 0°C. The mixture was stirred at this room temperature for 1 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(methylsulfinyl)pyridine (1.6 g, 9.20 mmol, 58.1% yield) as a white solid. LC-MS: m / z=176 (M+H) + , retention time 0.55 min (Method A).

[0710] The two isomers were separated by chiral preparative HPLC as white solids.

[0711] (S)-2-Chloro-5-(methylsulfinyl)pyridine (550 mg, 3.16 mmol).

[0712] (R)-2-Chloro-5-(methylsulfinyl)pyridine (500 mg, 2.87 mmol).

[0713] (S)-2-Hydrazino-5-(methylsulfinyl)pyridine

[0714]

[0715] To a solution of (S)-2-chloro-5-(methylsulfinyl)pyridine (200 mg, 1.15 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (350 mg, 5.74 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give (S)-2-hydrazino-5-(methylsulfinyl)pyridine (130 mg, 0.76 mmol, 66.1% yield) as a yellow solid. LC-MS: m / z = 172.0 (M + H) +, retention time of 0.37 minutes (Method A).

[0716] (S)-4-(5-hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile:

[0717]

[0718] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (165 mg, 0.76 mmol) and (S)-2-hydrazino-5-(methylsulfinyl)pyridine (130 mg, 0.76 mmol) in acetic acid (8.0 mL) was stirred at 120° C. for 1 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give (S)-4-(5-hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (52 mg, 0.15 mmol, 20.2% yield) as a white solid. LC-MS: m / z=339.0 (M+H) + , retention time 3.23 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.08(s,1H),8.73(s,2H),8.29-8.31(d,J=8.6Hz,2H),7 .90-7.91(d,J=8.5Hz,2H),7.81-7.91(d,J=8.5Hz,2H),2.89(s,3H),2.51(s,3H).

[0719] Example 23: Preparation of Compound 23

[0720] (R)-2-Hydrazino-5-(methylsulfinyl)pyridine

[0721]

[0722] To a solution of (R)-2-chloro-5-(methylsulfinyl)pyridine (350 mg, 2.01 mmol) (intermediate of Example 22) in ethanol (10.0 mL) was added hydrazine hydrate (610 mg, 10.05 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give (R)-2-hydrazino-5-(methylsulfinyl)pyridine (150 mg, 0.88 mmol, 43.6% yield) as a yellow solid. LC-MS: m / z = 172.0 (M + H) +, retention time of 0.37 minutes (Method A).

[0723] (R)-4-(5-hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile:

[0724]

[0725] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (190 mg, 0.88 mmol) and (R)-2-hydrazino-5-(methylsulfinyl)pyridine (150 mg, 0.88 mmol) in acetic acid (8.0 mL) was stirred at 120° C. for 1 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give (R)-4-(5-hydroxy-3-methyl-1-(5-(methylsulfinyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (60 mg, 0.18 mmol, 20.1% yield) as a white solid. LC-MS: m / z=339.0 (M+H) + , retention time 3.24 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.09(s,1H),8.73(s,2H),8.28-8.31(d,J=8.6Hz,2H),7 .89-7.91(d,J=8.3Hz,2H),7.81-7.83(d,J=8.3Hz,2H),2.89(s,3H),2.51(s,3H).

[0726] Example 24: Preparation of Compound 24

[0727] 3-((6-chloropyridin-3-yl)thio)2-propionic acid ethylhexyl ester

[0728]

[0729] A mixture of 5-bromo-2-chloropyridine (10.0 g, 52.1 mmol), 2-ethylhexyl 3-mercaptopropionate (13.6 g, 62.5 mmol), N,N-diisopropylethylamine (648 mg, 104.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.02 g, 10.4 mmol) and tris(dibenzylideneacetone)dipalladium (4.76 g, 5.2 mmol) in N,N-dimethylformamide (60.0 mL) was stirred at 120° C. under nitrogen for 12.0 hours and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to give ethylhexyl 3-((6-chloropyridin-3-yl)thio)2-propanoate (11.2 g, 34.04 mmol, 65.3% yield) as a yellow oil. LC-MS: m / z = 330.1 (M+H) + , retention time 2.31 minutes (Method A)

[0730] 6-Chloropyridine-3-thiol

[0731]

[0732] To a solution of ethylhexyl 3-((6-chloropyridin-3-yl)thio)2-propanoate (11.2 g, 34.04 mmol) in anhydrous tetrahydrofuran (30.0 mL) at -78 ° C., potassium tert-butoxide (51.1 mL, 51.1 mmol, 1 M in tetrahydrofuran) was added. The mixture was warmed to 0 ° C. and stirred for another 30 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=5 / 1) to give 6-chloropyridine-3-thiol (3.5 g, 24.1 mmol, 70.9% yield) as a yellow oil. LC-MS: m / z=289.1 (M+H) + , retention time 2.1 minutes (Method A)

[0733] 6-Chloropyridine-3-sulfinate methyl ester

[0734]

[0735] To a solution of 6-chloropyridine-3-thiol (3.5 g, 24.1 mmol) in methanol (30.0 mL) was added N-bromosuccinimide (9.0 g, 50.6 mmol). The mixture was stirred at room temperature for 1.0 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product 6-chloropyridine-3-sulfinic acid methyl ester (4.0 g, 20.94 mmol, 86.9% yield) was obtained as a yellow solid. LC-MS: m / z=192.1 (M+H) + , retention time 1.64 min (Method A). The product was used in the next step without purification.

[0736] 6-Chloropyridine-3-sulfenamide

[0737]

[0738] To a solution of methyl 6-chloropyridine-3-sulfinate (2.0 g, 10.47 mmol) in anhydrous tetrahydrofuran (15.0 mL) at -78 ° C., lithium bis(trimethylsilyl)amide (50.0 mL, 50.0 mmol, 1 M in tetrahydrofuran) was added. The mixture was stirred at -78 ° C. for 30 minutes, saturated aqueous ammonium chloride solution (10.0 mL) was added, and the mixture was stirred at room temperature for another 15 minutes. The reaction was extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=5 / 1) to give 6-chloropyridine-3-sulfinamide (1.5 g, 8.52 mmol, 81.4% yield) as a white solid. LC-MS: m / z=177.1 (M+H) + , retention time 1.36 minutes (Method A)

[0739] tert-Butyl ((6-chloropyridin-3-yl)sulfinyl)carbamate

[0740]

[0741] To a solution of 6-chloropyridine-3-sulfinamide (620 mg, 3.52 mmol) in anhydrous tetrahydrofuran (8.0 mL) at 0 ° C., lithium diisopropylamide (2.64 mL, 5.28 mmol, 2M in tetrahydrofuran) was added. The mixture was stirred at 0 ° C. for 1.0 hours, and di-tert-butyl dicarbonate (767 mg, 3.52 mmol) was added. The mixture was warmed to 20 ° C. and stirred for another 2.0 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain tert-butyl ((6-chloropyridin-3-yl)sulfinyl)carbamate (600 mg, 2.17 mmol, 61.7% yield) as a white solid. LC-MS: m / z=276.7 (M+H) + , retention time 1.84 minutes (Method A).

[0742] (Amino(6-chloropyridin-3-yl)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0743]

[0744] To a solution of tert-butyl ((6-chloropyridin-3-yl)sulfinyl)carbamate (600 mg, 2.17 mmol) in acetonitrile (10.0 mL) was added N-chlorosuccinimide (344 mg, 2.59 mmol). The mixture was stirred at room temperature for 1.0 hour and ammonia solution (5.0 mL, about 7 M in methanol) was added dropwise. The mixture was stirred for another 2 hours. The reaction was concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (amino(6-chloropyridin-3-yl)(oxo)-λ) as a white solid. 6 -sulfydene)carbamic acid tert-butyl ester (500 mg, 1.72 mmol, 79.2% yield). LC-MS: m / z=292.1 (M+H) + , retention time 1.72 minutes (Method A).

[0745] (Amino(6-hydrazinopyridin-3-yl)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0746]

[0747] To (amino (6-chloropyridin-3-yl) (oxo)-λ 6 To a solution of tert-butyl (6-thio)carbamate (100 mg, 0.34 mmol) in ethanol (3.0 mL) was added hydrazine hydrate (100 mg, 1.7 mmol, 85% in water). The mixture was stirred at 85 ° C for 45 minutes. The mixture was cooled and concentrated to dryness. The crude product (amino (6-hydrazinopyridin-3-yl) (oxo)-λ was obtained as a yellow syrup. 6 tert-Butyl-1,2-thiomethyl)carbamate (100 mg, crude product). LC-MS: m / z=288.0 (M+H)+, retention time 1.24 minutes (Method A). The crude product was used in the next step.

[0748] (Amino(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0749]

[0750] To methyl 2-(4-cyanophenyl)-3-oxobutanoate (73.8 mg, 0.34 mmol) and (amino(6-hydrazinopyridin-3-yl)(oxo)-λ 6To a solution of tert-butyl (6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(oxo)-λ-pyridin-1-yl)-1-(4-amino)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl (6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl) ... 6 -sulfydene)carbamic acid tert-butyl ester (50 mg, 0.11 mmol, 32.4% yield). LC-MS: m / z=455.0 (M+H) + , retention time 1.74 minutes (Method A).

[0751] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonylimideamide

[0752]

[0753] To (4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(oxo)-λ 6 To a solution of 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonylimide amide (4.0 mg, 0.011 mmol, 10.3% yield) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at 40° C. for 2.0 hours and concentrated. The residue was purified by reverse phase preparative HPLC to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonylimide amide (4.0 mg, 0.011 mmol, 10.3% yield) as a white solid. LC-MS: m / z=355.0 (M+H) + , retention time 3.11 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.93(s,1H),8.22-8.33(m,3H),7.97-7.98(d,J=5.5Hz,2H),7.53-7.55(d,J=5.8Hz,2H),3.82-4.61(s,3H),2.34(s,3H).

[0754] Example 25: Preparation of Compound 25

[0755] ((6-chloropyridin-3-yl)(dimethylamino)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0756]

[0757] To a solution of tert-butyl ((6-chloropyridin-3-yl)sulfinyl)carbamate (intermediate of Example 24) (1.0 g, 3.82 mmol) in acetonitrile (20.0 mL) was added N-chlorosuccinimide (6.10 g, 4.58 mmol). The mixture was stirred at room temperature for 1.0 hour and a dimethylamine solution (5.0 mL, 2 M in tetrahydrofuran) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain ((6-chloropyridin-3-yl)(dimethylamino)(oxo)-λ as a white solid. 6 -sulfydene)carbamic acid tert-butyl ester (800 mg, 2.51 mmol, 65.7% yield). LC-MS: m / z=320.1 (M+H) + , retention time 1.87 minutes (Method A).

[0758] ((Dimethylamino)(6-hydrazinopyridin-3-yl)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0759]

[0760] To ((6-chloropyridin-3-yl)(dimethylamino)(oxo)-λ 6 To a solution of tert-butyl ((dimethylamino)(6-hydrazinopyridin-3-yl)(oxo)-λ-yl)carbamate (800 mg, 2.51 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (740 mg, 12.6 mmol, 85% in water). The mixture was stirred at 85° C. overnight. The mixture was cooled and concentrated to dryness. The crude product ((dimethylamino)(6-hydrazinopyridin-3-yl)(oxo)-λ-yl) was obtained as a yellow syrup. 6 -butyl thio)carbamate (600 mg, 1.90 mmol, 75.9%). LC-MS: m / z=316.0 (M+H)+, retention time 1.68 min (Method A). The crude product was used in the next step.

[0761] ((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(dimethyl-amino)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0762]

[0763] To methyl 2-(4-cyanophenyl)-3-oxobutanoate (412.3 mg, 1.90 mmol) and ((dimethylamino)(6-hydrazinopyridin-3-yl)(oxo)-λ 6To a solution of tert-butyl (600 mg, 1.90 mmol) of thio)carbamate (600 mg, 1.90 mmol) in ethanol (10.0 mL) was added p-toluenesulfonic acid monohydrate (72.2 mg, 0.38 mmol). The mixture was stirred at 90° C. in a sealed tube for 12.0 hours and cooled to precipitate a solid. The solid was filtered, washed with ethanol, and dried to give ((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(dimethylamino)(oxo)-λ as a white solid. 6 -sulfydene)-carbamic acid tert-butyl ester (400 mg, 0.83 mmol, 43.7% yield). LC-MS: m / z=483.0 (M+H) + , retention time 2.08 minutes (Method A).

[0764] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N,N-dimethylpyridine-3-sulfonylimideamide

[0765]

[0766] To ((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(dimethylamino)(oxo)-λ 6 To a solution of tert-butyl 4-thiophenyl)carbamate (400 mg, 0.83 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (10.0 mL). The mixture was stirred at 40 ° C for 2.0 hours and concentrated. The residue was triturated with ethyl acetate and filtered to give 6- (4- (4-cyanophenyl) -5-hydroxy-3-methyl-1H-pyrazol-1-yl) -N, N-dimethylpyridine-3-sulfonylimide amide (170 mg, 0.45 mmol, 53.6% yield) as a yellow solid. LC-MS: m / z = 383.0 (M + H) + , retention time 4.13 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.16(s,1H),8.77(s,1H),8.66(s,1H),8.30-8.32(d,J=7.0Hz ,1H),7.89-7.91(d,J=8.7Hz,2H),7.81-7.83(d,J=8.7Hz,2H),2.62(s,6H),2.49(s,3H).

[0767] Example 26: Preparation of Compound 26

[0768] ((6-chloropyridin-3-yl)(methylamino)(oxo)-λ 6-sulfyminyl)carbamic acid tert-butyl ester

[0769]

[0770] To a solution of tert-butyl ((6-chloropyridin-3-yl)sulfinyl)carbamate (intermediate of Example 24) (500 mg, 1.81 mmol) in acetonitrile (10.0 mL) was added N-chlorosuccinimide (480 mg, 3.62 mmol). The mixture was stirred at room temperature for 1.0 hour and methylamine solution (2.0 mL, 2 M in tetrahydrofuran) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain ((6-chloropyridin-3-yl)(methylamino)(oxo)-λ as a white solid. 6 -sulfydene)carbamic acid tert-butyl ester (300 mg, 0.98 mmol, 54.3% yield). LC-MS: m / z=305.8.0 (M+H) + , retention time 1.73 minutes (Method A).

[0771] ((6-Hydrazinopyridin-3-yl)(methylamino)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0772]

[0773] To ((6-chloropyridin-3-yl)(methylamino)(oxo)-λ 6 To a solution of tert-butyl (6-hydrazinopyridin-3-yl)(methylamino)(oxo)-λ-thio)carbamate (300 mg, 0.98 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (287 mg, 4.9 mmol, 85% in water). The mixture was stirred at 85 ° C. overnight. The mixture was cooled and concentrated to dryness. The crude product ((6-hydrazinopyridin-3-yl)(methylamino)(oxo)-λ-thio)-carbamate was obtained as a yellow syrup. 6 -butyl thio)carbamate (300 mg, crude product). LC-MS: m / z=302.0 (M+H)+, retention time 1.3 minutes (Method A). The crude product was used in the next step.

