WO2023168686A1

WO2023168686A1 - Substituted cyclopentanes as cdk2 inhibitors

Info

Publication number: WO2023168686A1
Application number: PCT/CN2022/080313
Authority: WO
Inventors: Hailong Li; Hu HE; Wenge Zhong; Yuanhao WANG; Xiumei Chen; Wei Huang; Xianqiang SUN; Yang Yu; Junhong HUANG; Wei Liu; Xinde CHEN
Original assignee: Qilu Regor Therapeutics Inc.
Priority date: 2022-03-11
Filing date: 2022-03-11
Publication date: 2023-09-14

Abstract

The present disclosure provides a compound represented by structural formula (I) : or a pharmaceutically acceptable salt, or a stereoisomer thereof and their use in, e.g. treating a disease or disorder associated with CDK2. This disclosure also features compositions containing the same as well as methods of using and making the same.

Description

[Title established by the ISA under Rule 37.2] SUBSTITUTED CYCLOPENTANES AS CDK2 INHIBITORS

BACKGROUND

Cyclin-Dependent Kinases (CDKs) are a family of protein kinases first discovered for their roles in regulating cell cycle. They have since been identified to play roles in regulating a number of other biological functions such as transcription, mRNA processing, and the differentiation of nerve cells.

CDKs are relatively small proteins with molecular weights between about 34-40 kDa. They contain little more than the kinase domain, and are essentially inactive when not in complex with a class of regulatory proteins called cyclins. CDK levels remain relatively constant throughout the cell cycle, and most regulation is post-translational, most prominently by binding to cyclins.

CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in a variety of human cancers. CDK2 plays a crucial role in promoting G1/Stransition and S phase progression. In complex with cyclin E (CCNE) , CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb) , leading to de-repression of E2F transcription factors, expression of G1/Stransition related genes and transition from G1 to S phase (Henley, S.A. and F.A. Dick, Cell Div, 2012, 7 (1) : 10) . This in turn enables activation of CDK2/cyclin A, which phosphorylates endogenous substrates that permit DNA synthesis, replication and centrosome duplication (Ekholm, S.V. and S.I. Reed, Curr Opin Cell Biol, 2000, 12 (6) : 676-84) . It has been reported that the CDK2 pathway influences tumorigenesis mainly through amplification and/or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors (e.g., p27) , respectively (Xu, X., et al., Biochemistry, 1999, 38 (27) : 8713-22) .

CCNE1 copy-number gain and overexpression have been identified in ovarian, gastric, endometrial, breast and other cancers and been associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002, 347 (20) : 1566-75; Nakayama, N., et al., Cancer, 2010, 116 (11) : 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017, 23 (7) : 1862-1874; Rosen, D.G., et al., Cancer, 2006, 106 (9) : 1925-32) . Amplification and/or overexpression of CCNE1 also reportedly contribute to trastuzumab resistance in HER2+breast cancer and resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011, 108 (9) : 3761-6; Herrera-Abreu, M.T., et al., Cancer Res, 2016, 76 (8) : 2301-13) . Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, Y N., et al., Proc Natl Acad Sci USA, 1999, 96 (8) : 4325-9; Mendoza, N., et al., Cancer Res, 2003, 63 (5) : 1020-4) . Inhibition of CDK2 also reportedly restores sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in a preclinical model (Scaltriti, supra) .

These data provide a rationale for considering CDK2 as a potential target for new drug development in cancer associated with deregulated CDK2 activity. In the last decade there has been increasing interest in the development of CDK selective inhibitors. Despite significant efforts, there are no approved agents targeting CDK2 to date (Cicenas, J., et al., Cancers (Basel) , 2014, 6 (4) : 2224-42) .

Identifying selective CDK2 inhibitors is very difficult, partly due to the extreme similarity between the active sites of CDK2 and other CDKs, especially CDK1, which is the only essential CDK in the cell cycle. Inhibition of CDK1 could lead to many unintended side effects.

Therefore, it remains a need to discover CDK inhibitors having novel activity profiles, in particular those specifically or selectively targeting CDK2.

SUMMARY

Described herein are compounds of Formula (I) that inhibit (e.g., selectively inhibit) the activity of CDK2, and pharmaceutically acceptable salts, or stereoisomers thereof.

In one aspect, the present disclosure provides a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof:

wherein ring A and W are defined herein.

Also provided are pharmaceutical compositions comprising a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.

The present disclosure further provides methods of inhibiting CDK2 in a patient, comprising administering to the patient a compound of Formula (I) , or a pharmaceutically acceptable salt, or a stereoisomer thereof.

The present disclosure also provides methods of treating a disease or condition modulated at least in part by CDK2 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof.

The present disclosure further provides a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of (1) a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof; or (2) a pharmaceutically acceptable composition comprising a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the cancer is treatable by inhibiting (e.g., selectively inhibiting) CDK2, such as a cancer selected from the group consisting of: ovarian cancer, breast cancer (such as hormone receptor positive, HER2/neu negative advanced or metastatic breast cancer, HER2 positive breast cancer and triple negative breast cancer ) , lung cancer, endometrial cancer, neuroblastoma, gastric cancer, colorectal cancer, prostate cancer, glioblastoma, melanoma, mantel cell lymphoma, chronic myeloid leukemia and acute myeloid leukemia. In certain embodiments, the cancer exhibits abnormally up-regulated CCNE1/Cyclin E activity, through overexpression of Cyclin Eor duplication of the Cyclin E-coding CCNE1 gene. In certain embodiments, the cancer exhibits abnormally up-regulated Cyclin A2 activity.

In certain embodiments of the methods of the invention, the cancer can be treated by inhibiting (e.g., selectively inhibiting) the activity of CDK2.

In certain embodiments of the methods of the invention, the compounds of the invention are administered with any one of a second therapeutic agent as described herein that also treats the same cancer.

The present disclosure also provides a use of a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof or a pharmaceutical composition comprising the same in any of the methods described herein. In one embodiment, provided is a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof or a pharmaceutical composition comprising the same for use in any of the methods described herein. In another embodiment, provided is use of a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for any of the methods described herein.

DETAILED DESCRIPTION

1. Compounds

In a first embodiment, the present disclosure provides a compound represented by Formula I:

a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:

ring A is heteroaryl represented by

W is

3-12 membered heterocyclyl, or 5-10 membered heteroaryl; wherein said 3-12 membered heterocyclyl or 5-10 membered heteroaryl represented by W is optionally substituted by one or more halogen, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, or C _2-6alkynyl;

R ¹ is H or C _1-6alkyl; wherein said C _1-6alkyl represented by R ¹ is optionally substituted with one or more halogen, -OH, CN, oxo, or –NH ₂;

R ^1' is H, C _1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said C _1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl represented by R ^1' is optionally substituted with one or more halogen, CN, oxo, or C _1-6alkyl;

R ² is H, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, C _2-6alkynyl, C _1-6hydroxylalkyl, C _1-6alkoxylC _1-6alkylene, – (CH ₂) _0 or 1-3-12 membered carbocyclyl, – (CH ₂) _0 or 1-3-12 membered heterocyclyl, – (CH ₂) _0 or 1-6-10 membered aryl, or – (CH ₂) _0 or 1-5-10 membered heteroaryl; wherein said C _2-6alkenyl, C _2-6alkynyl, – (CH ₂) _0 or 1-3-12 membered carbocyclyl, – (CH ₂) _0 or 1-3-12 membered heterocyclyl, – (CH ₂) _0 or 1-6-10 membered aryl, or – (CH ₂) _0 or 1-5-10 membered heteroaryl represented by R ² is optionally substituted by one or more halogen, hydroxyl, CN, or C _1-6alkyl; or

R ¹ and R ², together with the attached N atom, form a 3-8 membered heterocyclyl; wherein said 3-8 membered heterocyclyl is optionally substituted by one or more R ^#; wherein each R ^#is independently F, hydroxyl, C _1-4 alkyl, C _1-4alkoxyl, or CN;

R ³ is H or halogen;

R ⁴ is

R ⁵ is H, halogen, C _1-6alkyl, C (O) OR ^5a, C (O) NR ^5aR ^5b, or

R ⁶ is H, halogen, or C _1-6alkyl;

wherein

each ring B is independently 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

U is a bond, -CH ₂-, -C≡C-, or –C (O) NH-;

R ^5a and R ^5b are independently H or C _1-6alkyl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-6alkyl, C _1-6haloalkyl, C _1-6hydroxylalkyl, C _1-6alkoxylC _1-6alkylene, C _2-6alkenyl, C _2-6alkynyl, -C (O) R ^*, -C (O) OR ^*, -C (O) NR ^*R ^*, -OR ^*, -SO ₂R ^*, -NR ^*R ^*, -NR ^*C (O) R ^*, -NR ^*C (O) OR ^*, -NR ^*SO ₂R ^*, -NR ^*SO ₂NR ^*R ^*, -P (O) R ^*R ^*, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein

said 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one or more halogen or C _1-6alkyl; and

each R ^*is independently selected from the group consisting of hydrogen, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, C _2-6alkynyl, 3-6 membered carbocyclyl, and 4-6 membered heterocyclyl;

n is 0, 1, 2, 3, 4, or 5 (as appropriate) ;

m is 0, 1, 2, 3, 4, or 5 (as appropriate) ;

R ⁷ is H or halogen; and

wherein said heterocyclyl comprises 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur; and said heteroaryl comprises 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.

In a second embodiment, the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by Formula IIA:

a pharmaceutically acceptable salt, or a stereoisomer thereof. The definitions of the variables are provided in the first embodiment.

In a third embodiment, the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by Formula IIB:

In a fourth embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is selected from the group consisting of:

The definitions of the remaining variables are provided in any one of the first through third embodiments.

In a fifth embodiment, the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is

The definitions of the remaining variables are provided in any one of the first through fourth embodiments.

In a sixth embodiment, the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is

In a seventh embodiment, the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is

In an eighth embodiment, the present disclosure provides a compound according to any one of the first through seventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is

The definitions of the remaining variables are provided in any one of the first through seventh embodiments.

In a ninth embodiment, the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-10 membered heteroaryl optionally substituted by 1 to 3 C _1-4alkyl, C _1-4haloalkyl, C _2-4alkenyl, or C _2-4alkynyl. The definitions of the remaining variables are provided in any one of the first through eighth embodiments.

In a tenth embodiment, the present disclosure provides a compound according to the ninth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-6 membered heteroaryl (e.g. pyridinyl, pyrimidinyl) optionally substituted by C _1-4alkyl (e.g., isopropyl) or C _2-4alkenyl (e.g., isopropenyl) . The definitions of the remaining variables are provided in the ninth embodiment.

In an eleventh embodiment, the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ is H. The definitions of the remaining variables are provided in any one of the first through eighth embodiments.

In a twelfth embodiment, the present disclosure provides a compound according to any one of the first through eighth and eleventh embodiments, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ² is H, C _1-6alkyl, C _1-6haloalkyl, C _2-4alkenyl, C _2-4alkynyl, C _1-6hydroxylalkyl, C _1-6alkoxylC _1-6alkylene, – (CH ₂) _0 or 1-3-6 membered carbocyclyl, – (CH ₂) _0 or 1-3-6 membered heterocyclyl, – (CH ₂) _0 or 1-phenyl, or – (CH ₂) _0 or 1-5-6 membered heteroaryl; wherein said C _2-4alkenyl, C _2-4alkynyl, – (CH ₂) _0 or 1-3-6 membered carbocyclyl, – (CH ₂) _0 or 1-3-6 membered heterocyclyl, – (CH ₂) _0 or 1-phenyl, or – (CH ₂) _0 or 1-5-6 membered heteroaryl represented by R ² is optionally substituted by one to three groups selected from halogen, hydroxyl, CN, and C _1-4alkyl. The definitions of the remaining variables are provided in any one of the first through eighth and eleventh embodiments.

In a thirteenth embodiment, the present disclosure provides a compound according to any one of the first through eighth, eleventh, and twelfth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is H, C _1-5alkyl, C _1-5haloalkyl, C _1-4hydroxylalkyl, C _1-4alkoxylC _1-4alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH ₂) -phenyl; wherein said 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH ₂) -phenyl represented by R ² is optionally substituted by one or two groups selected from halogen, hydroxyl, CN, and C _1-4alkyl. The definitions of the remaining variables are provided in any one of the first through eighth, eleventh, and twelfth embodiments.

In a fourteenth embodiment, the present disclosure provides a compound according to any one of the first through eighth and eleventh through thirteen embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is C _1-4alkyl, C _1-4hydroxylalkyl, or cyclopropyl; wherein said cyclopropyl represented by R ² is optionally substituted by C _1-2alkyl. The definitions of the remaining variables are provided in any one of the first through eighth and eleventh through thirteen embodiments.