[0774] ((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(methyl-amino)(oxo)-λ 6 -sulfyminyl)carbamic acid tert-butyl ester

[0775]

[0776] To methyl 2-(4-cyanophenyl)-3-oxobutanoate (212 mg, 0.98 mmol) and ((6-hydrazinopyridin-3-yl)(methylamino)(oxo)-λ 6 To a solution of tert-butyl (6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(methylamino)(oxo)-λ-pyrazol-1-yl)-1-yl)-1-methyl-1H-pyrazol ... 6 -sulfydene)carbamic acid tert-butyl ester (50 mg, 0.11 mmol, 10.9% yield). LC-MS: m / z=469.0 (M+H) + , retention time 1.80 min (Method A).

[0777] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-methylpyridine-3-sulfonylimideamide

[0778]

[0779] To ((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(methylamino)(oxo)-λ 6 To a solution of tert-butyl 4-thiophenyl)carbamate (50 mg, 0.11 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at 40 ° C for 2.0 hours and concentrated. The residue was purified by reverse phase preparative HPLC to give 6- (4- (4-cyanophenyl) -5-hydroxy-3-methyl-1H-pyrazol-1-yl) -N-methylpyridine-3-sulfonylimide amide (formate) (13.2 mg, 0.04 mmol, 32.6% yield) as a yellow solid. LC-MS: m / z = 369.0 (M + H) + , retention time 3.37 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.81(s,1H),8.52(s,1H),8.15(s,2H),7.95-7.97(d,J=7.2Hz,2H),7.57-7.59(d,J=7.3Hz,2H),2.43(s,3H),2.37(s,3H).

[0780] Example 27: Preparation of Compound 27

[0781] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-(methylsulfonyl)nicotinamide

[0782]

[0783] A mixture of 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (intermediate of Example 10) (220.0 mg, 0.69 mmol), methanesulfonamide (72.1 mg, 0.76 mmol), benzotriazole-1-yl-oxytripyrrolidinyl hexafluorophosphate (359 mg, 0.69 mmol) and triethylamine (140 mg, 1.37 mmol) in dichloromethane (10.0 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-(methylsulfonyl)nicotinamide (formate) (130.8 mg, 0.30 mmol, 42.8% yield) as a white solid. LC-MS: m / z = 398.1 (M+H) + , retention time 3.58 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.56(s,1H),8.46-8.44(m,1H),7.90-7.88(m,2H),7.82-7.80(m,2H),3.39(s,3H),2.50(s,3H).

[0784] Example 28: Preparation of Compound 28

[0785] tert-Butyl 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate

[0786]

[0787] A solution of ethyl 2-(4-chlorophenyl)-3-oxobutanoate (intermediate of Example 1) (200 mg, 0.83 mmol) and tert-butyl 6-hydrazinenicotinate (intermediate of Example 10) (173 mg, 0.83 mmol) in acetic acid (5.0 mL) was stirred at 120 ° C. for 1.0 hour and concentrated to dryness. The residue was purified by flash chromatography (methanol / dichloromethane=1 / 10) to give tert-butyl 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate (220 mg, 0.57 mmol, 68.8% yield) as a yellow solid. LC-MS: m / z=386.1 (M+H) + , retention time 2.41 minutes (Method A).

[0788] 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid

[0789]

[0790] To a solution of tert-butyl 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate (220 mg 0.57 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at 40 ° C. for 2.0 hours and concentrated. The residue was triturated with ethyl acetate and filtered to give 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (150 mg, 0.46 mmol, 80% yield) as a yellow solid. LC-MS: m / z = 330.1 (M + H) + , retention time 1.94 minutes (Method A).

[0791] 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-(methylsulfonyl)nicotinamide

[0792]

[0793] A mixture of 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.61 mmol), methanesulfonamide (69 mg, 0.73 mmol), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (319 mg, 0.61 mmol), and triethylamine (308 mg, 3.06 mmol) in dichloromethane (5.0 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC to give 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-N-(methylsulfonyl)nicotinamide (172.6 mg, 0.43 mmol, 70.5% yield) as a white solid. LC-MS: m / z=407.1 (M+H) + , retention time 4.55 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ12.77-12.75(m,2H),8.98(s,1H),8.60-8.43(m,3H),7.67-7.65(m,2H),7.45-7.43(m,2H),3.41(s,3H),2.42(s,3H).

[0794] Example 29: Preparation of Compound 29

[0795] 6-Hydrazinopyridine-3-sulfonamide

[0796]

[0797] To a solution of 6-chloropyridine-3-sulfonamide (1.63 g, 8.5 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 6-hydrazinopyridine-3-sulfonamide (600 mg, 3.20 mmol, 37.7% yield) as a yellow solid. LC-MS: m / z = 189.0 (M + H) + , retention time 0.32 min (Method A).

[0798] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide

[0799]

[0800] A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (500 mg, 2.30 mmol) and 6-hydrazinopyridine-3-sulfonamide (432 mg, 2.30 mmol) (intermediate of Example 11) in acetic acid (5.0 mL) was stirred at 120 ° C for 1.0 hour and concentrated to dryness. The residue was triturated with ethyl acetate and filtered to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide (450 mg, 1.27 mmol, 55.1% yield) as a yellow solid. LC-MS: m / z = 356.0 (M + H) + , retention time 1.70 minutes (Method A).

[0801] 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide

[0802]

[0803] To a solution of 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide (450 mg, 1.27 mmol) in dichloromethane / methanol (10.0 mL / 1.0 mL) was added (diazomethyl)trimethylsilane (0.76 mL, 1.52 mmol, 2 M in hexanes). The mixture was stirred at 25° C. overnight and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol=100 / 2) to afford two isomers, 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide (234 mg, 0.63 mmol, 50% yield), as yellow solids. LC-MS: m / z=370.0 [M+H] + , retention time 1.80 min (Method A). Both isomers were used directly in the next step without separation.

[0804] N-((6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide

[0805]

[0806] To a solution of 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide (234 mg, 0.63 mmol) in anhydrous tetrahydrofuran (10.0 mL) at 0° C. was added triethylamine (127 mg, 1.26 mmol) and acetyl chloride (60 mg, 0.76 mmol). The mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol=20 / 1) to afford two isomers, N-((6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)-acetamide and N-((6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (200 mg, 0.49 mmol, 77.2% yield) as yellow solids. LC-MS: m / z=412.0 [M+H] + , retention time 1.86 min (Method A). Both isomers were used in the next step without separation.

[0807] N-((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide:

[0808]

[0809] To a solution of N-((6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide and N-((6-(4-(4-cyanophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (200 mg, 0.49 mmol) in N,N-dimethylformamide (10.0 mL) was added lithium chloride (206 mg, 4.9 mmol). The mixture was stirred at 60° C. overnight. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give N-((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (formate) (29.8 mg, 0.07 mmol, 13.7% yield) as a white solid. LC-MS: m / z = 398.1 (M+H) + , retention time 3.97 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.72(s,2H),8.89(d,J=1.0Hz,1H),8.63(d,J=4.6Hz,1H),8.38- 8.35(m,1H),8.14(s,1H),7.92-7.90(m,2H),7.80-7.78(m,2H),2.48(s,3H),1.93(s,3H).

[0810] Example 30: Preparation of Compound 30

[0811] 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide

[0812]

[0813] A solution of ethyl 2-(4-chlorophenyl)-3-oxobutanoate (600 mg, 2.5 mmol) (intermediate of Example 1) and 6-hydrazinopyridine-3-sulfonamide (intermediate of Example 11) (470 mg, 2.5 mmol) in acetic acid (8.0 mL) was stirred at 120 ° C for 1.0 hour and concentrated to dryness. The residue was triturated with ethyl acetate and filtered to give 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide (610 mg, 1.67 mmol, 67.03% yield) as a yellow solid. LC-MS: m / z = 365.0 (M + H) + , retention time 1.89 minutes (Method A).

[0814] 6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide

[0815]

[0816] To a solution of 6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide (610 mg, 1.67 mmol) in dichloromethane / methanol (10.0 mL / 1.0 mL) was added (diazomethyl)trimethylsilane (1.0 mL, 2.0 mmol, 2 M in hexanes). The mixture was stirred at 25° C. overnight and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol=100 / 2) to afford two isomers, 6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide (550 mg, 1.46 mmol, 87.1% yield), as yellow solids. LC-MS: m / z=379.0 [M+H] + , retention time 1.98 min (Method A). Both isomers were used directly in the next step without separation.

[0817] N-((6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide and N-((6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide

[0818]

[0819] To a solution of 6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-3-sulfonamide and 6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-sulfonamide (550 mg, 1.46 mmol) in anhydrous tetrahydrofuran (10.0 mL) at 0° C. was added triethylamine (295 mg, 2.92 mmol) and acetyl chloride (136 mg, 1.75 mmol). The mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by flash chromatography (dichloromethane / methanol=20 / 1) to afford two isomers, N-((6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide and N-((6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (500 mg, 1.19 mmol, 81.5% yield) as yellow solids. LC-MS: m / z=421.0 [M+H] + , retention time 2.05 min (Method A). Both isomers were used in the next step without separation.

[0820] N-((6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide

[0821]

[0822] To a solution of N-((6-(4-(4-chlorophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide and N-((6-(4-(4-chlorophenyl)-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (500 mg, 1.19 mmol) in N,N-dimethylformamide (10.0 mL) was added lithium chloride (500 mg, 11.9 mmol). The mixture was stirred at 60° C. overnight. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give N-((6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfonyl)acetamide (formate) (78.9 mg, 0.17 mmol, 14.7% yield) as a white solid. LC-MS: m / z = 407.0 (M+H) + , retention time 4.62 minutes (Method A). 1HNMR(400MHz,DMSO-d6)δ12.61(s,2H),8.87(d,J=1.0Hz,1H),8.62(d,J=4.2Hz,1H),8.38- 8.35(m,1H),8.14(s,1H),7.68-7.66(m,2H),7.46-7.44(m,2H),2.42(s,3H),1.91(s,3H).

[0823] Example 31: Preparation of Compound 31

[0824] 4-(5-Hydroxy-1-(5-isocyanatopyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0825]

[0826] A mixture of 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (intermediate of Example 10) (150 mg, 0.47 mmol), diphenylphosphonic acid azide (194 mg, 0.71 mmol) and triethylamine (95 mg, 0.94 mmol) in toluene (5.0 mL) was stirred at 110 ° C for 3 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product 4-(5-hydroxy-1-(5-isocyanatopyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)benzonitrile (150 mg, crude product) was obtained as a yellow syrup. LC-MS: m / z=318.0 (M+H) + , retention time 1.27 min (Method A). The crude product was used in the next step.

[0827] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)morpholine-4-carboxamide

[0828]

[0829] A mixture of 4-(5-hydroxy-1-(5-isocyanatopyridin-2-yl)-3-methyl-1H-pyrazol-4-yl)benzonitrile (150 mg, crude product), morpholine (87 mg, 1.0 mmol) in dichloromethane (5.0 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)morpholine-4-carboxamide (formate) (13.8 mg, 0.03 mmol, 7.26% yield) as a white solid. LC-MS: m / z=405.0 (M+H) + , retention time 3.89 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.81(s,1H),8.61(s,1H),8.23(d,J=0.6Hz,1H),8.15(s,1H),7.99-7.96 (m,1H),7.94-7.92(m,2H),7.76-7.74(m,2H),3.64-3.62(m,4H),3.47-3.44(m,4H),2.35(s,3H).

[0830] Example 32: Preparation of Compound 32

[0831] tert-Butyl 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinate

[0832]

[0833] To a solution of tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate (1.0 g, 2.66 mmol) in dichloromethane / methanol (15.0 mL / 2.0 mL) was added (diazomethyl)trimethylsilane (2.0 mL, 4.0 mmol, 2 M in hexane). The mixture was stirred at 25 ° C. overnight and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinate (400 mg, 1.02 mmol, 38.5% yield) as a yellow solid. LC-MS: m / z=391.0 [M+H] + , retention time 2.29 minutes (Method A).

[0834] 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid

[0835]

[0836] To a solution of tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinate (400 mg 1.19 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at 40 ° C. for 2.0 hours and concentrated. The residue was triturated with ethyl acetate and filtered to give 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (290 mg, 0.87 mmol, 73.0% yield) as a yellow solid. LC-MS: m / z = 335.1 (M + H) + , retention time 1.85 min (Method A).

[0837] 4-(1-(5-Isocyanatopyridin-2-yl)-5-methoxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0838]

[0839] A mixture of 6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.60 mmol), diphenylphosphonic acid azide (247 mg, 0.90 mmol) and triethylamine (121 mg, 1.2 mmol) in toluene (5.0 mL) was stirred at 110 ° C for 3 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product 4-(1-(5-isocyanatopyridin-2-yl)-5-methoxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (200 mg, crude product) was obtained as a yellow syrup. LC-MS: m / z = 332.0 (M + H) + , retention time 1.85 min (Method A). The crude product was used in the next step.

[0840] tert-Butyl 4-((6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate

[0841]

[0842] A mixture of 4-(1-(5-isocyanatopyridin-2-yl)-5-methoxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (200 mg, crude product) and tert-butyl piperazine-1-carboxylate (334 mg, 1.8 mmol) in dichloromethane (8.0 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain tert-butyl 4-((6-(4-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate (150 mg, 0.29 mmol, 48.3% yield) as a yellow solid. LC-MS: m / z = 517.9 [M+H] + , retention time 1.93 minutes (Method A).

[0843] tert-Butyl 4-((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate

[0844]

[0845] To a solution of tert-butyl 4-((6-(4-cyanophenyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate (150 mg, 0.29 mmol) in N,N-dimethylformamide (6.0 mL) was added lithium chloride (121 mg, 2.9 mmol). The mixture was stirred at 60 ° C overnight. The solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give tert-butyl 4-((6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate (90 mg, 0.18 mmol, 62.1% yield) as a white solid. LC-MS: m / z=504.0 (M+H) + , retention time 2.05 minutes (Method A).

[0846] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide hydrochloride

[0847]

[0848] To a mixture of 4-((6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)piperazine-1-carboxylate (90 mg, 0.18 mmol) in methanol (10.0 mL) was added hydrochloric acid solution (3.0 mL, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 2.0 hours and concentrated. The residue was triturated with diethyl ether and filtered to give N-(6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperazine-1-carboxamide hydrochloride (61.5 mg, 0.14 mmol, 77.7% yield) as a white solid. LC-MS: m / z=404.0 (M+H) + , retention time 2.67 minutes (Method A). 1 HNMR(400MHz,D2O)δ7.80(s,1H),7.56-7.52(m,2H),7.38-7.32(m,4H),3.62(s,4H),3.21(s,4H),2.18(s,3H).

[0849] Example 33: Preparation of Compound 33

[0850] 2-Chloro-5-(cyclopropylthio)pyridine

[0851]

[0852] To a mixture of 6-chloropyridine-3-thiol (the intermediate of Example 24) (350 mg, 2.41 mmol) and cyclopropyl bromide (430 mg, 3.62 mmol) in dimethyl sulfoxide (8.0 mL) was added sodium tert-butoxide (278 mg, 2.89 mmol). The mixture was stirred overnight at 70 ° C in a sealed tube. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-chloro-5- (cyclopropylthio) pyridine (250 mg, 1.35 mmol, 56% yield) as a yellow oil. LC-MS: m / z = 186.0 (M + H) + , retention time 1.97 minutes (Method A).