In a fifteenth embodiment, the present disclosure provides a compound according to any one of the first through eighth and eleventh through thirteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is selected from the group consisting of:

H,

The definitions of the remaining variables are provided in any one of the first through eighth and eleventh through thirteenth embodiments.

In a sixteenth embodiment, the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ and R ², together with the attached N, form a 4-6 membered heterocyclyl; wherein said 4-6 membered heterocyclyl is optionally substituted by one to three halogen (e.g. F) or C _1-4alkyl. The definitions of the remaining variables are provided in any one of the first through eighth embodiments.

In a seventeenth embodiment, the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ and R ², together with the attached N, form a pyrrolidinyl group. The definitions of the remaining variables are provided in any one of the first through eighth embodiments.

In a eighteenth embodiment, the present disclosure provides a compound according to any one of the first through fifth and eighth through seventeenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ³ is H or F. The definitions of the remaining variables are provided in any one of the first through fifth and eighth through seventeenth embodiments.

In a nineteenth embodiment, the present disclosure provides a compound according to any one of the first through fifth and eighth through eighteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ³ is H. The definitions of the remaining variables are provided in any one of the first through fifth and eighth through eighteenth embodiments.

In an twentieth embodiment, the present disclosure provides a compound according to any one of the first through fourth and sixth through seventeenth embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ⁵ is H, halogen, CH ₃, isopropyl, C (O) OH, C (O) N (CH ₃) ₂, or

The definitions of the remaining variables are provided in any one of the first through fourth and sixth through seventeenth embodiments.

In a twenty-first embodiment, the present disclosure provides a compound according to any one of the first through fourth, sixth through seventeenth, and twentieth embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ⁵ is

The definitions of the remaining variables are provided in any one of the first through fourth, sixth through seventeenth, and twentieth embodiments.

In a twenty-second embodiment, the present disclosure provides a compound according to any one of the first through fourth, sixth through seventeenth, twentieth, and twenty-first embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein U is a bond. The definitions of the remaining variables are provided in any one of the first through fourth, sixth through sixteenth, eighteenth, and nineteenth embodiments.

In a twenty-third embodiment, the present disclosure provides a compound according to any one of the first through twenty-second embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

each ring B is independently 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4hydroxylalkyl, C _1-4alkoxylC _1-4alkylene, C _2-4alkenyl, C _2-6alkynyl, -OR ^*, -SO ₂R ^*, -C (O) NR ^*R ^*, -NR ^*SO ₂NR ^*R ^*, -C (O) R ^*, -C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one to three halogen or C _1-4alkyl; and

each R ^*is independently selected from the group consisting of hydrogen, C _1-4alkyl, C _1-4haloalkyl, C _2-4alkenyl, C _2-4alkynyl, 4-6 membered carbocyclyl, and 5-6 membered heterocyclyl;

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3.

The definitions of the remaining variables are provided in any one of the first through twenty-second embodiments.

In a twenty-fourth embodiment, the present disclosure provides a compound according to any one of the first through twentieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

each ring B is independently 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4hydroxylalkyl, C _2-4alkenyl, C _2-4alkynyl, -C _1-4alkyleneC _1-2alkoxy, -OR ^*, -SO ₂R ^*, -C (O) NR ^*R ^*, C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one to two halogen or C _1-2alkyl; and

each R ^*is independently selected from the group consisting of hydrogen, C _1-4alkyl, and C _1-4haloalkyl;

m is 0, 1, or 2; and

n is 0, 1, or 2.

The definitions of the remaining variables are provided in any one of the first through twenty-third embodiments.

In a twenty-fifth embodiment, the present disclosure provides a compound according to the twenty-second embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁴ is 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;

each R ^4a is F, -CN, -OH, C _1-3alkyl, C _1-2hydroxylalkyl, -C _1-2alkyleneC _1- ₂alkoxy, -OC _1-2alkyl, -SO ₂C _1-2alkyl, -C (O) NR ^*R ^*, C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a is optionally substituted by halogen or C _1-2alkyl;

each R ^*is independently selected from the group consisting of hydrogen or C _1-3alkyl; and

m is 0, 1, or 2.

The definitions of the remaining variables are provided in the twenty-fourth embodiment.

In a twenty-six embodiment, the present disclosure provides a compound according to the twenty-fourth or twenty-fifth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁴ is 6 membered heteroaryl;

each R ^4a is C _1-2hydroxylalkyl; and

m is 0 or 1.

The definitions of the remaining variables are provided in the twenty-fourth or twenty-fifth embodiment.

In a twenty-seventh embodiment, the present disclosure provides a compound according to any one of the first through twenty-fifth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R ⁴ is selected from the group consisting of

The definitions of the remaining variables are provided in any one of the first through twenty-fifth embodiments.

In a twenty-eighth embodiment, the present disclosure provides a compound according to any one of the first through fifth, eighth through twenty-fifth, and twenty-seventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^4a is selected from the group consisting of

F,

The definitions of the remaining variables are provided in any one of the first through fifth, eighth through twenty-fifth, and twenty seventh embodiments.

In a twenty-ninth embodiment, the present disclosure provides a compound according to the twenty-fourth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁵ is 5-6 membered monocyclic carbocyclyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;

each R ^5c is halogen, -CN, C _1-3alkyl, C _1-3haloalkyl, C _1-3alkoxy, C _1-3haloalkoxy, C _1-2alkoxylC _1-2alkylene, -SO ₂C _1-3alkyl, or -SO ₂C _1-3haloalkyl; and

n is 0, 1, or 2.

In a thirtieth embodiment, the present disclosure provides a compound according to the first through twenty-ninth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R ⁵ is selected from the group consisting of

The definitions of the remaining variables are provided in the the first through twenty-ninth embodiments.

In a thirty-first embodiment, the present disclosure provides a compound according to the first through thirtieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^5c is selected from the group consisting of

F, Cl,

The definitions of the remaining variables are provided in the the first through thirtieth embodiments.

In a thirty-second embodiment, the present disclosure provides a compound according to the first through seventh and eighteenth through thirty first embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^1' is H or C _1-4alkyl (e.g., isopropyl) . The definitions of the remaining variables are provided in the the first through seventh and eighteenth through thirty-first embodiments.

In one embodiment, the present disclosure provides a compound selected from the compounds disclosed in examples and Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.

Table 1

2. Definitions

The term “halogen, ” as used herein, refers to fluoride, chloride, bromide, or iodide.

The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula -C _nH _(2n+1) . Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. C _1-6alkyl. As used herein, a “C _1-6alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.