[0853] 2-Chloro-5-(cyclopropylsulfinyl)pyridine

[0854]

[0855] 3-Chlorobenzoic acid (286 mg, 1.42 mmol, 85%) was added to a solution of 2-chloro-5-(cyclopropylthio)pyridine (250 mg, 1.35 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(cyclopropylsulfinyl)pyridine (130 mg, 0.65 mmol, 47.9% yield) as a white solid. LC-MS: m / z=202.1 (M+H) + , retention time 1.49 minutes (Method A).

[0856] (6-Chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone

[0857]

[0858] To a mixture of 2-chloro-5-(cyclopropylsulfinyl)pyridine (130 mg, 0.65 mmol) and ammonium carbamate (202 mg, 2.6 mmol) in methanol (8.0 mL) was added (diacetoxyiodine)benzene (628 mg, 1.95 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ as a yellow solid. 6 -sulfonone (100 mg, 0.46 mmol, 71.2% yield). LC-MS: m / z=217.1 (M+H) + , retention time 1.45 minutes (Method A).

[0859] Cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 -sulfonone

[0860]

[0861] To (6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6To a solution of -sulfonone (100 mg, 0.46 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (280 mg, 4.6 mmol, 85% in water). The mixture was stirred at 90 ° C overnight. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product cyclopropyl (6-hydrazinopyridin-3-yl) (imino) -λ was obtained as a yellow syrup. 6 -sulfonone (90 mg, 0.42 mmol, 92.3% yield). LC-MS: m / z=213.0 (M+H)+, retention time 0.35 min (Method A). The product was used directly in the next step.

[0862] 4-(1-(5-(cyclopropanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0863]

[0864] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (91 mg, 0.42 mmol) and cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 A mixture of -sulfonone (90 mg, 0.42 mmol) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(cyclopropanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) (10.6 mg, 0.024 mmol, 5.93% yield) as a white solid. LC-MS: m / z=380.0 (M+H) + , retention time 3.66 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.82(s,1H),8.57(s,1H),8.24-8.26(d,J=6.9Hz,1H),8.14(s,1H),7.94-7.96(d,J=8.6Hz, 2H),7.65-7.67(d,J=7.6Hz,2H),4.44(s,1H),2.71-2.72(m,1H),2.40(s,3H),1.12-1.14(m,1H),0.90-1.00(m,3H).

[0865] Example 34: Preparation of Compound 34

[0866] 2-Chloro-5-(cyclobutylthio)pyridine

[0867]

[0868] To a mixture of 6-chloropyridine-3-thiol (the intermediate of Example 24) (500 mg, 3.45 mmol) and cyclopropyl bromide (615 mg, 5.18 mmol) in dimethyl sulfoxide (10.0 mL) was added sodium tert-butoxide (398 mg, 4.13 mmol). The mixture was stirred overnight at 70 ° C in a sealed tube. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to give 2-chloro-5-(cyclobutylthio)pyridine (400 mg, 2.01 mmol, 58.3% yield) as a yellow oil. LC-MS: m / z=200.0 (M+H) + , retention time 2.07 minutes (Method A).

[0869] 2-Chloro-5-(cyclobutylsulfinyl)pyridine

[0870]

[0871] 3-Chlorobenzoic acid (427 mg, 2.11 mmol, 85%) was added to a solution of 2-chloro-5-(cyclobutylthio)pyridine (400 mg, 2.01 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(cyclobutylsulfinyl)pyridine (330 mg, 1.53 mmol, 76.4% yield) as a white solid. LC-MS: m / z=216.0 (M+H) + , retention time 1.60 min (Method A).

[0872] (6-Chloropyridin-3-yl)(cyclobutyl)(imino)-λ 6 -sulfonone

[0873]

[0874] To a mixture of 2-chloro-5-(cyclobutylsulfinyl)pyridine (330 mg, 1.53 mmol) and ammonium carbamate (475 mg, 6.11 mmol) in methanol (12.0 mL) was added (diacetoxyiodine)benzene (1.48 g, 4.58 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-chloropyridin-3-yl)(cyclobutyl)(imino)-λ as a yellow solid. 6 -sulfonone (250 mg, 1.09 mmol, 71.0% yield). LC-MS: m / z=231.1 (M+H) + , retention time 1.56 minutes (Method A).

[0875] Cyclobutyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 -sulfonone

[0876]

[0877] To (6-chloropyridin-3-yl)(cyclobutyl)(imino)-λ 6 To a solution of -sulfonone (250 mg, 1.09 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (332 mg, 5.45 mmol, 85% in water). The mixture was stirred at 90 ° C overnight. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product cyclobutyl (6-hydrazinopyridin-3-yl) (imino) -λ was obtained as a yellow syrup. 6 -sulfonone (150 mg, 0.66 mmol, 60.9% yield). LC-MS: m / z=227.0 (M+H)+, retention time 0.68 min (Method A). The product was used directly in the next step.

[0878] 4-(1-(5-(cyclobutanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0879]

[0880] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (143 mg, 0.66 mmol) and cyclobutyl(6-hydrazinopyridin-3-yl)(imino)-λ 6A mixture of -sulfonone (150 mg, 0.66 mmol) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(cyclobutanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) (78 mg, 0.18 mmol, 26.9% yield) as a white solid. LC-MS: m / z=394.1.0 (M+H) + , retention time 3.85 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.15(s,1H),8.80(s,1H),8.62-8.64(d,J=9.1Hz,1H),8.30-8.33(d,J=9.1Hz,1H),8.14(s,1H),7.90-7.92(d,J=7 .8Hz,2H),7.79-7.81(d,J=7.7Hz,2H),4.49(s,1H),3.99-4.03(m,2H) ,2.48(s,3H),2.31-2.33(m,2H),2.01-2.12(m,2H),1.80-1.88(m,2H).

[0881] Example 35: Preparation of Compound 35

[0882] 2-Chloro-5-(cyclopentylthio)pyridine

[0883]

[0884] To a mixture of 6-chloropyridine-3-thiol (the intermediate of Example 24) (500 mg, 3.45 mmol) and bromocyclopentane (770 mg, 5.18 mmol) in dimethyl sulfoxide (10.0 mL) was added sodium tert-butoxide (398 mg, 4.13 mmol). The mixture was stirred overnight at 70 ° C in a sealed tube. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-chloro-5- (cyclopentylthio) pyridine (400 mg, 1.87 mmol, 54.4% yield) as a yellow oil. LC-MS: m / z = 214.0 (M + H) + , retention time 2.13 minutes (Method A).

[0885] 2-Chloro-5-(cyclopentylsulfinyl)pyridine

[0886]

[0887] 3-Chlorobenzoic acid (454 mg, 2.24 mmol, 85%) was added to a solution of 2-chloro-5-(cyclopentylthio)pyridine (400 mg, 1.87 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-5-(cyclopentylsulfinyl)pyridine (350 mg, 1.43 mmol, 76.7% yield) as a white solid. LC-MS: m / z=230.0 (M+H) + , retention time 1.74 minutes (Method A).

[0888] (6-Chloropyridin-3-yl)(cyclopentyl)(imino)-λ 6 -sulfonone

[0889]

[0890] To a mixture of 2-chloro-5-(cyclopentylsulfinyl)pyridine (350 mg, 1.43 mmol) and ammonium carbamate (446 mg, 5.72 mmol) in methanol (12.0 mL) was added (diacetoxyiodine)benzene (1.39 g, 4.30 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-chloropyridin-3-yl)(cyclopentyl)(imino)-λ as a yellow solid. 6 -sulfonone (250 mg, 1.02 mmol, 71.6% yield). LC-MS: m / z=245.1 (M+H) + , retention time 1.59 minutes (Method A).

[0891] Cyclopentyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 -sulfonone

[0892]

[0893] To (6-chloropyridin-3-yl)(cyclopentyl)(imino)-λ 6To a solution of -sulfonone (250 mg, 1.02 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (310 mg, 5.1 mmol, 85% in water). The mixture was stirred at 90 ° C overnight. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product cyclopentyl (6-hydrazine pyridin-3-yl) (imino) -λ was obtained as a yellow syrup. 6 -sulfonone (200 mg, 0.83 mmol, 81.7% yield). LC-MS: m / z=241.0 (M+H) + , retention time 0.96 min (Method A). The crude product was used in the next step.

[0894] 4-(1-(5-(cyclopentanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0895]

[0896] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (180 mg, 0.83 mmol) and cyclopentyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 A mixture of 4-(1-(5-(cyclopentanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) (118 mg, 0.26 mmol, 31.4% yield) was stirred at 120° C. for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(cyclopentanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) as a white solid (118 mg, 0.26 mmol, 31.4% yield). LC-MS: m / z=408.0 (M+H) + , retention time 4.07 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.15(s,1H),8.83(s,1H),8.63-8.65(d,J=8.6Hz,1H),8.33-8.36(d,J=8.6Hz,1H),8.14(s,1H),7.90-7. 92(d,J=8.6Hz,2H),7.78-7.80(d,J=8.6Hz,2H),4.43(s,2H),3.67-3.71(m,1H),2.48(m,3H),1.75-1.92(m,4H),1.52-1.62(m,4H).

[0897] Example 36: Preparation of Compound 36

[0898] (6-Bromo-4-methylpyridin-3-yl)dimethylphosphine oxide

[0899]

[0900] By 2- bromo -5- iodo -4- methylpyridine (800mg, 2.69mmol), dimethyl phosphine oxide (314mg4.04mmol), triethylamine (817mg, 8.07mmol), 4,5- bis (diphenylphosphino) -9,9- dimethylxanthene (310mg, 0.54mmol) and tris (dibenzylideneacetone) dipalladium (492mg, 0.54mmol) in 1,4- dioxane (15.0mL) mixture is stirred at 50 DEG C under nitrogen overnight. The reaction mixture is filtered with celite, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain (6- bromo -4- methylpyridin-3-yl) dimethyl phosphine oxide (600mg, 2.42mmol, 89.9% yield) as yellow oil. LC-MS: m / z = 247.9 [M+H] + , retention time = 1.44 minutes (Method A).

[0901] (6-Hydrazino-4-methylpyridin-3-yl)dimethylphosphine oxide

[0902]

[0903] To a solution of (6-bromo-4-methylpyridin-3-yl)dimethylphosphine oxide (600 mg, 2.42 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (760 mg, 12.1 mmol, 85% in water). The mixture was stirred at 90 ° C overnight. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (6-hydrazino-4-methylpyridin-3-yl)dimethylphosphine oxide (600 mg, crude product) was obtained as a yellow syrup. LC-MS: m / z = 200.0 (M + H) +, retention time of 0.29 minutes (Method A).

[0904] 4-(1-(5-(dimethylphosphoryl)-4-methylpyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[0905]

[0906] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (163 mg, 0.75 mmol) and (6-hydrazino-4-methylpyridin-3-yl)dimethylphosphine oxide (150 mg, 0.75) in acetic acid (5.0 mL) was stirred at 100 ° C. for 2.0 hours and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(dimethylphosphoryl)-4-methylpyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (formate) (20.3 mg, 0.05 mmol, 6.57% yield) as a white solid. LC-MS: m / z = 367.1 (M + H) + , retention time 3.54 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.58-8.56(m,1H),8.34(s,1H),7.91-7.89(m,2H),7.79-7.77(m,2H),2.65(s,3H),2.46(s,3H),1.80-1.77(m,6H).

[0907] Example 37: Preparation of Compound 37

[0908] 1-(6-chloro-4-methylpyridin-3-yl)pyrrolidin-2-one

[0909]

[0910] By 5- bromo -2- chloro -4- methylpyridine (1.0g, 4.85mmol), dimethylphosphine oxide (824mg 9.7mmol), cesium carbonate (2.62g, 8.07mmol), 4,5- bis (diphenylphosphino) -9,9- dimethylxanthene (560mg, 0.97mmol) and tris (dibenzylideneacetone) dipalladium (457mg, 0.5mmol) in 1,4- dioxane (20.0mL) mixture is stirred at 100 DEG C under nitrogen overnight.The reaction mixture is filtered with celite, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by flash chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain 1- (6- chloro -4- methylpyridin-3-yl) pyrrolidin-2-one (150mg, 0.71mmol, 14.7% yield) as yellow oil. LC-MS: m / z = 211.1 [M+H] + , retention time = 1.58 minutes (Method A).

[0911] 1-(6-Hydrazino-4-methylpyridin-3-yl)pyrrolidin-2-one

[0912]

[0913] To a solution of 1-(6-chloro-4-methylpyridin-3-yl)pyrrolidin-2-one (150 mg, 0.71 mmol) in ethanol (4.0 mL) was added hydrazine hydrate (2.0 mL, 85% in water). The mixture was stirred at 130 ° C in a sealed tube for 18.0 hours. The mixture was cooled and concentrated to dryness. The crude product 1-(6-hydrazino-4-methylpyridin-3-yl)pyrrolidin-2-one (130 mg, crude product) was obtained as a yellow oil. LC-MS: m / z = 207.1 [M + H] + , retention time = 0.43 min (Method A). The crude product was used in the next step.

[0914] 4-(5-hydroxy-3-methyl-1-(4-methyl-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0915]

[0916] A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (154 mg, 0.71 mmol) and 1-(6-hydrazino-4-methylpyridin-3-yl)pyrrolidin-2-one (130 mg, crude product) in acetic acid (5.0 mL) was stirred at 100 ° C. for 2.0 hours and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(4-methyl-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (13.2 mg, 0.03 mmol, 3.53% yield) as a white solid. LC-MS: m / z = 374.1 (M + H) + , retention time 4.15 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.27(s,2H),7.95-7.93(m,2H),7.72-7.70(m,2H),3.68(s,2H),2.54-2.33(m,5H),2.22(s,3H),2.15–2.13(m,2H).

[0917] Example 38: Preparation of Compound 38

[0918] 6-Chloro-4-methylpyridine-3-sulfonyl chloride

[0919]

[0920] Sulfur dioxide solution is prepared by adding thionyl chloride (2.42mL) into the stirred water (15.0mL) containing copper chloride (I) (45mg, 0.45mmol). The solution is stirred at room temperature overnight. 6-chloro-4-methylpyridine-3-amine (1.0g, 7.04mmol) is added in batches into the concentrated hydrochloric acid solution (8.0mL) of stirring. The mixture is stirred until all solids dissolve, and then cooled to-5 ℃. Sodium nitrite (3.0g, 42.8mmol) solution dissolved in water (10.0mL) is added dropwise into the mixture, while the temperature is maintained between-5 ℃ and 0 ℃. After the addition is complete, the resulting mixture is stirred for 30 minutes, and then dropwise added into the sulfur dioxide aqueous solution. During the addition, the temperature is maintained below 0 ℃. After the addition, the mixture is stirred for 1.0 hours below 0 ℃, and then filtered. The filter cake is washed with ice water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-chloro-4-methylpyridine-3-sulfonyl chloride (350 mg, 1.55 mmol, 21.9% yield) as a gray solid. LC-MS: m / z=226.0 (M+H) + , retention time 2.00 min (Method A).

[0921] 6-Chloro-4-methylpyridine-3-sulfonamide

[0922]

[0923] To a solution of 6-chloro-4-methylpyridine-3-sulfonyl chloride (350 mg, 1.55 mmol) in anhydrous tetrahydrofuran (10.0 mL) at 0 ° C., ammonia solution (2.0 mL, 0.5 M in 1,4-dioxane) was added. The mixture was stirred at room temperature for 3.0 hours and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 6-chloro-4-methylpyridine-3-sulfonamide (200 mg, 0.97 mmol, 62.6% yield) as a white solid. LC-MS: m / z = 207.1 (M + H) + , retention time 1.39 minutes (Method A).

[0924] 6-Hydrazino-4-methylpyridine-3-sulfonamide

[0925]

[0926] To a solution of 6-chloro-4-methylpyridine-3-sulfonamide (200 mg, 0.97 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (5.0 mL, 85% in water). The mixture was stirred at 90 ° C in a sealed tube for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 6-hydrazino-4-methylpyridine-3-sulfonamide (180 mg, 0.89 mmol, 91.8% yield) as a yellow solid. LC-MS: m / z = 203.0 (M + H) + , retention time 0.32 min (Method A).

[0927] 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-4-methylpyridine-3-sulfonamide

[0928]

[0929] A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (193 mg, 0.89 mmol) and 6-hydrazino-4-methylpyridine-3-sulfonamide (180 mg, 0.89 mmol) in acetic acid (5.0 mL) was stirred at 100 ° C. for 2.0 hours and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-4-methylpyridine-3-sulfonamide (60 mg, 0.16 mmol, 18.3% yield) as a white solid. LC-MS: m / z = 370.0 (M + H) + , retention time 4.02 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.11(s,1H),8.77(s,1H),8.52(s,1H),8.89-7.91(d,J =7.4Hz,2H),7.82-7.84(d,J=7.9Hz,2H),7.68(s,1H),3.34(s,3H),2.67(s,3H).

[0930] Example 39: Preparation of Compound 39

[0931] N-(6-chloro-4-methylpyridin-3-yl)methanesulfonamide

[0932]

[0933] Methanesulfonyl chloride (2.5 mL) was added to a solution of 6-chloropyridin-3-amine (600 mg, 4.22 mmol) in pyridine (2.5 mL) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give N-(6-chloropyridin-3-yl)methanesulfonamide (900 mg, 4.09 mmol, 96.9% yield) as a yellow solid. LC-MS: m / z=221.0 [M+H] + , retention time 1.60 min (Method A).

[0934] N-(6-Hydrazino-4-methylpyridin-3-yl)methanesulfonamide

[0935]

[0936] To a solution of N-(6-chloropyridin-3-yl)methanesulfonamide (900 mg, 4.09 mmol) in ethanol (4.0 mL) was added hydrazine hydrate (2.0 mL, 85% in water). The mixture was stirred overnight at 130 ° C in a sealed tube. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give N-(6-hydrazino-4-methylpyridin-3-yl)methanesulfonamide (600 mg, 2.77 mmol, 67.9% yield) as a yellow oil. LC-MS: m / z = 217.0 [M + H] + , retention time 0.40 min (Method A). The crude product was used in the next step.

[0937] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-4-methylpyridin-3-yl)methanesulfonamide

[0938]

[0939] A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (341 mg, 1.48 mmol) and N-(6-hydrazino-4-methylpyridin-3-yl)methanesulfonamide (600 mg, 2.77 mmol) in acetic acid (5.0 mL) was stirred at 100 ° C. for 2.0 hours and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)-4-methylpyridin-3-yl)methanesulfonamide (formate) (75.8 mg, 0.18 mmol, 11.9% yield) as a white solid. LC-MS: m / z = 384.0 (M + H) +, retention time 4.17 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ8.32–8.29(m,2H),8.14(s,1H),7.92–7.90(m,2H),7.80–7.78(m,2H),3.05(s,3H),2.46(s,3H),2.42(s,3H).

[0940] Example 40: Preparation of Compound 40

[0941] 2-Chloro-4-methyl-5-(methylthio)pyridine

[0942]

[0943] To a solution of 5-bromo-2-chloro-4-methylpyridine (800 mg, 3.88 mmol) and N,N,N',N'-tetramethylethylenediamine (0.59 g, 5.05 mmol) in anhydrous tetrahydrofuran (10.0 mL) at -78 ° C was added n-butyllithium (2.91 mL, 4.66 mmol, 1.6 M in hexane) under nitrogen. The mixture was stirred at -78 ° C for 50 minutes and dimethyl disulfide (1.13 g, 4.66 mmol) was added. The mixture was warmed to 20 ° C and stirred for another hour. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=50 / 1) to obtain 2-chloro-4-methyl-5-(methylthio)pyridine (600 mg, 3.47 mmol, 89.4% yield) as a yellow oil. LC-MS: m / z=174.1 (M+H) + , retention time 1.73 minutes (Method A).

[0944] 2-Chloro-4-methyl-5-(methylsulfinyl)pyridine

[0945]

[0946] 3-Chlorobenzoic acid (772 mg, 3.82 mmol, 85%) was added to a solution of 2-chloro-4-methyl-5-(methylthio)pyridine (600 mg, 3.47 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain 2-chloro-4-methyl-5-(methylsulfinyl)pyridine (500 mg, 2.65 mmol, 76.2% yield) as a white solid. LC-MS: m / z=190.1 (M+H) + , retention time 1.47 minutes (Method A).

[0947] (6-Hydrazino-4-methylpyridin-3-yl)(Imino)(methyl)-λ 6 -sulfonone

[0948]

[0949] To a mixture of 2-chloro-4-methyl-5-(methylsulfinyl)pyridine (500 mg, 2.65 mmol) and ammonium carbamate (823 mg, 10.6 mmol) in methanol (15.0 mL) was added (diacetoxyiodine)benzene (2.56 g, 7.95 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-hydrazino-4-methylpyridin-3-yl)(imino)(methyl)-λ as a yellow solid. 6 -sulfonone (350 mg, 1.72 mmol, 64.7% yield). LC-MS: m / z=205.0 (M+H) + , retention time 1.40 minutes (Method A).

[0950] (6-Hydrazino-4-methylpyridin-3-yl)(Imino)(methyl)-λ 6 -sulfonone

[0951]

[0952] To (6-hydrazino-4-methylpyridin-3-yl)(imino)(methyl)-λ 6To a solution of -sulfonone (350 mg, 1.72 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (1.05 g, 17.2 mmol, 85% in water). The mixture was stirred at 90 ° C overnight. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude product (6-hydrazino-4-methylpyridin-3-yl)(imino)(methyl)-λ was obtained as a yellow syrup. 6 -sulfonone (150 mg, 0.75 mmol, 43.6% yield). LC-MS: m / z=251.0 (M+H)+, retention time 0.3 min (Method A). The crude product was used in the next step.

[0953] 4-(5-Hydroxy-3-methyl-1-(4-methyl-5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0954]

[0955] 2-(4-cyanophenyl)-3-oxobutanoic acid methyl ester (162 mg, 0.75 mmol) and (6-hydrazino-4-methylpyridin-3-yl)(imino)(methyl)-λ 6 A mixture of -sulfonone (150 mg, 0.75 mmol) in acetic acid (8.0 mL) was stirred at 110 ° C for 1.0 hour and evaporated to dryness. The residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(4-methyl-5-(S-methylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (12.2 mg, 0.029 mmol, 3.93% yield) as a white solid. LC-MS: m / z = 368.0 (M + H) + , retention time 3.61 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.85(s,1H),8.48(s,1H),8.13(s,1H),7.90-7.92(d,J=8.3Hz ,2H),7.76-7.78(d,J=7.9Hz,2H),4.54(s,1H),3.15(s,3H),2.74(s,3H),2.43(s,3H).

[0956] Example 41: Preparation of Compound 41

[0957] (S)-(6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6 -sulfonone and (R)-(6-chloropyridin-3-yl)(imino)-(isopropyl)-λ6 -sulfonone

[0958]

[0959] To a mixture of 2-chloro-5-(isopropylsulfinyl)pyridine (1.6 g, 7.28 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) in methanol (20.0 mL) was added (diacetoxyiodine)benzene (7.04 g, 21.8 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain (6-chloropyridin-3-yl)(imino)(isopropyl)-λ as a yellow solid. 6 -sulfonone (1.27 g, 5.82 mmol, 80% yield). LC-MS: m / z=218.1 (M+H) + , retention time 0.55 min (Method A). The two chiral isomers were separated by chiral preparative HPLC as white solids.

[0960] (S)-(6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6 -sulfonone (550 mg, 2.52 mmol).

[0961] (R)-(6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6 -sulfonone (600 mg, 2.75 mmol).

[0962] (S)-(6-Hydrazinopyridin-3-yl)(Imino)(Isopropyl)-λ 6 -sulfonone

[0963]

[0964] To (S)-(6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6 To a solution of -sulfurone (150 mg, 0.69 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (219 mg, 3.45 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to obtain (S)-(6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ as a yellow syrup. 6-sulfonone (100 mg, crude product). LC-MS: m / z=215.0 (M+H)+, retention time 0.34 min (Method A). The crude product was used in the next step.

[0965] (S)-4-(5-Hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0966]

[0967] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (150 mg, 0.69 mmol) and (S)-(6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ 6 A mixture of 1-sulfonone (100 mg, crude product) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (S)-4-(5-hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (30.1 mg, 0.07 mmol, 10.2% yield) as a white solid. LC-MS: m / z=381.0 (M+H) + , retention time 3.72 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.02-13.13(m,1H),8.79(s,1H),8.63-8.85(d,J=8.5Hz,1H),8.31-8.33(d,J=8.7Hz,1H) ,8.13(s,1H),7.89-7.91(d,J=7.9Hz,2H),7.79-7.81(d,J=7.9Hz,2H),4.48(s,1H),2.48(s,3H),1.16-1.19(m,6H).

[0968] Example 42: Preparation of Compound 42

[0969] (R)-(6-Hydrazinopyridin-3-yl)(Imino)(Isopropyl)-λ 6 -sulfonone

[0970]

[0971] To (R)-(6-chloropyridin-3-yl)(imino)(isopropyl)-λ 6To a solution of -sulfonone (150 mg, 0.69 mmol) (intermediate of Example 41) in ethanol (5.0 mL) was added hydrazine hydrate (219 mg, 3.45 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give (R)-(6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ as a yellow syrup. 6 -sulfonone (100 mg, crude product). LC-MS: m / z=215.0 (M+H)+, retention time 0.34 min (Method A). The crude product was used in the next step.

[0972] (R)-4-(5-Hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0973]

[0974] Methyl 2-(4-cyanophenyl)-3-oxobutanoate (150 mg, 0.69 mmol) and (R)-(6-hydrazinopyridin-3-yl)(imino)(isopropyl)-λ 6 A mixture of 1-sulfonone (100 mg, crude product) in acetic acid (8.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (R)-4-(5-hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (30.9 mg, 0.07 mmol, 10.5% yield) as a white solid. LC-MS: m / z=381.0 (M+H) + , retention time 3.72 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.11-13.19(m,1H),8.79(s,1H),8.64-8.66(d,J=9.1Hz,1H),8.28-8.32(d,J=8.9Hz,1H) ,8.14(s,1H),7.90-7.92(d,J=8.3Hz,2H),7.78-7.80(d,J=8.2Hz,2H),4.51(s,1H),2.47(s,3H),1.16-1.19(m,6H).

[0975] Example 43: Preparation of Compound 43

[0976] tert-Butyl 3-(2-chloropyridin-4-yl)azetidine-1-carboxylate

[0977]

[0978] Chlorotrimethylsilane and 1,2- dibromoethane (0.1mL, 7:5v / v ratio) are added to the solution of zinc powder (1.5g, 6.26mmol) in N, N- dimethylacetamide (5.0mL).The mixture is stirred at room temperature for 15 minutes, and then 3- iodoazetidine -1- tert-butyl formates (3.2g, 11.3mmol) are added.The mixture is stirred for 30 minutes.In a separate flask, [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II) (196mg, 0.24mmol) and then copper iodide (92mg, 0.48mmol) are added to the degassed solution of 2- chloro- 4- iodine pyridine in N, N- dimethylacetamide (20.0mL).After stirring for 30 minutes, above-mentioned zinc suspension is added in 2- chloro- 4- iodine pyridine solution, and reaction mixture is stirred at room temperature for 2.0 hours. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate (2 times). The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=4 / 1) to give tert-butyl 3-(2-chloropyridin-4-yl)azetidine-1-carboxylate (600 mg, 3.29 mmol, 62.6% yield) as a white solid. LC-MS: m / z=269.1 (M+H) + , retention time 1.98 minutes (Method A).

[0979] 4-(azetidin-3-yl)-2-chloropyridine

[0980]

[0981] To a solution of tert-butyl 3-(2-chloropyridin-4-yl)azetidine-1-carboxylate (600mg 3.29mmol) in dichloromethane (10.0mL) was added trifluoroacetic acid (5.0mL). The mixture was stirred at 40°C for 2.0 hours and concentrated. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over sodium sulfate and concentrated. 4-(azetidine-3-yl)-2-chloropyridine (600mg, 2.23mmol, 68% yield) was obtained as a yellow syrup. LC-MS: m / z=169.0 (M+H)+, retention time of 0.33 minutes (Method A).

[0982] 2-Chloro-4-(1-(methylsulfonyl)azetidin-3-yl)pyridine

[0983]

[0984] Methanesulfonyl chloride (305 mg, 2.68 mmol) was added to a solution of 4- (azetidin-3-yl) -2-chloropyridine (600 mg, 2.23 mmol) in pyridine (2.5 mL) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 2-chloro-4- (1- (methylsulfonyl) azetidin-3-yl) pyridine (400 mg, 1.63 mmol, 72.9% yield) as a yellow solid. LC-MS: m / z = 247 [M + H] + , retention time 1.63 minutes (Method A).

[0985] 2-Hydrazino-4-(1-(methylsulfonyl)azetidin-3-yl)pyridine

[0986]

[0987] To a solution of 2-chloro-4-(1-(methylsulfonyl)azetidin-3-yl)pyridine (400 mg, 1.63 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (4.0 mL). The mixture was stirred overnight in a sealed tube at 130 ° C. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-hydrazino-4-(1-(methylsulfonyl)azetidin-3-yl)pyridine (300 mg, crude product) as a yellow syrup. The product was used directly in the next step. LC-MS: m / z=243.0 (M+H) +, retention time of 0.3 minutes (Method A).

[0988] 4-(5-hydroxy-3-methyl-1-(5-(1-(methylsulfonyl)azetidin-3-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0989]

[0990] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (30 mg, 0.14 mmol) and 2-hydrazino-4-(1-(methylsulfonyl)azetidin-3-yl)pyridine (300 mg, crude product) in acetic acid (5.0 mL) was stirred at 120 ° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(1-(methylsulfonyl)azetidin-3-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (formate) (8.4 mg, 0.02 mmol, 13.2% yield) as a white solid. LC-MS: m / z = 409.0 (M + H) + , retention time was 5.10 minutes (method A). 1 HNMR(400MHz,DMSO-d6)δ8.44-8.45(d,J=5.5Hz,1H),8.39(s,1H),8.14(s,1H),7.91-7.93(d,J=8.9Hz,2H) ,7.76-7.78(d,J=8.1Hz,2H),7.31(s,1H),4.28-4.31(m,2H),3.94-3.98(m,2H),3.09(s,3H),2.45(s,3H).