The terms “haloalkyl” means alkyl, as the case may be, substituted with one or more halogen atoms. In one embodiment, the alkyl can be substituted by one to three halogens. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the like.

The term “alkylene” as used herein, means a straight or branched chain divalent hydrocarbon group of formula -C _nH _2n-. Non-limiting examples include ethylene, and propylene.

The terms “haloalkylene” means alkylene, as the case may be, substituted with one or more halogen atoms. In one embodiment, the alkylene can be substituted by one to three halogens.

The term “alkenyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.

The term “alkynyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.

The term “carbocyclyl” refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl. In one embodiment, carbocyclyl is 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated. Any substitutable ring atom can be substituted (e.g., by one or more substituents) . Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include, bridged, fused, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiro [3.3] heptanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo [2.2.1] heptanyl, bicyclo [2.2.1] hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two-or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl) , indenyl, indanyl (dihydroindenyl) , anthracenyl, phenanthrenyl, and decalinyl.

The term “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, cycloalkyl may have 3 to 7 ring cabons. Any substitutable ring atom can be substituted (e.g., by one or more substituents) . Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl include: bicyclo [1.1.0] butane, bicyclo [2.1.0] pentane, bicyclo [1.1.0] pentane, bicyclo [3.1.0] hexane, bicyclo [2.1.1] hexane, bicyclo [3.2.0] heptane, bicyclo [4.1.0] heptane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane, bicyclo [4.2.0] octane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom) . Non-limiting examples of spirocyclic cycloalkyls include spiro [2.2] pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro [3.5] nonane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [2.6] nonane, spiro [4.5] decane, spiro [3.6] decane, spiro [5.5] undecane, and the like.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3-to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone ( “3-12 membered heterocyclyl” ) . In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “3-7 membered heterocyclyl” ) . In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or polycyclic (e.g., a bicyclic system ( “bicyclic heterocyclyl” ) or tricyclic system ( “tricyclic heterocyclyl” ) ; polycyclic ring systems include fused, bridged, or spiro ring systems) . Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.

Spiro heterocyclyl refers to 5 to 12 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom) , wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Representive examples of spiro heterocyclyl include, but are not limited to the following groups:

Fused heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but at least one of the rings does not have a completely conjugated π-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C. Representive examples of fused heterocyclyl include, but are not limited to the following groups:

Bridged heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated π-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, the remaining ring atoms being C. Representive examples of bridged heterocyclyl include, but are not limited to the following groups:

Generally, the carbocyclyl, the cycloalkyl, or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein the substituents can be independently selected from a number of groups such as oxo, -CN, halogen, alkyl and alkoxyl, opotionally, the alkyl substitution may be further substituted.

The term “aryl” refers to a 6 to 10 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated π-electron system. The term “aryl” may be used interchangeably with the terms “aryl ring” “carbocyclic aromatic ring” , “aryl group” and “carbocyclic aromatic group” . Representive examples of aryl are phenyl and naphthyl.

The term “heteroaryl, ” as used herein, refers to a monocyclic or multicyclic aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based on a C _5-10 aryl with one or more of its ring carbon atoms replaced by the heteroatom. A heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom. Generally, the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows with the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH ₂, NHalkyl, N (alkyl) ₂) , optionally, the alkyl may be further substituted.

Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl) , imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) , oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl) , pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl) , thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , triazolyl (e.g., 2-triazolyl, 5-triazolyl) , tetrazolyl (e.g., tetrazolyl) , thienyl (e.g., 2-thienyl, 3-thienyl) , pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A “substituted heteroaryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.

As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl ) are referred to as being either “substituted” or “optionally substituted” . When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and/or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety.

Where suitable substituents are not specifically enumerated, exemplary substituents include, but are not limited to: C _1-5alkyl, C _1-5hydroxyalkyl, C _1-5haloalkyl, C _1-5alkoxy, C _1-5 haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO ₂, -OR ^c1, -NR ^a1R ^b1, -S (O) _iR ^a1, -NR ^a1S (O) _iR ^b1, -S (O) _iNR ^a1R ^b1, -C (=O) OR ^a1, -OC (=O) OR ^a1, -C (=S) OR ^a1, -O (C=S) R ^a1, -C (=O) NR ^a1R ^b1, -NR ^a1C (=O) R ^b1, -C (=S) NR ^a1R ^b1, -C (=O) R ^a1, -C (=S) R ^a1, NR ^a1C (=S) R ^b1, -O (C=O) NR ^a1R ^b1, -NR ^a1 (C=S) OR ^b1, -O (C=S) NR ^a1R ^b1, -NR ^a1 (C=O) NR ^a1R ^b1, -NR ^a1 (C=S) NR ^a1R ^b1, phenyl, or 5-6 membered heteroaryl. Each R ^a1 and each R ^b1 are independently selected from –H and C _1-5alkyl, optionally substituted with hydroxyl or C _1-3alkoxy; R ^c1 is –H, C _1-5haloalkyl or C _1-5alkyl, wherein the C _1-5alkyl is optionally substituted with hydroxyl or C ₁-C ₃alkoxy.

The symbol

as used herein, refers to the point where the moiety attaches.

Pharmaceutically Acceptable Salts

The term “pharmaceutically-acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19.

Pharmaceutically acceptable salts of the compounds of any one of the formulae described above include acid addition and base salts.

Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid (s) . Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids) . Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base (s) . Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) .

Pharmaceutically acceptable salts of compounds of any one of the formulae described above may be prepared by one or more of three methods:

(i) by reacting the compound of any one of the formulae described above with the desired acid or base;

(ii) by removing an acid-or base-labile protecting group from a suitable precursor of the compound of any one of the formulae described above or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of any one of the formulae described above to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms.

Stereoisomers and Other Variations

The compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism) . Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure.

Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifcal and are not mirror images of each other.

When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S” ) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99%or 99.9%optically pure (also referred to as “enantiomerically pure” ) . Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair) , it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99%or 99.9%by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

When two stereoisomers are depicted by their chemical names or structures, and the chemical names or structures are connected by an “and” , a mixture of the two stereoisomers is intended.

When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or” , one or the other of the two stereoisomers is intended, but not both.

When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R” , the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

Racemic mixture means 50%of one enantiomer and 50%of the corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

The term “geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclic ring, or to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carbon- carbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.