[0991] Example 44: Preparation of Compound 44

[0992] Methyl 2-(5-bromopyridin-2-yl)acetate

[0993]

[0994] To a solution of 5-bromopyridine-2-acetic acid (3.00 g, 13.89 mmol) in MeOH (50 mL) at room temperature was added SOCl2 (2 mL) dropwise over 5 minutes. The reaction was stirred at 60 ° C for 2 hours. After completion of the TLC analysis reaction, most of the solvent was evaporated in vacuo. The residue was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 (20 g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc: Hex = 1: 5) to obtain the title product (3.01 g) as a yellow oil. LCMS (ESI+): m / z 230 (M+H) + ; 1H NMR (300MHz, CDCl3) δ8.61(d,J=2.1Hz,1H),7.78(dd,J=2.4Hz,8.4Hz,1H),7.21(d,J=8.4Hz,1H),3.81(s,2H),3.72(s,3H).

[0995] Methyl 2-(5-cyanopyridin-2-yl)acetate

[0996]

[0997] Under a nitrogen atmosphere, Zn(CN)2(2.17g, 18.52mmol) and Pd(PPh3)4(1.00g, 0.86mmol) were added to a solution of 2-(5-bromopyridin-2-yl)methyl acetate (2.84g, 12.35mmol) in anhydrous DMF (50mL). The mixture was stirred at 120°C for 1 hour. After the reaction was completed by TLC analysis, the mixture was cooled to room temperature and filtered through a celite pad. The filtrate was quenched with water (200mL) and extracted with EtOAc (50mL×3). The combined organic phases were dried over anhydrous Na2SO4(30g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=8:1 to 5:1) to obtain 1.81g of the title compound as a yellow oil. LCMS(ESI+):m / z=177(M+H) + ; 1 H NMR (300MHz, CDCl3) δ8.84(d,J=1.5Hz,1H),7.95(dd,J=2.1Hz,8.1Hz,1H),7.47(d,J=8.1Hz,1H),3.94(s,2H),3.75(s,3H).

[0998] Methyl 2-(5-cyanopyridin-2-yl)-3-oxobutanoate

[0999]

[1000] Under nitrogen atmosphere, LiHMDS (6.78mL, 6.78mmol) was added dropwise to a solution of 2-(5-cyanopyridine-2-yl) methyl acetate (0.80g, 4.52mmol) in anhydrous THF (30mL) at -30°C over 10 minutes. After the reaction was stirred at -30°C for 30 minutes, a solution of acetyl chloride (0.53g, 6.78mmol) in anhydrous THF (5mL) was added dropwise over 5 minutes, and the reaction was continued to stir for 30 minutes under the same conditions. The reaction was warmed to room temperature and stirred for another 2 hours. After completing the reaction by TLC analysis, the mixture was quenched with saturated aqueous ammonium chloride solution (30mL) and extracted with EtOAc (20mL × 3). The organic phases merged were dried with anhydrous Na2SO4 (20g), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=15:1 to 10:1) to give 250 mg of the title compound as a yellow solid. LCMS (ESI+): m / z 219 (M+H) + ; 1 H NMR (300MHz, CDCl3) δ8.43 (s, 1H), 7.89 (d, J = 9.3Hz, 1H), 7.81 (dd, J = 9.0Hz, 2.1Hz, 1H), 3.86 (s, 3H), 3.73 (s, 1H), 2.40 (s, 3H).

[1001] 6-(5-hydroxy-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)nicotinecarbonitrile

[1002]

[1003] To a solution of methyl 2-(5-cyanopyridin-2-yl)-3-oxobutanoate (72 mg, 0.33 mmol) in acetic acid (3 mL) was added 2-hydrazino-5-(methylsulfonyl)pyridine (93 mg, 0.49 mmol). After the reaction was stirred at 100 ° C overnight, a large amount of solid was precipitated. The suspension was filtered with a funnel, and the filter cake was washed with acetic acid (1 mL). The solid was slurried in ethanol (3 mL) and filtered to obtain 31 mg of the title compound as a yellow solid. LCMS (ESI+): m / z 356 (M+H) + HPLC purity is 95.9%, 1H NMR(300MHz,DMSO-d6)δ13.92(brs,1H),8.89(dd,J=7.8Hz,2.4Hz,,2H),8.69(d,J=9.0Hz,1 H), 8.45 (dd, J = 8.7Hz, 2.1Hz, 2H), 8.16 (dd, J = 8.7Hz, 2.1Hz, 1H), 3.32 (s, 3H), 2.65 (s, 3H).

[1004] Example 45: Preparation of Compound 45

[1005] 6-Chloro-2-methyl-3-(methylthio)pyridine

[1006]

[1007] To a solution of 6-chloro-2-methylpyridin-3-amine (1 g, 7.01 mmol) in concentrated HCl (5 mL) was added dropwise a solution of NaNO2 (726 mg, 10.52 mmol) in water (5 mL) at 0 ° C over 5 minutes. After the reaction was stirred at 0 ° C for 1 hour, some solids were precipitated. The suspension was quickly filtered, with the internal temperature maintained below 5 ° C. The filtrate was added dropwise to a solution of NaBF4 (8 mg, 0.07 mmol) and MeSNa (2.95 g, 8.42 mmol) in MeCN (10 mL) at 0 ° C over 5 minutes. The resulting mixture was stirred at 0 ° C for about 3 hours. As indicated by TLC analysis, after the reaction was complete, the reaction was quenched with water (50 mL) and the pH was adjusted to 6-7 with a diluted NaOH solution (1 N). The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were dried and concentrated to give 745 mg of crude product, which was used in the next step without further purification. LC-MS (ESI+): m / z 174 (M+H) + .

[1008] 6-Chloro-2-methyl-3-(methylsulfonyl)pyridine

[1009]

[1010] To a solution of the crude product 6-chloro-2-methyl-3-(methylthio)pyridine (745 mg, 4.29 mmol) in DCM (40 mL) at 0 ° C. was added m-CPBA (1.48 g, 8.58 mmol) in portions over 5 minutes. The reaction was stirred in an ice-water bath for about 2 hours. As indicated by TLC analysis, after the reaction was complete, the reaction was quenched with saturated NaHCO solution (20 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried and concentrated to give 1.03 g of crude product. LC-MS (ESI+): m / z 206 (M+H) + ;

[1011] 6-Hydrazino-2-methyl-3-(methylsulfonyl)pyridine

[1012]

[1013] A solution of crude product 6-chloro-2-methyl-3-(methylsulfonyl)pyridine (1.03 g, 5.01 mmol) and hydrazine hydrate (1.57 g, 25 mmol, 80% wt) in ethanol (50 mL) was stirred at 70 ° C overnight. After the reaction was completed based on TLC analysis, the reaction was concentrated to dryness. The residue was added to ethanol (15 mL) and stirred at room temperature for 30 minutes, a large amount of solid was precipitated. The suspension was filtered and the filter cake was washed with ice-cold ethanol (5 mL). The separated solid was dried in a high vacuum to obtain 445 mg of the title compound. LC-MS (ESI+): m / z 202 (M+H) + ;

[1014] 4-(5-Hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1015]

[1016] A solution of the crude product 6-hydrazino-2-methyl-3-(methylsulfonyl)pyridine (270 mg, 1.17 mmol) and methyl 2-(4-cyanophenyl)-3-oxobutanoate (235 mg, 1.17 mmol) in AcOH (6 mL) was stirred at 110 ° C for 3 hours. As indicated by TLC analysis, after the reaction was completed, the reaction was cooled to room temperature and quenched with water (80 mL). A large amount of solid was precipitated. The suspension was filtered and the filter cake was slurried three times in methanol (30 mL) to obtain 43 mg of the title compound. LC-MS (ESI+): m / z 369 (M+H) + ; 1H-NMR (300MHz, CD3OD) δ8.43(d,J=8.7Hz,1H),8.25(d,J=8.7Hz,1H),7.89(d ,J=8.7Hz,2H),7.60(d,J=8.7Hz,2H),3.19(s,3H),2.88(s,3H),2.42(s,3H).

[1017] Example 46: Preparation of Compound 46

[1018] 2-Chloro-4-methyl-5-(methylthio)pyridine

[1019]

[1020] The compound was synthesized according to the procedure used to prepare 6-chloro-2-methyl-3-(methylthio)pyridine (intermediate of Example 45). LC-MS (ESI+): m / z 174 (M+H) + ;

[1021] 2-Chloro-4-methyl-5-(methylsulfonyl)pyridine

[1022]

[1023] This compound was synthesized according to the procedure used to prepare 6-chloro-2-methyl-3-(methylsulfonyl)pyridine (intermediate of Example 45) using 2-chloro-4-methyl-5-(methylthio)pyridine. 1 H-NMR (300MHz, CDCl3) δ8.93(s,1H),7.34(s,1H),3.16(s,3H),2.71(s,3H).

[1024] 2-Hydrazino-4-methyl-5-(methylsulfonyl)pyridine

[1025]

[1026] The compound was synthesized according to the procedure used to prepare 6-hydrazino-2-methyl-3-(methylsulfonyl)pyridine (intermediate of Example 45) using 2-chloro-4-methyl-5-(methylsulfonyl)pyridine. LC-MS (ESI+): m / z 202 (M+H) + .

[1027] 4-(5-Hydroxy-3-methyl-1-(4-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1028]

[1029] This compound was synthesized according to the procedure for preparing 4-(5-hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (intermediate of Example 45) using 2-hydrazino-4-methyl-5-(methylsulfonyl)pyridine. LC-MS (ESI+): m / z 369 (M+H) + ; 1 H-NMR (300MHz, DMSO-d6) δ8.76(s,1H),8.58(s,1H),7.93(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,2H),3.52(s,3H),2.69(s,3H),2.44(s,3H).

[1030] Example 47: Preparation of Compound 47

[1031] 2-(6-Hydrazinopyridin-3-yl)acetic acid

[1032]

[1033] A solution of 2-(6-bromopyridin-3-yl)acetic acid (420 mg, 1.94 mmol) and hydrazine hydrate (5 mL, 80 wt %, 80 mmol) in water (3 mL) was stirred overnight at reflux. After completion of the reaction as indicated by TLC analysis, the reaction was concentrated to dryness to give 540 mg of crude product, which was used in the next step without further purification. LC-MS (ESI+): m / z 168 (M+H) + .

[1034] 2-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)acetic acid

[1035]

[1036] A solution of 2-(4-cyanophenyl)-3-oxobutanoic acid methyl ester (302mg, 1.31mmol) and crude product 2-(6-hydrazinopyridin-3-yl)acetic acid (218mg, 1.31mmol) in AcOH (8mL) was stirred under reflux for 3 hours. As indicated by TLC analysis, after the completion of the reaction, the reaction was cooled to room temperature and diluted with water (20mL). A large amount of solids were precipitated. The solid was collected by filtration to obtain 192mg crude product. The crude product was purified by preparative HPLC to obtain 10mg title compound. LC-MS (ESI+): m / z 335 (M+H) + ; 1H-NMR (300MHz, CD3OD) δ8.35(s,1H),8.20(d,J=8.7Hz,1H),7.90(d,J=8.7Hz ,1H),7.82(d,J=8.4Hz,2H),7.72(d,J=8.7Hz,2H),3.60(s,3H),2.46(s,3H).

[1037] Example 48: Preparation of Compound 48

[1038] 2-Bromo-5-(methylthio)pyridine

[1039]

[1040] Under nitrogen protection, n-BuLi (23.2 mL, 37 mmol) was added dropwise to a solution of 2,5-dibromopyridine (8.34 g, 35.2 mmol) in anhydrous Et2O (200 mL) at -78 ° C over 20 minutes. After the resulting mixture was stirred at -78 ° C for 1 hour, dimethyl disulfide (3.65 g, 38.7 mmol) was added dropwise to the reaction over 10 minutes. The reaction was continued to stir for another 1 hour at -78 ° C. As indicated by TLC analysis, after the reaction was complete, the reaction was warmed to 0 ° C and quenched with dilute HCl solution (40 mL, 1 N) and extracted with MTBE (100 mL × 2). The combined organic phases were washed with water (20 mL), dried and concentrated to give 6.035 g of crude product, which was used in the next step without further purification. LC-MS (ESI+): m / z 204,206 (M+H) + .

[1041] 2-Bromo-5-(methylsulfonyl)pyridine

[1042]

[1043] This compound was synthesized according to the procedure used to prepare 6-chloro-2-methyl-3-(methylsulfonyl)pyridine (intermediate of Example 45) using 2-bromo-5-(methylthio)pyridine. 1 H-NMR (300MHz, CDCl3) δ8.92(d,J=1.8Hz,1H),8.05(dd,J=8.1,1.8Hz,1H),7.72(d,J=8.1Hz,1H),3.12(s,3H).

[1044] 2-Hydrazino-5-(methylsulfonyl)pyridine

[1045]

[1046] The compound was synthesized according to the procedure for preparing 6-hydrazino-2-methyl-3-(methylsulfonyl)pyridine (intermediate of Example 45) using 2-bromo-5-(methylsulfonyl)pyridine. LC-MS (ESI+): m / z 188 (M+H) + .

[1047] Methyl 2-(4-hydroxy-3-methylphenyl)-3-oxobutanoate

[1048]

[1049] Under nitrogen protection, LHMDS (12.9 mL, 12.9 mmol) was added dropwise to a solution of 2- (4- hydroxy -3- methylphenyl) methyl acetate (930 mg, 5.16 mmol) in anhydrous DMF (15 mL) at -78 ° C over 15 minutes. After the reaction was stirred at -78 ° C for 30 minutes, a solution of 1- acetylimidazole (1.25 g, 11.35 mmol) in DMF (15 mL) was added dropwise to the reaction over 15 minutes. The reaction was slowly warmed to room temperature over 2 hours. As indicated by TLC analysis, after the reaction was complete, the reaction was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water (25 mL), dried and concentrated to obtain 1.47 g of the crude title compound, which was used in the next step without further purification. LC-MS (ESI+): m / z 245 (M+Na) + .

[1050] 4-(4-Hydroxy-3-methylphenyl)-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-5-ol

[1051]

[1052] This compound was synthesized according to the procedure for preparing 4-(5-hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (intermediate of Example 45) using methyl 2-(4-hydroxy-3-methylphenyl)-3-oxobutanoate. LC-MS (ESI+): m / z 358 (M+H) + ; 1H-NMR(300MHz,CD3OD)δ8.92(d,J=1.8Hz,1H),8.69(brs,1H),8.38(dd,J=9.0,2.4Hz,1H),7.2 1(s,1H),7.13(d,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),3.21(s,3H),2.36(s,3H),2.22(s,3H).

[1053] Example 49: Preparation of Compound 49

[1054] Methyl 2-(4-methoxy-3-methylphenyl)acetate

[1055]

[1056] To a solution of 2-(4-methoxy-3-methylphenyl)acetic acid (2.15 g, 11.9 mmol) in methanol was added SOCl2 (4 mL) dropwise in an ice-water bath over 5 minutes. The reaction was stirred at room temperature for approximately 1 hour. After completion of the reaction as indicated by TLC analysis, the reaction was concentrated to dryness. The residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 solution (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried and concentrated to give 2.14 g of crude product. 1 H-NMR (300MHz, CDCl3) δ7.05-7.07(m,2H),6.77(d,J=8.1Hz,1H),3.82(s,3H),3.68(s,3H),3.53(s,2H),2.20(s,3H).

[1057] Methyl 2-(4-methoxy-3-methylphenyl)-3-oxobutanoate

[1058]

[1059] The compound was synthesized according to the procedure for preparing methyl 2-(4-hydroxy-3-methylphenyl)-3-oxobutanoate (intermediate of Example 48) using methyl 2-(4-methoxy-3-methylphenyl)acetate. LC-MS (ESI+): m / z 259 (M+Na) + .

[1060] 4-(4-methoxy-3-methylphenyl)-3-methyl-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-5-ol

[1061]

[1062] This compound was synthesized according to the procedure for preparing 4-(5-hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (intermediate of Example 45) using methyl 2-(4-methoxy-3-methylphenyl)-3-oxobutanoate. LC-MS (ESI+): m / z 374 (M+H) + ; 1 H-NMR (300MHz, DMSO-d6) δ12.37(s,1H),8.89(s,1H),8.72(s,1H),8.42(dd,J=9.0,2.1H z,1H),7.34-7.36(m,2H),6.96(d,J=9.0Hz,1H),3.80(s,3H),2.36(s,3H),2.18(s,3H).

[1063] Example 50: Preparation of Compound 50

[1064] 6-Chloronicotinimidohydrazide

[1065]

[1066] Under nitrogen protection, MeONa (78 mg, 1.44 mmol) was added in batches to a solution of 6-chloronicotinonitrile (1 g, 7.19 mmol) in methanol (2.5 mL) and dioxane (2.5 mL) in an ice-water bath over 2 minutes. After the reaction was stirred at room temperature for 2 hours, hydrazine hydrate (480 mg, 7.69 mmol) was added once. The resulting mixture was stirred at 30 ° C for 30 minutes. A large amount of solid was precipitated. The suspension was diluted with MTBE (5 mL) and continued to stir for 30 minutes. After filtration, 764 mg of crude product was obtained. 1 H-NMR (300MHz, DMSO-d6) δ8.67(d,J=2.1Hz,1H),8.06(d,J=8.4,2.1Hz,1H),7.48(d,J=8.4Hz,1H),5.79(brs,2H),5.33(brs,2H).

[1067] 2-Chloro-5-(2H-tetrazol-5-yl)pyridine

[1068]

[1069] To a solution of 6-chloronicotinimide hydrazide (664 mg, 3.91 mmol) in AcOH (2 mL) and water (1.6 mL) at room temperature was added dropwise NaNO aqueous solution (323 mg, 4.69 mmol in 0.6 mL water) over 5 minutes. After the reaction was stirred at room temperature for 5 hours, a large amount of solid was precipitated. The suspension was cooled to 0 ° C with an ice-water bath and the pH was adjusted to 2 using a diluted HCl solution (1 N). The resulting suspension was filtered to obtain 540 mg of the title compound. 1 H-NMR (300MHz, DMSO-d6) δ9.05 (d, J = 2.4Hz, 1H), 8.06 (d, J = 8.4, 2.4Hz, 1H), 7.80 (d, J = 8.4Hz, 1H).

[1070] 2-Hydrazino-5-(2H-tetrazol-5-yl)pyridine

[1071]

[1072] This compound was synthesized according to the procedure used to prepare 6-hydrazino-2-methyl-3-(methylsulfonyl)pyridine (intermediate of Example 45) using 2-chloro-5-(2H-tetrazol-5-yl)pyridine. 1 H-NMR (300MHz, DMSO-d6) δ8.65(d,J=2.1Hz,1H),8.00(d,J=8.4,2.1Hz,1H),6.95(brs,4H),6.78(d,J=8.4Hz,1H).

[1073] 4-(1-(5-(2H-tetrazol-5-yl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[1074]

[1075] This compound was synthesized according to the procedure for preparing 4-(5-hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (intermediate of Example 45) using 2-hydrazino-5-(2H-tetrazol-5-yl)pyridine. LC-MS (ESI+): m / z 345 (M+H) + ; 1 H-NMR (300MHz, DMSO-d6) δ9.01 (s, 1H), 8.37-8.47 (m, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.75 (d, J = 8.4Hz, 2H), 2.45 (s, 3H).

[1076] Example 51: Preparation of Compound 51

[1077] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N'-methylsulfonamide

[1078]

[1079] The compound was synthesized according to the procedure used to prepare N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide (Example 6).

[1080] Example 52: Preparation of Compound 52

[1081] N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N'-dimethylsulfonamide

[1082]

[1083] The compound was synthesized according to the procedure used to prepare N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide (Example 6).

[1084] Example 53: Preparation of Compound 53

[1085] 4-(1-(4-cyclopropyl-5-(methylsulfonyl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[1086]

[1087] This compound was synthesized according to the method used to prepare 4-(5-hydroxy-3-methyl-1-(6-methyl-5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (Example 45).

[1088] Example 54: Preparation of Compound 54

[1089] 4-(5-Hydroxy-3-methyl-1-(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1090]

[1091] This compound was synthesized according to the procedure used to prepare 4-(1-(5-(2H-tetrazol-5-yl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (Example 50) using 2-hydrazino-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine.

[1092] Example 55: Preparation of Compound 55

[1093] 2-(N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)sulfamoyl)acetic acid

[1094]

[1095] The compound was synthesized according to the procedure used to prepare N-(6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide (Example 6).

[1096] Example 56: Preparation of Compound 56

[1097] (S)-4-(1-(5-(cyclopropanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[1098]

[1099] This compound was synthesized according to the method used to prepare (S)-4-(5-hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (Example 41).

[1100] Example 57: Preparation of Compound 57

[1101] (S)-4-(1-(5-(cyclopropanesulfonylimino)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[1102]

[1103] This compound was synthesized according to the method used to prepare (S)-4-(5-hydroxy-3-methyl-1-(5-(S-isopropylsulfonylimino)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (Example 41).

[1104] Example 58: Preparation of Compound 58

[1105] (6-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfonone

[1106]

[1107] To a mixture of 2-chloro-5-(methylsulfinyl)pyridine (0.50 g, 2.8 mmol) (intermediate of Example 12) and ammonium carbamate (0.88 g, 11.2 mmol) in methanol (25.0 mL) was added (diacetoxyiodo)benzene (2.7 g, 8.5 mmol). The mixture was stirred at 55 ° C for 1.0 hour and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane / methanol = 50 / 1) to give (6-chloropyridin-3-yl)(imino)(methyl)-λ as a yellow syrup. 6 -sulfonone (300 mg, 1.58 mmol, 56.3% yield). LC-MS: m / z=191.0 (M+H) + , retention time 1.22 minutes (Method A).

[1108] N-((6-chloropyridin-3-yl)(methyl)(oxo)-λ 6 -sulfyminyl)cyanamide

[1109]

[1110] To (6-chloropyridin-3-yl)(imino)(methyl)-λ 6 To a solution of -sulfonone (190 mg, 1.0 mmol) in dichloromethane (10.0 mL) was added N, N-dimethylpyridine-4-amine (0.15 g, 1.2 mmol) and cyanogen bromide (0.21 g, 2.0 mmol). The mixture was stirred at room temperature for 1.0 hours. The reaction was distributed between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (dichloromethane / methanol=50 / 1) to obtain N-((6-chloropyridin-3-yl)(methyl)(oxo)-λ as a yellow oil. 6 -sulfylidene)cyanamide (100 mg, 0.46 mmol, 46.3% yield). LC-MS: m / z=216.0 (M+H) + , retention time 1.53 minutes (Method A).

[1111] N-((6-Hydrazinopyridin-3-yl)(methyl)(oxo)-λ 6 -sulfyminyl)cyanamide

[1112]

[1113] To N-((6-chloropyridin-3-yl)(methyl)(oxo)-λ 6To a solution of 6-thio)cyanamide (100 mg, 0.46 mmol) in ethanol (3.0 mL) was added hydrazine hydrate (115 mg, 1.8 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give N-((6-hydrazinopyridin-3-yl)(methyl)(oxo)-λ as a yellow solid 6 -sulfylidene)cyanamide (70 mg, 0.33 mmol, 72.1% yield). LC-MS: m / z=212.0 (M+H) + , retention time 0.32 min (Method A).

[1114] N-((6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(methyl)(oxo)-λ 6 -sulfyminyl)cyanamide

[1115]

[1116] N-((6-hydrazinopyridin-3-yl)(methyl)(oxo)-λ 6 A mixture of 6-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(methyl)(oxo)-λ-pyrazol-1-yl)-1-methyl-2-( ... 6 -sulfylidene)cyanamide (20.8 mg, 0.06 mmol, 16.7% yield). LC-MS: m / z=379.0 (M+H) + , retention time 4.49 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ8.99(d,J=2.3Hz,1H),8.80(d,J=9.1Hz,1H),8.53(dd ,J=9.1,2.5Hz,1H),7.92(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),3.83(s,3H).

[1117] Example 59: Preparation of Compound 59

[1118] 2-(6-bromopyridin-3-yl)oxazole

[1119]

[1120] Under nitrogen atmosphere, -78 DEG C of n-butyllithium (2.4mL, 5.99mmol, 2.5M) is added dropwise to a stirred solution of oxazole (340.57mg, 4.93mmol) in tetrahydrofuran (50mL). The reaction mixture is stirred for 10 minutes, and then zinc chloride (1M in tetrahydrofuran, 10.6mL, 10.57mmol) is added to the above mixture in batches. The mixture is warmed to room temperature. Then tetrakis(triphenylphosphine)palladium (203.53mg, 0.18mmol) and 2-bromo-5-iodopyridine (1000.00mg, 3.52mmol) are added to the reaction mixture, and the mixture is stirred at 60 DEG C for 4 hours. The reaction mixture is quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50mL×3). The organic phase is washed with saturated saline solution (50mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage, 40 g normal phase silica gel, UV 254, petroleum ether / ethyl acetate = 5 / 1) to give 2-(6-bromopyridin-3-yl)oxazole (420 mg, 1.87 mmol, 53% yield). LC-MS: m / z = 225 (M+H) + , retention time 1.838 minutes (Method A).

[1121] 2-(6-Hydrazinopyridin-3-yl)oxazole

[1122]

[1123] To a solution of 2-(6-pyridin-3-yl)oxazole (150.00 mg, 0.67 mmol) in ethanol (3 mL) was added hydrazine hydrate (2 mL) and the reaction was stirred at 110 ° C in a sealed tube for 3 hours. The mixture was treated with water and a white solid precipitated. The white solid was then filtered and dried to give the title compound (crude product, 82 mg). LC-MS: m / z = 177 (M + H) + , retention time 1.186 min (Method A). The crude product was used in the next step.

[1124] 4-(5-Hydroxy-3-methyl-1-(5-(oxazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1125]

[1126] In a sealed tube equipped with a magnetic stir bar, acetic acid (2 mL) containing methyl 2-(4-cyanophenyl)-3-oxobutanoate (90.00 mg, 0.41 mmol) and 2-(6-hydrazinopyridin-3-yl)oxazole (73.00 mg, 0.41 mmol) was suspended. The reaction mixture was heated to 120 ° C for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by slurrying in ethyl acetate to obtain 4-(5-hydroxy-3-methyl-1-(5-(oxazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (66.9 mg, 0.20 mmol, 47% yield) as a yellow solid. LC-MS: m / z=344 (M+H) + , retention time 4.750 min (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.13(s,1H),9.03(s,1H),8.68-8.64(m,1H),8.52-8.47( m,1H),8.31(s,1H),7.93-7.90(m,2H),7.85-7.80(m,2H),7.45(s,1H),2.50(s,3H).

[1127] Example 60: Preparation of Compound 60

[1128] 2-(6-chloropyridin-3-yl)thiazole

[1129]

[1130] To a solution of 5-bromo-2-chloropyridine (500.0 mg, 2.60 mmol) and 2- (tributylstannyl) thiazole (1458.2 mg, 3.90 mmol) in N, N-dimethylformamide (10.0 mL) was added bis(triphenylphosphine) palladium dichloride (II) (182.37 mg, 0.26 mmol). The reaction was stirred in a sealed tube at 100 ° C for 3 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=20 / 1) to obtain 2- (6-chloropyridin-3-yl) thiazole (350 mg, 1.77 mmol, 68% yield). LCMS: m / z=197.0 [M+H] +, retention time of 1.719 minutes (method A).

[1131] 2-(6-Hydrazinopyridin-3-yl)thiazole

[1132]

[1133] A mixture of 2- (6- chloropyridin-3-yl) thiazole (300.0 mg, 1.53 mmol) in ethanol (3.0 mL) and hydrazine hydrate (3.0 mL, 85% in water) was stirred at 110 ° C in a sealed tube for 3 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was ground with petroleum ether and filtered to obtain 2- (6- hydrazine pyridin-3-yl) thiazole (185 mg, 0.96 mmol, 63% yield). LCMS: m / z = 193.0 [M + H] +, retention time of 1.120 minutes (method B). The product is pure enough and used directly in the next step.

[1134] 4-(5-Hydroxy-3-methyl-1-(5-(thiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1135]

[1136] In a sealed tube equipped with a magnetic stir bar, acetic acid (3 mL) containing methyl 2-(4-cyanophenyl)-3-oxobutanoate (180.00 mg, 0.83 mmol) and 2-(6-hydrazinopyridin-3-yl)thiazole (159.30 mg, 0.83 mmol) was suspended. The reaction mixture was heated to 120 ° C for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by slurrying in ethyl acetate to give 4-(5-hydroxy-3-methyl-1-(5-(thiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (214.2 mg, 0.60 mmol, 72% yield) as a yellow solid. LC-MS: m / z=360 (M+H) + , retention time 5.064 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.13(br,1H),9.03(d,J=2.0Hz,1H),8.67-8.58(m,1H),8.52 -8.46(m,1H),8.00(d,J=3.6Hz,1H),7.93-7.87(m,3H),7.84-7.81(m,2H),2.50(s,3H).

[1137] Example 61: Preparation of Compound 61

[1138] 2-Bromo-5-phenylthiazole

[1139]

[1140] To a solution of 5-phenylthiazol-2-amine (2.0 g, 11.40 mmol) in acetonitrile (50.0 mL) was added copper bromide (1.96 g, 13.60 mmol) and tert-butyl nitrite (14.0 g, 13.60 mmol). The mixture was stirred at 60 ° C under nitrogen for 0.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-bromo-5-phenylthiazole (780 mg, 11.40 mmol, 28.9% yield) as a white solid. LC-MS: m / z = 239.9 (M + H) + , retention time 2.202 minutes (Method A).

[1141] 2-(6-chloropyridin-3-yl)-5-phenylthiazole

[1142]

[1143] To a solution of 2-bromo-5-phenylthiazole (510 mg, 2.10 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (750.0 mg, 3.14 mmol) and potassium carbonate (869.4 mg, 6.30 mmol) was added 1,4-dioxane / water (10.0 mL / 2.5 mL) containing tetrakis(triphenylphosphine)palladium (127.0 mg, 0.11 mmol). The mixture was stirred at 120° C. under nitrogen for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to give 2-(6-chloropyridin-3-yl)-5-phenylthiazole (200.0 mg, 2.10 mmol, 34.6% yield) as a white solid. LC-MS: m / z=273.0 (M+H) + , retention time 2.223 minutes (Method A).

[1144] 2-(6-Hydrazinopyridin-3-yl)-5-phenylthiazole

[1145]

[1146] To a solution of 2-(6-chloropyridin-3-yl)-5-phenylthiazole (400 mg, 1.5 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (4.0 mL, 85% in water). The mixture was stirred at 110 ° C in a sealed tube for 2.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-(6-hydrazinopyridin-3-yl)-5-phenylthiazole (150.0 mg, 1.50 mmol, 38.1% yield) as a yellow solid. LC-MS: m / z = 269.1 (M + H) + , retention time 1.538 min (Method A).