Substituents around a carbon-carbon double bond can also be referred to as “cis” or “trans, ” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans. ” The term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans. ”

Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ( “tautomerism” ) can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

In certain instances tautomeric forms of the disclosed compounds exist, such as the tautomeric structures shown below:

When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9%pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers/diastereomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) . Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of any one of the formulae described above contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer (s) by means well known to a skilled person. Chiral compounds of any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50%by volume of isopropanol, typically from 2%to 20%, and from 0 to 5%by volume of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998) , 75 (Supercritical Fluid Chromatography with Packed Columns) , pp. 223-249 and references cited therein) . Columns can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of

Chemical Industries, Ltd., Tokyo, Japan.

It must be emphasized that the compounds of any one of the formulae described above have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present disclosure.

3. Administration and Dosing

Typically, a compound of the present disclosure is administered in an amount effective to treat a condition as described herein. The compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.

The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

The compounds of the present disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be administered directly to the eye or ear.

The dosage regimen for the compounds of the present disclosure and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg/kg (i.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.

For oral administration, the compositions may be provided in the form of tablets containing 0.1-500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc) . In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

4. Pharmaceutical Compositions

In another embodiment, the present disclosure comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present disclosure presented, a pharmaceutically acceptable salt, or a stereoisomer thereof with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances can also be present.

As used herein, “pharmaceutically acceptable carrier or excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.

The compositions of present disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions) , dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g. intravenous, subcutaneous, intraperitoneal, intramuscular) . In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water) . Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening) , and/or perfuming agents.

In another embodiment, the present disclosure comprises a parenteral dose form.

“Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.

In another embodiment, the present disclosure comprises a topical dose form.

“Topical administration” includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of present disclosure are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated -see, for example, Finnin and Morgan, J. Pharm. Sci., 88: 955-958, 1999.

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) , or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

In another embodiment, the present disclosure comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.

The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3 ^rd Ed. ) , American Pharmaceutical Association, Washington, 1999.

5. Method of Treatment

Compounds of the present disclosure can inhibit CDK2 and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by CDK2. Such diseases include cancer and other diseases with proliferation disorder.

In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula (I) , or a pharmaceutically acceptable salt, or a stereoisomer thereof such that growth of cancerous tumors is inhibited. A compound of Formula (I) or of any of the formulae as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK2 kinase activity. These include, but not limited to, diseases (e.g., cancers) that are characterized by amplification or overexpression of CCNE1 such as ovarian cancer, uterine carcinosarcoma and breast cancer and p27 inactivation such as breast cancer and melanomas. Accordingly, in some embodiments of the methods, the patient has been previously determined to have an amplification of the cyclin E1 (CCNE1) gene and/or an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. Alternatively, a compound of Formula (I) or of any of the formulae as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (I) or of any of the formulae as described herein, or of a compound as recited in any of the claims and described herein, or of a pharmaceutically acceptable salt or a stereoisomer thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with CCNE1 amplification and overexpression in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I) or of any of the formulae as described herein, or of a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, compounds of the present disclosure selectively inhibit CDK2 over CDK1, with a ratio of IC ₅₀ values for the latter (CDK1) against the former (CDK2) of at least about 2, 5, 10, 15, 20, 40, 50, 60, 80, 100 or more.

In some embodiments, provided herein is a method of inhibiting CDK2, comprising contacting the CDK2 with a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt, or a stereoisomer thereof. In some embodiments, provided herein is a method of inhibiting CDK2 in a patient, comprising administering to the patient a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient (in need thereof) , a therapeutically effective amount of a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is characterized by inactivation of a CDK2 inhibitor, such as p21Cip1 or p27Kip1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

In certain embodiments, the patient has been diagnosed with a cancer characterized by amplification or overexpression of CCNE1, and/or loss of function of p21Cip1 or p27Kip1.

In certain embodiments, the method further comprises determining the status of expression of CCNE1, p21Cip1 and/or p27Kip1.

In certain embodiments, the method further comprises selecting patients characterized by amplification or overexpression of CCNE1, and/or loss of function of p21Cip1 or p27Kip1 for treatment.

In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the disease or disorder associated with CDK2 is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1.

In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (See Molenaar et al., Proc Natl Acad Sci USA, 106 (31) : 12968-12973) , K-Ras mutant lung cancers (see Hu, S., et al., Mol Cancer Ther, 2015, 14 (11) : 2576-85, and cancers with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017, 77 (18) : 4881-4893) .

In some embodiments, the disease or disorder associated with CDK2 is breast, lung, colorectal, gastric, or bone cancer, leukemia or lymphoma.

In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

In some embodiments, the disease or disorder associated with CDK2 is a cancer.

In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1.

In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/6 inhibition.

In some embodiments, the breast cancer is advanced or metastatic breast cancer. Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS) , primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma) , renal cancer (e.g., clear cell carcinoma) , prostate cancer (e.g., hormone refractory prostate adenocarcinoma) , breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer) , squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSI ^high) . Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. ) , hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular) , Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing’s sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer. In some embodiments, the compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , acute promyelocytic leukemia (APL) , chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular) , Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF) , polycythemia vera (PV) , and essential thrombocytosis (ET) ) , myelodysplasia syndrome (MDS) , T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM) .

Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC) , small cell lung cancer (SCLC) , bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) , and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma] ) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) .

Exemplary liver cancers include hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , and spinal cord (neurofibroma, meningioma, glioma, sarcoma) , as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma) , cervix (cervical carcinoma, pre -tumor cervical dysplasia) , ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , and fallopian tubes (carcinoma) .

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia) , triple-negative breast cancer (TNBC) , myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

It is believed that compounds of Formula (I) , or any of the embodiments thereof, may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

The terms “individual” or “patient, ” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

The terms “treatment, ” “treat, ” and “treating” refer to reversing, alleviating, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed (i.e., therapeutic treatment) . In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen) . Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

The terms “condition, ” “disease, ” and “disorder” are used interchangeably.

The term “administer, ” “administering, ” or “administration” refers to methods introducing a compound disclosed herein, or a composition thereof, in or on a patient. These methods include, but are not limited to, intraarticular (in the joints) , intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition) , Mack Publishing Co., Easton, Pa.

Generally, an effective amount of a compound taught herein varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.

The term “therapeutically effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be an amount effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anticancer agent, its mode of administration, combination treatment with other therapies, and the like.

6. Combination Therapies

I. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction in multiple signaling pathways. Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-estrogen agents, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4/6 kinase inhibitors such as, for example, those described in WO 2006/056399 can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

In some embodiments, the CDK2 inhibitor is administered or used in combination with an anti-estrogen agent or a CDK4/6 inhibitor or a mTOR inhibitor or a BCL2 inhibitor or a chemotherapy.