[1147] 4-(5-Hydroxy-3-methyl-1-(5-(5-phenylthiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1148]

[1149] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (108.5 mg, 0.50 mmol) and 2-(6-hydrazinopyridin-3-yl)-5-phenylthiazole (134.0 mg, 0.50 mmol) in acetic acid (3.0 mL) was stirred at 120 ° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(5-phenylthiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (76.4 mg, 0.50 mmol, 35.5% yield) as a white solid. LC-MS: m / z = 435.9 (M + H) + , retention time 6.278 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.13(s,1H),9.08(s,1H),8.60(m,2H),8.27(s,1H),8.08(d,J=8.0Hz,2H),7.9 2(d,J=8.0Hz,2H),7.83(d,J=8.0Hz,2H),7.50(t,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),2.56–2.49(m,3H).

[1150] Example 62: Preparation of Compound 62

[1151] 2-Bromo-4-phenylthiazole

[1152]

[1153] To a solution of 4-phenylthiazol-2-amine (2.0 g, 11.40 mmol) in acetonitrile (50.0 mL) was added copper bromide (1.96 g, 13.60 mmol) and tert-butyl nitrite (14.0 g, 13.60 mmol). The mixture was stirred at 60 ° C under nitrogen for 0.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-bromo-4-phenylthiazole (900 mg, 11.40 mmol, 33.3% yield) as a white solid. LC-MS: m / z = 239.9 (M + H) + , retention time 2.204 minutes (Method A).

[1154] 2-(6-chloropyridin-3-yl)-4-phenylthiazole

[1155]

[1156] To a solution of 2-bromo-4-phenylthiazole (450 mg, 1.90 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (675.0 mg, 2.80 mmol) and potassium carbonate (786.60 mg, 5.70 mmol) was added 1,4-dioxane / water (20.0 mL / 5.0 mL) containing tetrakis(triphenylphosphine)palladium (440.0 mg, 0.38 mmol). The mixture was stirred at 120° C. under nitrogen for 16.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to give 2-(6-chloropyridin-3-yl)-4-phenylthiazole (220.0 mg, 1.90 mmol, 43.1% yield) as a white solid. LC-MS: m / z=273.0 (M+H) + , retention time 2.288 minutes (Method A).

[1157] 2-(6-Hydrazinopyridin-3-yl)-4-phenylthiazole

[1158]

[1159] To a solution of 2-(6-chloropyridin-3-yl)-4-phenylthiazole (400 mg, 1.5 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (4.0 mL, 85% in water). The mixture was stirred at 110 ° C in a sealed tube for 2.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-(6-hydrazinopyridin-3-yl)-4-phenylthiazole (140.0 mg, 1.50 mmol, 36.10% yield) as a white solid. LC-MS: m / z = 269.1 (M + H) + , retention time 1.552 minutes (Method A).

[1160] 4-(5-Hydroxy-3-methyl-1-(5-(4-phenylthiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1161]

[1162] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (81.0 mg 0.37 mmol) and 2-(6-hydrazinopyridin-3-yl)-4-phenylthiazole (100.0 mg, 0.37 mmol) in acetic acid (3.0 mL) was stirred at 120 ° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(4-phenylthiazol-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (97.5 mg, 0.37 mmol, 59.9% yield) as a white solid. LC-MS: m / z = 435.9 (M + H) + , retention time 6.385 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ13.15(s,1H),9.04(d,J=4Hz,1H),8.64(s,1H),8.51(d,J=8.0Hz,1H),8.41(s,1H),7.92(d, J=8.0Hz,2H),7.83(d,J=8.0Hz,2H),7.76(d,J=8.0Hz,2H),7.50(t,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),2.52(m,3H).

[1163] Example 63: Preparation of Compound 63

[1164] 2-Bromo-5-(1H-pyrazol-1-yl)pyridine

[1165]

[1166] A mixture of 2-bromo-5-iodopyridine (1.00 g, 3.52 mmol), 1H-pyrazole (239.8 mg, 3.52 mmol), cuprous iodide (67.09 mg, 0.35 mmol), potassium phosphate (1.87 g, 8.81 mmol) and (1R, 2R)-cyclohexane-1,2-diamine (45.6 mg, 0.4 mmol) in 1,4-dioxane (10.0 mL) was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=6 / 1) to give 2-bromo-5-(1H-pyrazol-1-yl)pyridine (220 mg, 2.85 mmol, 81.12% yield) as a yellow oil. LCMS: m / z=224.1 (M+H)+, retention time 1.55 minutes (Method A).

[1167] 2-Hydrazino-5-(1H-pyrazol-1-yl)pyridine

[1168]

[1169] To a solution of 2-bromo-5-(1H-pyrazol-1-yl)pyridine (200 mg, 0.89 mmol) in ethanol (2.0 mL) was added hydrazine hydrate (223.2 mg, 4.46 mmol, 85% in water). The mixture was stirred at 100 ° C in a sealed tube for 2 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give 2-hydrazino-5-(1H-pyrazol-1-yl)pyridine (140 mg, 0.80 mmol, 90.32% yield) as a yellow solid. LCMS: m / z = 176.1 (M + H) +, retention time of 1.01 minutes (method B).

[1170] 4-(1-(5-(1H-pyrazol-1-yl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile

[1171]

[1172] A mixture of (E)-methyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (210.3 mg, 0.91 mmol) and 2-hydrazino-5-(1H-pyrazol-1-yl)pyridine (0.14 g, 0.8 mmol) in acetic acid (5.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(1-(5-(1H-pyrazol-1-yl)pyridin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)benzonitrile (47.5 mg, 0.14 mmol, 17.3% yield) as a white solid. LC-MS: m / z=343.0 (M+H) + , retention time 4.72 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.01(s,1H),8.96(d,J=2.6Hz,1H),8.61(d,J=2.4Hz,2H),8. 50–8.27(m,1H),7.97–7.88(m,2H),7.86–7.75(m,3H),6.76–6.46(m,1H),2.51(s,3H).

[1173] Example 64: Preparation of Compound 64

[1174] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1175]

[1176] To a solution of 4-bromo-1H-pyrazole (2.9 g, 20.0 mmol), bis(pinacolato)diboron (7.68 g, 30.0 mmol) and potassium acetate (3.8 g, 40.0 mmol) in 1,4-dioxane (100.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 2.0 mmol). The mixture was stirred at 100 ° C under nitrogen for 8.0 hours and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The crude product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.1 g, 5.64 mmol, 28.2% yield) was obtained. LC-MS: m / z=195.0 (M+H) + , retention time 1.70 min (Method A). The product was used directly in the next step.

[1177] 4-Phenyl-1H-pyrazole

[1178]

[1179] To a solution of bromobenzene (1.32 g, 8.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.1 g, 5.6 mmol) and potassium carbonate (2.35 g, 17.0 mmol) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (580 mg, 0.8 mmol) in N,N-dimethylformamide / water (15.0 mL / 3.0 mL). The mixture was stirred at 100 ° C for 4.0 hours under nitrogen and cooled to room temperature. Ethyl acetate and water were added to the solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain 4-phenyl-1H-pyrazole (600 mg, 6.32 mmol, 74.4% yield) as a yellow solid. LC-MS: m / z=145.0 (M+H) + , retention time 1.65 minutes (Method A).

[1180] 2-Bromo-5-(4-phenyl-1H-pyrazol-1-yl)pyridine

[1181]

[1182] A mixture of 2-bromo-5-iodopyridine (1.0 g, 3.52 mmol), 4-phenyl-1H-pyrazole (500 mg, 3.5 mmol), cuprous iodide (67.09 mg, 0.35 mmol), potassium phosphate (1.87 g, 8.81 mmol), (1R, 2R)-cyclohexane-1,2-diamine (45.6 mg, 0.4 mmol) in 1,4-dioxane (10.0 mL) was stirred at 100 ° C for 4.0 hours. The reaction solution was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 2-bromo-5- (4-phenyl-1H-pyrazol-1-yl) pyridine (520 mg, 1.74 mmol, 49.5% yield) as a yellow oil. LC-MS: m / z = 300.0 (M + H) + , retention time 2.05 minutes (Method A).

[1183] 2-Hydrazino-5-(4-phenyl-1H-pyrazol-1-yl)pyridine

[1184]

[1185] To a solution of 2-bromo-5-(4-phenyl-1H-pyrazol-1-yl)pyridine (480 mg, 1.6 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (400 mg, 8.0 mmol, 85% in water). The mixture was stirred at 110 ° C in a sealed tube for 2.0 hours. The mixture was cooled and concentrated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to give (2-hydrazino-5-(4-phenyl-1H-pyrazol-1-yl)pyridine (160 mg, 0.64 mmol, 39.9% yield) as a yellow solid. LC-MS: m / z = 252.0 (M + H) + , retention time 1.65 minutes (Method A).

[1186] 4-(5-Hydroxy-3-methyl-1-(5-(4-phenyl-1H-pyrazol-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[1187]

[1188] A mixture of methyl 2-(4-cyanophenyl)-3-oxobutanoate (0.1 g, 0.48 mmol) and 2-hydrazino-5-(4-phenyl-1H-pyrazol-1-yl)pyridine (0.1 g, 0.4 mmol) in acetic acid (10.0 mL) was stirred at 120° C. for 0.5 h and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give 4-(5-hydroxy-3-methyl-1-(5-(4-phenyl-1H-pyrazol-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (42.8 mg, 0.43 mmol, 25.6% yield) as a white solid. LC-MS: m / z=419.0 (M+H) + , retention time 3.52 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ13.04(s,1H),9.09(s,1H),9.01(s,1H),8.73–8.58(m,1H),8.54–8.40(m,1H),8.31(s, 1H),8.01–7.87(m,2H),7.87–7.78(m,2H),7.79–7.67(m,2H),7.52–7.36(m,2H),7.35–7.20(m,1H),2.51(s,3H).

[1189] Example 65: Preparation of Compound 65

[1190] 2-Chloro-5-(cyclopropylthio)pyridine

[1191]

[1192] A mixture of 6-chloropyridine-3-thiol (1.0 g, 6.90 mmol) (intermediate of Example 24), cyclopropylboronic acid (2.97 g, 34.48 mmol), copper acetate (2.48 g, 13.8 mmol) and triethylamine (4.19 g, 41.4 mmol) in dichloromethane (50.0 mL) was stirred at 40 ° C for 12.0 hours under oxygen. The reaction mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 2-chloro-5- (cyclopropylthio) pyridine (900 mg, 4.86 mmol, 70.9% yield) as a yellow oil. LC-MS: m / z = 186.1 (M + H) + , retention time 2.04 minutes (Method A)

[1193] 2-Chloro-5-(cyclopropylsulfinyl)pyridine

[1194]

[1195] 3-Chlorobenzoic acid (1.08 g, 5.35 mmol, 85%) was added to a solution of 2-chloro-5-(cyclopropylthio)pyridine (900 mg, 4.86 mmol) in dichloromethane (10.0 mL) at 0 ° C. The mixture was stirred at this temperature for 1.0 hour. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain 2-chloro-5-(cyclopropylsulfinyl)pyridine (900 mg, 4.47 mmol, 92.1% yield) as a yellow solid. LC-MS: m / z=202.1 (M+H) + , retention time 1.49 minutes (Method A).

[1196] (S)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone and (R)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone

[1197]

[1198] To a mixture of 2-chloro-5-(cyclopropylsulfinyl)pyridine (900 mg, 4.47 mmol) and ammonium carbamate (1.39 g, 17.9 mmol) in methanol (25.0 mL) was added (diacetoxyiodo)benzene (4.30 g, 13.4 mmol). The mixture was stirred at room temperature for 30 minutes and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain (6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ as a yellow syrup. 6 -sulfonone (1.2 g, crude product). LC-MS: m / z=217.0 (M+H) + , retention time 0.55 min (Method A).

[1199] It was separated by chiral preparative HPLC to give two isomers as yellow solids: (S)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone (400 mg, 1.85 mmol) and (R)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone (430 mg, 1.99 mmol).

[1200] (S)-Cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 -sulfonone

[1201]

[1202] To (S)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 To a solution of -sulfurone (120 mg, 0.56 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (180 mg, 2.87 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to obtain (S)-cyclopropyl (6-hydrazine pyridin-3-yl) (imino)-λ as a yellow solid. 6 -sulfonone (120 mg, crude product). LC-MS: m / z=213.0 (M+H) + , retention time 0.35 min (Method A).

[1203] (R)-Cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 -sulfonone

[1204]

[1205] To (R)-(6-chloropyridin-3-yl)(cyclopropyl)(imino)-λ 6 To a solution of -sulfurone (120 mg, 0.56 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (180 mg, 2.87 mmol, 85% in water). The mixture was stirred at 80 ° C for 4.0 hours. The mixture was cooled and concentrated to dryness. The residue was distributed between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with petroleum ether and filtered to obtain (R)-cyclopropyl (6-hydrazinylpyridin-3-yl) (imino)-λ as a yellow solid. 6 -sulfonone (130 mg, crude product). LC-MS: m / z=213.0 (M+H) + , retention time 0.35 min (Method A).

[1206] (S)-(6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone

[1207]

[1208] Ethyl 2-(4-chlorophenyl)-3-oxobutanoate (130 mg, 0.56 mmol) (intermediate of Example 1) and (S)-cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 A mixture of 1-sulfonone (100 mg, 0.47 mmol) in acetic acid (5.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (S)-(6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)(imino)-λ as a white solid. 6 -sulfonone (37.95 mg, 0.10 mmol, 20.8% yield). LC-MS: m / z=389.0 (M+H) + , retention time 7.68 minutes (Method A). 1HNMR (400MHz, DMSO-d6) δ12.73(s,1H),8.85(d,J=2.0Hz,1H),8.69–8.51(m,1H),8.37(dd,J=8.9,2.3Hz,1H),7.68(d,J =8.6Hz,2H),7.43(d,J=8.5Hz,2H),4.55(s,1H),2.87–2.71(m,1H),2.41(s,3H),1.28–1.10(m,1H),1.07–0.85(m,3H).

[1209] Example 66: Preparation of Compound 66

[1210] (R)-(6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)(imino)-λ 6 -sulfonone

[1211]

[1212] Ethyl 2-(4-chlorophenyl)-3-oxobutanoate (130 mg, 0.56 mmol) (intermediate of Example 1) and (R)-cyclopropyl(6-hydrazinopyridin-3-yl)(imino)-λ 6 A mixture of 1-sulfonone (100 mg, 0.47 mmol) in acetic acid (5.0 mL) was stirred at 120° C. for 1.0 hour and concentrated. The resulting residue was purified by reverse phase preparative HPLC to give (R)-(6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(cyclopropyl)(imino)-λ as a white solid. 6 -sulfonone (49.9 mg, 0.13 mmol, 27.4% yield). LC-MS: m / z=389.0 (M+H) + , retention time 7.68 minutes (Method A). 1 HNMR (400MHz, DMSO-d6) δ12.74(s,1H),8.85(d,J=2.1Hz,1H),8.63(d,J=8.6Hz,1H),8.38(dd,J=8.9,2.4Hz,1H),7.67(d ,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H),4.56(s,1H),2.85–2.72(m,1H),2.42(s,3H),1.21–1.12(m,1H),1.09–0.84(m,3H).

[1213] Example 67: Preparation of Compound 67

[1214] N-(6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide

[1215]

[1216] A solution of methyl 2-(4-chlorophenyl)-3-oxobutanoate (258.00 mg 1.07 mmol) and N-(6-hydrazinopyridin-3-yl)methanesulfonamide (217.0 mg, 1.07 mmol) (intermediate of Example 6) in acetic acid (5.0 mL) was stirred at 120 ° C for 1.0 hour and concentrated to dryness. The residue was triturated with ethyl acetate and filtered to give N-(6-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanesulfonamide (210 mg, 1.07 mmol, 53.4% ​​yield) as a white solid. LC-MS: m / z = 378.9 (M + H) + , retention time 4.70 minutes (Method A). 1 HNMR(400MHz,DMSO-d6)δ12.52(s,1H),9.92(s,1H),8.47(s,1H),8.31(m,1H ),7.76(m,1H),7.67(m,1H),7.43(d,J=8.0Hz,1H),3.06(s,3H),2.40(s,3H).

[1217] Example 68: Preparation of Compound 68

[1218] 3-((6-chloro-4-methylpyridin-3-yl)thio)2-propionic acid ethylhexyl ester

[1219]

[1220] A mixture of 5-bromo-2-chloro-4-methylpyridine (4.3 g, 20.9 mmol), 2-ethylhexyl 3-mercaptopropionate (4.5 g, 20.9 mmol), N,N-diisopropylethylamine (5.4 g, 41.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3 g, 2.1 mmol) and tris(dibenzylideneacetone)dipalladium (0.96 g, 1.1 mmol) in toluene (100.0 mL) was stirred at 120° C. under nitrogen for 12 hours and cooled. The reaction was diluted with ice water and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1) to give ethylhexyl 3-((6-chloro-4-methylpyridin-3-yl)thio)2-propanoate (3.2 g, 9.32 mmol, 44.6% yield) as a brown oil. LC-MS: m / z = 344.0 (M+H) + , retention time 2.50 minutes (Method A).

[1221] 6-Chloro-4-methylpyridine-3-thiol

[1222]

[1223] To a solution of ethylhexyl 3-((6-chloro-4-methylpyridin-3-yl)thio)2-propanoate (3.4 g, 10 mmol) in anhydrous tetrahydrofuran (100.0 mL) at -78 ° C., potassium tert-butoxide (15.0 mL, 15.0 mmol, 1 M in tetrahydrofuran) was added. The mixture was warmed to 0 ° C. and stirred for another 30 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=5 / 1) to give 6-chloro-4-methylpyridine-3-thiol (1.0 g, 6.25 mmol, 62.5% yield) as a yellow oil. LC-MS: m / z=160.0 (M+H) + , retention time 1.82 minutes (Method A).

[1224] 2-Chloro-5-(cyclopropylthio)-4-methylpyridine

[1225]

[1226] A mixture of 6-chloro-4-methylpyridine-3-thiol (1.59 g, 10.0 mmol), cyclopropylboronic acid (0.43 g, 50.0 mmol), copper acetate (3.5 g, 20.0 mmol) and triethylamine (6.07 g, 60.0 mmol) in dichloromethane (100.0 mL) was stirred at 40 ° C under oxygen for 12.0 hours. The reaction mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1) to give 2-chloro-5-(cyclopropylthio)-4-methylpyridine (200 mg, 1.0 mmol, 10% yield) as a yellow oil. LC-MS: m / z=200.0 (M+H) + , retention time 2.06 minutes (Method A).

[1227] 2-Chloro-5-(cyclopropylsulfinyl)-4-methylpyridine

[1228]

[1229] 3-Chlorobenzoic acid (200 mg, 1.0 mmol, 85%) was added to a solution of 2-chloro-5-(cyclopropylthio)-4-methylpyridine (200 mg, 1.0 mmol) in dichloromethane (20.0 mL) at 0 ° C. The mixture was stirred at this temperature for 2.0 hours. The reaction was basified with 10% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain 2-chloro-5-(cyclopropylsulfinyl)-4-methylpyridine (200 mg, 0.92 mmol, 92.5% yield) as a yellow solid. LC-MS: m / z=216.0 (M+H) + , retention time 1.55 minutes (Method A).

[1230] (S)-(6-chloro-4-methylpyridin-3-yl)(cyclopropyl)(methylene)-λ 6 -sulfonone and (R)-(6-chloro-4...

Claims

1. A compound having the structure of Formula III: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 It is SO2R 6 、SOR 7 R 8 、SOR 9 、COR 10 、(CH2) p COOH、NHR 11 、POR 12 R 13 、 Selected from The heterocycloalkyl group is optionally substituted by C 1-3 Alkyl or phenyl substituted C 4-7 Heteroaryl, or C optionally substituted by one or more halogen 1-3 alkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 6 It is C 1-3 Alkyl, NHCOR 15 NR 16 R 17 or phenyl; R 7 It is C 1-3 Alkyl, C 3-5 Cycloalkyl, phenyl or NR 18 R 19 ; R 8 is NH, NCN or NCH3; R 9 It is C 1-3 alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 11 It's COR 21 or SO2R 22 ; R 12 and R 13 Each is independently C 1-3 alkyl; R 14 It is C 1-3 alkyl; R 15 It is C 1-3 alkyl; R 16 and R 17 Each independently is H, C 1-3 Alkyl, C 6-14 Aryl, or R 16 and R 17 Together with the carbon to which it is attached, R 18 and R 19 are independently H or C 1-3 alkyl; R 20 It is C 1-3 alkyl; R 21 yes or C 1-3 alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl; R 23 and R 24 are independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

2. The compound according to claim 1, having a structure according to formula VI: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 is cyclopropyl or optionally SO2R 14 or =O substituted selected from Heterocycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 14 It is C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

3. The compound according to claim 2, which has the structure of Formula VIa: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 2 is hydrogen or C 1-3 alkyl; R 3 is cyclopropyl or optionally SO2R 14 or =O substituted selected from a heterocycloalkyl group; and R 14 It is C 1-3 alkyl.

4. The compound according to claim 2 or 3, wherein A is CH3.

5. The compound according to claim 2, wherein R 2 It’s H.

6. The compound according to claim 2, wherein R 2 It is C 1-3 alkyl.

7. The compound according to claim 6, wherein R 2 It is CH3.

8. The compound according to claim 2, wherein R 3 It is cyclopropyl.

9. The compound according to claim 2, wherein R 3 is optionally SO2R 14 or =O substituted selected from heterocycloalkyl, and wherein R 14 It is C 1-3 alkyl.

10. The compound according to claim 9, wherein R 3 yes 11. The compound according to claim 9, wherein R 3 yes 12. The compound according to claim 9, wherein R 3 yes 13. The compound according to claim 1, having a structure according to Formula VII: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 11 It's COR 21 or SO2R 22 ; R 21 yes or C 1-3 alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl; R 23 and R 24 are independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

14. The compound according to claim 13, which has the structure of Formula VIIa: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 2 It is hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl; R 11 It's COR 21 or SO2R 22 ; R 21 yes or C 1-3 alkyl; R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl; and R 23 and R 24 are independently H or C 1-3 alkyl.

15. The compound according to claim 13 or 14, wherein A is CH3.

16. The compound according to claim 13, wherein R 2 It’s H.

17. The compound according to claim 13, wherein R 2 It is C 1-3 alkyl.

18. The compound according to claim 17, wherein R 2 It is CH3.

19. The compound according to claim 13, wherein R 11 It's COR 21 , and where R 21 yes or C 1-3 alkyl.

20. The compound according to claim 19, wherein R 21 yes 21. The compound according to claim 20, wherein R 21 yes 22. The compound according to claim 20, wherein R 21 yes 23. The compound according to claim 19, wherein R 21 It is cyclopropyl.

24. The compound according to claim 19, wherein R 21 It is C 1-3 alkyl.

25. The compound according to claim 24, wherein R 21 It is CH2CH3.

26. The compound according to claim 13, wherein R 11 It is SO2R 22 , where R 22 It is NR 23 R 24 or C optionally substituted by carboxyl 1-3 alkyl, and wherein R 23 and R 24 are independently H or C 1-3 alkyl.

27. The compound according to claim 26, wherein R 22 is C optionally substituted by carboxyl 1-3 alkyl.

28. The compound according to claim 27, wherein R 22 It is CH3.

29. The compound according to claim 27, wherein R 22 It is CH2CH3.

30. The compound according to claim 27, wherein R 22 It is CH2COOH.

31. The compound according to claim 26, wherein R 22 It is NR 23 R 24 , and where R 23 and R 24 are independently H or C 1-3 alkyl.

32. The compound according to claim 31, wherein R 22 It is NHCH3.

33. The compound according to claim 31, wherein R 22 It is N(CH3)2.

34. The compound of claim 1, having a structure according to Formula VIII: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 3 is optionally C 1-3 Alkyl or phenyl substituted C 4-7 heteroaryl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

35. The compound of claim 34, having the structure of Formula VIIIa: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; and R 3 is optionally C 1-3 Alkyl or phenyl substituted C 4-7 Heteroaryl.

36. The compound of claim 34 or 35, wherein A is CH3.

37. The compound according to claim 34, wherein R 3 It is C 4-7 Heteroaryl.

38. The compound according to claim 37, wherein R 3 yes 39. The compound according to claim 37, wherein R 3 yes 40. The compound according to claim 37, wherein R 3 yes 41. The compound according to claim 37, wherein R 3 yes 42. The compound according to claim 37, wherein R 3 yes 43. The compound according to claim 37, wherein R 3 yes 44. The compound according to claim 34, wherein R 3 is C optionally substituted by phenyl 4-7 Heteroaryl.

45. The compound according to claim 44, wherein R 3 yes 46. ​​The compound according to claim 44, wherein R 3 yes 47. The compound according to claim 44, wherein R 3 yes 48. The compound according to claim 44, wherein R 3 yes 49. The compound according to claim 44, wherein R 3 yes 50. The compound according to claim 44, wherein R 3 yes 51. The compound of claim 1 having a structure according to Formula IX: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 10 It is C 1-3 Alkyl or NHSO2R 20 ; R 20 It is C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

52. The compound of claim 51 , having the structure of Formula IXa: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1a is CN or halogen; R 10 It is C 1-3 Alkyl or NHSO2R 20 ;and R 20 It is C 1-3 alkyl.

53. The compound according to claim 51 or 52, wherein R 1a It is CN.

54. The compound according to claim 51 or 52, wherein R 1a It's a halogen.

55. The compound according to claim 54, wherein R 1a It's Cl.

56. The compound according to claim 51, wherein R 10 It is C 1-3 alkyl.

57. The compound according to claim 56, wherein R 10 It is CH3.

58. The compound according to claim 56, wherein R 10 It is CH(CH3)2.

59. The compound according to claim 56, wherein R 10 It is CH2CH3.

60. The compound according to claim 51, wherein R 10 It is NHSO2R 20 , and where R 20 It is C 1-3 alkyl.

61. The compound according to claim 60, wherein R 20 It is CH3.

62. The compound of claim 1, having a structure according to Formula X: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 9 It is C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

63. The compound according to claim 62, wherein R 1a It is CN.

64. The compound according to claim 62 or 63, wherein R 1 It’s H.

65. The compound of claim 62 or 63, wherein A is CH3.

66. The compound according to claim 62, wherein R 2 It’s H.

67. The compound according to claim 62, wherein R 9 It is C 1-3 alkyl.

68. The compound according to claim 67, wherein R 9 It is CH3.

69. The compound of claim 1, having a structure according to Formula XI: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen, or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; n is 0, 1, 2, or 3; and p is 1, 2, or 3.

70. The compound according to claim 69, wherein R 1a It is CN.

71. The compound according to claim 69 or 70, wherein R 1 It’s H.

72. The compound of claim 69, wherein A is CH3.

73. The compound according to claim 69, wherein R 2 It’s H.

74. The compound of claim 69, wherein p is 1.

75. The compound of claim 1, having a structure according to Formula XII: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 Each independently selected from the group consisting of: hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

76. The compound according to claim 75, wherein R 1a It is CN.

77. The compound according to claim 75 or 76, wherein R 1 It’s H.

78. The compound according to claim 75, wherein R 2 It’s H.

79. The compound of claim 1, having a structure according to Formula XIII: or a pharmaceutically acceptable salt thereof, wherein: A is C 1-3 alkyl; R 1 are each independently selected from the group consisting of: hydrogen and C 1-3 alkyl; R 1a is CN, halogen or C optionally substituted by CN 1-3 alkyl; R 2 are each independently selected from the group consisting of hydrogen, halogen, NR 4 R 5 , OH, C 1-3 Alkyl and C 3-6 Cycloalkyl; R 4 and R 5 are each independently H or C 1-3 alkyl; R 12 It is C 1-3 alkyl; R 13 It is C 1-3 alkyl; and m is 1, 2, 3 or 4.

80. The compound according to claim 79, wherein R 1a It is CN.

81. The compound according to claim 79 or 80, wherein R 1 It’s H.

82. The compound of claim 79, wherein A is CH3.

83. The compound according to claim 79, wherein R 2 It is C 1-3 alkyl.

84. The compound according to claim 83, wherein R 2 It is CH3.

85. The compound according to claim 79, wherein R 12 It is C 1-3 alkyl.

86. The compound according to claim 85, wherein R 12 It is CH3.

87. The compound according to claim 79, wherein R 13 It is C 1-3 alkyl.

88. The compound according to claim 87, wherein R 13 It is CH3.

89. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

90. The compound of claim 89, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

91. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

92. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

93. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

94. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

95. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

96. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

97. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

98. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

99. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

100. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

101. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein the compound is:

102. The compound of claim 89, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

103. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by a deuterium atom.

104. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

105. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease mediated by PHD activity.

106. The use according to claim 105, wherein the disease mediated by PHD activity is ischemia-reperfusion injury.

107. The use according to claim 106, wherein the ischemia-reperfusion injury is selected from the group consisting of stroke, myocardial infarction and acute kidney injury.

108. The use of claim 105, wherein the disease mediated by PHD activity is inflammatory bowel disease.

109. Use according to claim 108, wherein the inflammatory bowel disease is ulcerative colitis.

110. The use according to claim 108, wherein the inflammatory bowel disease is Crohn's disease.

111. The use of claim 105, wherein the disease mediated by PHD activity is cancer.

112. The use according to claim 111, wherein the cancer is colorectal cancer.

113. The use of claim 105, wherein the disease mediated by PHD activity is a liver disease.

114. The use of claim 105, wherein the disease mediated by PHD activity is atherosclerosis.

115. The use of claim 105, wherein the disease mediated by PHD activity is a cardiovascular disease.

116. The use of claim 105, wherein the disease mediated by PHD activity is a disease or condition of the eye.

117. The use according to claim 116, wherein the disease or condition of the eye is selected from radiation retinopathy, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration and ocular ischemia.

118. The use according to claim 105, wherein the disease is anemia.

119. The use according to claim 118, wherein the anemia is anemia associated with chronic kidney disease.

120. The use according to claim 105, wherein the disease is chronic kidney disease.

121. The use according to claim 105, wherein the disease is associated with hyperoxia.

122. The use according to claim 121, wherein the disease is retinopathy of prematurity.

123. The use according to claim 121, wherein the disease is bronchopulmonary dysplasia (BPD).

124. The use according to claim 105, wherein the disease is selected from ischemic heart disease, valvular heart disease, congestive heart failure, acute lung injury, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute liver failure, liver fibrosis and cirrhosis.

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