The compounds as disclosed herein can be used in combination with one or more other enzyme/protein/receptor inhibitors therapies for the treatment of diseases, such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapies include those as described herein. Examples of cancers include solid tumors and non-solid tumors, such as liquid tumors, blood cancers. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-DR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGF βR, PI3K (alpha, beta, gamma, delta, and multiple or selective) , CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3) , FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828) , INCB62079) , an EGFR inhibitor (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab) , a VEGFR inhibitor or pathway blocker (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept) , a PARP inhibitor (e.g., olaparib, rucaparib, veliparib or niraparib) , a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110) , INCB052793, or INCB054707) , an IDO inhibitor (e.g., epacadostat, NLG919, or BMS-986205, MK7162) , an LSD1 inhibitor (e.g., GSK2979552, INCB59872 and INCB60003) , a TDO inhibitor, a PI3K-delta inhibitor (e.g., parsaclisib (INCB50465) or INCB50797) , a PI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914) , a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer; e.g., INCB081776) , an adenosine receptor antagonist (e.g., A2a/A2b receptor antagonist) , an HPK1 inhibitor, a chemokine receptor inhibitor (e.g., CCR2 or CCR5 inhibitor) , a SHP1/2 phosphatase inhibitor, a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) , c-MET inhibitors (e.g., capmatinib) , an anti-CD19 antibody (e.g., tafasitamab) , an ALK2 inhibitor (e.g., INCB00928) ; or combinations thereof.

In some embodiments, the compound or salt described herein is administered with a PI3K6 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib) . In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor, which is selective over JAK2. Example antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2) , ranibizumab (e.g., anti-VEGF-A) , bevacizumab (AVASTINTM , e.g., anti-VEGF) , panitumumab (e.g., anti-EGFR) , cetuximab (e.g., anti-EGFR) , rituxan (e.g., anti-CD20) , and antibodies directed to c-MET. One or more of the following agents may be used in combination with the compounds of the present disclosure and are presented as a non-limiting list: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778, 123, BMS 214662, IRESSATM (gefitinib) , TARCEVATM (erlotinib) , antibodies to EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN ^TM (oxaliplatin) , pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17. alpha. -ethinylestradiol, diethylstilbestrol, testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN ^TM (trastuzumab) , BEXXAR ^TM (tositumomab) , VELCADE ^TM (bortezomib) , ZEVALIN ^TM (ibritumomab tiuxetan) , TRISENOX ^TM (arsenic trioxide) , XELODA ^TM (capecitabine) , vinorelbine, porfimer, ERBITUX ^TM (cetuximab) , thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225 (cetuximab) , Campath (alemtuzumab) , clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101, 731.

The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2) , CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecific or multi-specific antibody, antibody drug conjugate, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor, PI3Kd inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutic agent. Examples of chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

Additional examples of chemotherapeutics include proteasome inhibitors (e.g., bortezomib) , thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone or prednisone. Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC ^TM) , nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts. Other example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and their pharmaceutically acceptable salts. Other example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptable salts. Other example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and their pharmaceutically acceptable salts. Other example suitable CDK4/6 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074, and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.

In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma, can include, without limitation, melphalan, melphalan plus prednisone [MP] , doxorubicin, dexamethasone, and Velcade (bortezomib) . Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY) , melphalan (MEL) , and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX) . In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM) . Additive or synergistic effects are desirable outcomes of combining a CDK2 inhibitor of the present disclosure with an additional agent.

The agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the disclosure where the dexamethasone is administered intermittently as opposed to continuously.

The compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules) , cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

The compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV) , Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV) . In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

In some further embodiments, combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.

The compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, &C) , Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus) , flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc. ) , Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc. ) , Genus Mucorales (mucor, absidia, rhizophus) , Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents) .

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ) , the disclosure of which is incorporated herein by reference as if set forth in its entirety.

II. Immune-checkpoint therapies

Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases, such as cancer or infections. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB) , ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B) .

In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) , pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent (s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab) .

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) , or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 bispecific antibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136. In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675, 206.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab. The compounds of the present disclosure can be used in combination with bispecific antibodies.

In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFb receptor.

In some embodiments, the compounds of the disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the present compound in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

7. Treatment Kits

One aspect of the present invention relates to a kit for conveniently and effectively carrying out the methods or uses in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Optionally associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

The following representative examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and the equivalents thereof. These examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit its scope. Indeed, various modifications of the invention, and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon review of this document, including the examples which follow and the references to the scientific and patent literature cited herein.

The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

In addition, for purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry, ” Thomas Sorrell, University Science Books, Sausalito: 1999, and “Organic Chemistry, ” Morrison &Boyd (3d Ed) , the entire contents of both of which are incorporated herein by reference.

8. Preparation

The compounds of any one of the formulae described above, may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience) . The starting materials used herein are commercially available or may be prepared by routine methods known in the art.

In the preparation of the compounds of any one of the formulae described above, it is noted that some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the formulae described above precursors) . The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.

For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) , and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.

The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present disclosure. Some of the compounds of the present present disclosure may contain single or multiple chiral centers with the stereochemical designation (R) or (S) . It will be apparent to one skilled in the art that all of the synthetic transformations can be conducted in a similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.

EXAMPLES

Abbreviations

AcOH Acetic acid

DCE 1, 2-Dichloroethane

DCM 1, 2-Dichloromethane

DIPEA N-ethyl-N-isopropylpropan-2-amine

DMAP 4-Dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO Dimethyl sulfoxide

Dppf 1, 1'-Bis (diphenylphosphino) ferrocene

EDCI N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride

EtOH Ethanol

EtOAc Ethyl acetate

HATU N- [ (Dimethylamino) -lH-l, 2, 3-triazolo- [4, 5-b] pyridin-l-ylmethylene] -N

methylmethanaminium hexafluorophosphate N-oxide

HOBT 1-Hydroxybenzotriazole

HPLC High-performance liquid chromatography

Prep-HPLC Preparative High-performance liquid chromatography

LC-MS Liquid chromatography -mass spectrometry

MeOH Methanol

NBS N-bromosuccinimide

NMM N-Methylmorpholine

PE Petroleum ether

Pd (dppf) Cl ₂ Dichloro [l, l'-bis (diphenylphosphino) ferrocene] palladium

Pd (dtbpf) Cl ₂ Dichloro [1, 1'-bis (di-t-butylphosphino) ferrocene] palladium

Pd (PPh ₃) ₄ Tetrakis (triphenylphosphine) palladium

TFA Trifluoroacetic acid

SFC Supercritical fluid chromatography

Xantphos 4, 5-Bis (diphenylphosphino) -9, 9-dimethylxanthene

wt. % Weight percentage

rac Racemic

General Procedures. All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Low-resolution mass spectra (LC-MS) was used to monitor progression of reactions and was recorded on Waters ACQUITY UPLC with SQ Detectors using a Waters CORTECS C18 column (2.7 μm, 4.6 × 30 mm) using a gradient elution method: solvent A: 0.1%formic acid in water; solvent B: 0.1%formic acid in CH ₃CN; 5%solvent B to 95%solvent B in 1.0 min, hold 1.0 min, equilibration to 5%solvent B in 0.5 min; flow rate: 1.8 mL/min; column temperature 40 ℃. Purification of final products by Prep-HPLC were carried out on Waters Prep-HPLC with QDA detector, using Xbridge C18 column (5 μm, 150 × 19 mm) using a gradient elution method. Benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate, Benzyl (1- (tert-butyl) -3- ( (1R, 3S) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate and (trans, rac) -3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl methanesulfonate were purchased from PharmaBlock.

Intermediates

Intermediate 1

Step 1: benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) carbamate

To a suspension of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (6.00 g, 16.8 mmol) in CH ₂Cl ₂ (100 mL) were sequentially added imidazole (1.71 g, 25.2 mmol) and TBDPSCl (6.93 g, 25.2 mmol) at 20 ℃. The mixture was stirred at that temperature for 6 h before it was quenched with water (50 mL) and extracted with CH ₂Cl ₂ (100 mL ×3) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 8 %in 15 min) to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert- butyldiphenylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (9.30 g, 92%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 595.8.

Step 2: benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4- fluoro-1H-pyrazol-5-yl) carbamate

To a suspension of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (6.50 g, 10.9 mmol) in CH ₃CN (200 mL) was added Selectfluor (7.92 g, 22.4 mmol) at 25 ℃. The mixture was stirred at that temperature for 1 h before it was quenched with water (200 mL) . The mixture was concentrated under reduced pressure to remove most of CH ₃CN and extracted with EtOAc (100 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 15 %in 15 min) to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-yl) carbamate (3.70 g, 55%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 614.3.

Step 3: 1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H- pyrazol-5-amine

To a stirred mixture of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-yl) carbamate (3.70 g, 6.03 mmol) in THF (50.0 mL) and EtOAc (50.0 mL) was added Pd/C (1.28 g, 5%wt. %, 6.75 mmol) at 25 ℃. The mixture was stirred at that temperature under H ₂ atmosphere (balloon) for 2 h before it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-amine (2.44 g, 84%yield) as yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 480.3.

Synthetic Examples

Example 1

(1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate and Intermediate 2

Step 1: 2-methylpyrazolo [1, 5-a] pyrazin-4 (5H) -one

To a stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (2.50 g, 19.8 mmol) in 1, 4-dioxane (15.0 mL) was added CDI (3.42 g, 23.8 mmol) at 25 ℃. The mixture was stirred at that temperature for 0.5 h before 2, 2-dimethoxyethanamine (2.18 mL, 2.10 g, 20.0 mmol) was added at 25 ℃. The mixture was stirred at that temperature for 0.5 h before HCl (1.0 mL, 12.0 M aq., 12.0 mmol) was added. The mixture was warmed to 100 ℃ and stirred at that temperature for 48 h. The reaction mixture was cooled to 25 ℃, quenched with water (50 mL) and then extracted with EtOAc (50 mL × 2) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-methyl-5H-pyrazolo [1, 5-a] pyrazin-4-one (2.00 g, 68%yield) as a brown oil. LC-MS: m/z [M+H] ⁺ 150.1.

Step 2: 4-bromo-2-methylpyrazolo [1, 5-a] pyrazine

To a stirred solution of 2-methyl-5H-pyrazolo [1, 5-a] pyrazin-4-one (500 mg, 3.35 mmol) and DMF (0.1 mL) in toluene (10.0 mL) was added POBr ₃ (0.511 mL, 1.44 g, 5.03 mmol) at 25 ℃. The reaction mixture was warmed to 90 ℃ and stirred at that temperature for 12 h before it was cooled, quenched with water at 0 ℃ and extracted with EtOAc (50 mL × 3) . The combined organic phases were washed with saturated aqueous of Na ₂CO ₃ (10 mL) and brine (10 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 60 %in 30 min) to give 4-bromo-2-methyl-pyrazolo [1, 5-a] pyrazine (180 mg, 25%yield) as a yellow sloid. LC-MS: m/z [M+H] ⁺ 211.9.

Step 3: N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine

To a stirred solution of 2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-amine (200 mg, 592 μmol) in DMF (5.0 mL) were sequentially added 4-bromo-2-methylpyrazolo [1, 5-a] pyrazine (163 mg, 770 μmol) and KOt-Bu (199 mg, 1.78 mmol) at 0 ℃. The reaction mixture was stirred at that temperature for 1 h before it was quenched with water (30 mL) , extracted with EtOAc (30 mL × 3) . The combined organic phases were washed with brine (10 mL) , dried over Na ₂SO ₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30 %in 20 min) to give N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine (180 mg, 65%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 469.3.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentan-1-ol (Intermediate 2)

To a stirred solution of N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine (180 mg, 384 μmol) in THF (5.0 mL) was added TBAF (1.92 mL, 1.0 M in THF, 1.92 mmol) at 20 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 16 h before it was quenched with water (5 mL) , extracted with EtOAc (5 mL × 2) . The combined organic phases were washed with brine (10 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 60 %in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (100 mg, 73%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 355.0.

Step 5: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (50.0 mg, 141 μmol) in CH ₃CN (2.0 mL) were sequentially added DIPEA (39.3 μL, 28.6 mg, 282 μmol) , CDI (34.3 mg, 212 μmol) and DMAP (3.45 mg, 28.2 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 12 h before it was concentrated under reduced pressure. To the residue were sequentially CH ₃CN (2.0 mL) and Et ₃N (39.3 μL, 28.6 mg, 282 μmol) , propan-2-amine (36.2 μL, 25.0 mg, 423 μmol) at 25 ℃. The mixture was stirred at that temperature for 12 h before it was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE = 1: 1) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (40.0 mg, 65%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 440.3.

Step 6: (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (40.0 mg, 91.0 μmol) in TFA (2.0 mL) was warmed to 70 ℃ and stirred at that temperature for 2 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was diluted with CH ₂Cl ₂ (20 mL) , washed with saturated aqueous solution of NaHCO ₃ (5 mL) , extracted with CH ₂Cl ₂ (5 mL × 2) . The combined organic phases were washed with brine (5 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE = 1: 1) to give (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (10.1 mg, 29%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 384.2.

Example 2

(1R, 3S) -3- (4-fluoro-3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

Step 1: N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro- 1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine

To a stirred solution of 1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-amine (220 mg, 1.04 mmol) in DMF (5.0 mL) were sequentially added 4-bromo-2-methylpyrazolo [1, 5-a] pyrazine (385 mg, 800 μmol) and KOt-Bu (270 mg, 2.41 mmol) at 0 ℃. The reaction mixture was stirred at that temperature for 30 min before it was quenched with water (30 mL) and extracted with EtOAc (30 mL × 2) . The combined organic phases were washed with brine (20 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10 %in 15 min) to give N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine (250 mg, 39%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 611.3.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol

To a stirred solution of N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine (300 mg, 491 μmol) in THF (5.0 mL) was added TBAF (385 mg, 1.47 mmol) at 25 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled, diluted with EtOAc (50 mL) and washed with saturated aqueous of NH ₄Cl (40 mL) and brine (10 mL) . The organic phase was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50 %in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (180 mg, 98%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 373.1.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (180 mg, 483 μmol) in CH2Cl2 (10.0 mL) were sequentially added CDI (209 mg, 1.45 mmol) , DMAP (59.0 mg, 483 μmol) and Et3N (202 μL, 147 mg, 1.45 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl 1H-imidazole-1-carboxylate (220 mg, 98%yield) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z [Methyl ester + H] ⁺ 431.2.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate (220 mg, 472 μmol) in CH ₃CN (6.0 mL) were sequentially added propan-2-amine (202 μL, 139 mg, 2.36 mmol) and Et ₃N (197 μL, 143 mg, 1.41 mmol) at 25 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80 %in 20 min) to afford the (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (198 mg, 92%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 458.1.

Step 5: (1R, 3S) -3- (4-fluoro-3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-5-yl) cyclopentyl isopropylcarbamate

A stirred solution of (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (180 mg, 393 μmol) in HCO ₂H (5.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 70%in 30 min) to afford the (1R, 3S) -3- (4-fluoro-3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (28.1 mg, 18%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 402.1.

The following compounds were prepared using the similar procedure disclosed in synthetic example 1.

Example 11

(1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclobutyl) carbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (40.0 mg, 113 μmol) in CH ₃CN (1.0 mL) were sequentially added DMAP (13.8 mg, 113 μmol) , NMM (37.2 μL, 34.2 mg, 339 μmol) and (4-nitrophenyl) carbonochloridate (68.2 mg, 339 μmol) at 20 ℃. The reaction mixture was stirred at that temperature for 3 h before it was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (50.0 mg, 85%yield) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 520.2.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl (1-methylcyclobutyl) carbamate

To a stirred suspension of 1-methylcyclobutanamine hydrochloride (81.9 mg, 674 μmol) in CH ₃CN (1.0 mL) were sequentially added Et ₃N (268 μL, 195 mg, 1.92 mmol) and a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (50.0 mg, 96.2 μmol) in CH ₃CN (1.0 mL) at 20 ℃. The reaction mixture was stirred at that temperature for 16 h before it was poured into H ₂O (5 mL) and extracted with EtOAc (15 mL × 3) . The combined organic phases were washed with brine (5 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE = 1: 1) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (1-methylcyclobutyl) carbamate (25.0 mg, 56%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 466.3.

Step 3: (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl (1-methylcyclobutyl) carbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (1-methylcyclobutyl) carbamate (20.0 mg, 43.0 μmol) in HCO ₂H (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 25%to 65%in 30 min) to give (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclobutyl) carbamate (4.6 mg, 26%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 410.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 11.

Example 20

(1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol

To a stirred solution of 2-bromopyrazine (100 mg, 631 μmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (4-amino-1-tert-butyl-pyrazol-3-yl) cyclopentanol (94.0 mg, 421 μmol) , Cs ₂CO ₃ (411 mg, 1.26 mmol) , Pd ₂ (dba) ₃ (24.4 mg, 42.1 μmol) , XantPhos (24.1 mg, 42.1 μmol) at 25 ℃. The reaction mixture was warmed to 90 ℃ and stirred at that temperature for 4 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 60%in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol (60.0 mg, 47%yield) as a light-yellow solid. LC-MS: m/z. [M+H] ⁺ 302.1.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol (60.0 mg, 199 μmol) in CH ₃CN (20.0 mL) were sequentially added NMM (109 μL, 100 mg, 995 μmol) , (4-nitrophenyl) carbonochloridate (120 mg, 597 μmol) and DMAP (48.7 mg, 398 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before isopropylamine (340 μL, 235 mg, 3.98 mmol) was added. The reaction mixture was stirred at 25 ℃ for 1 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to give the desired product (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (30.0 mg, 39%yield) as a yellow solid. LC-MS: m/z. [M+H] ⁺ 387.2.

Step 3: (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbama te

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (30.0 mg, 77.6 μmol) in HCO ₂H (10.0 mL) was warmed to 50 ℃ and stirred at that temperature for 12 h. The reaction was it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 0%to 70%in 50 min) to give (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (13.0 mg, 51%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 331.2.

Example 143

(1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2-methylpropan-2- yl) carbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy- 2-methylpropan-2-yl) carbamate

To a stirred solution of [ (1R, 3S) -3- [1-tert-butyl-5- (pyrazin-2-ylamino) pyrazol-3-yl] cyclopentyl] (4-nitrophenyl) carbonate (70.0 mg, 150 μmol) in CH ₃CN (2.0 mL) were sequentially added Et ₃N (105 μL, 75.9 mg, 750 μmol) and 2-amino-2-methylpropan-1-ol (143 μL, 134 mg, 1.50 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 12 h. The mixture was treated with H ₂O (5.0 mL) and extracted with EtOAc (10 mL × 3) . The combined organic phases were washed with brine (10 mL) , dried over Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc) to give (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (25.0 mg, 40%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 417.3.

Step 2: 2-methyl-2- ( ( ( ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) propyl 2, 2, 2-trifluoroacetate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (20.0 mg, 48.0 μmol) in TFA (1.0 mL) was warmed to 70 ℃ and stirred at that temperature for 16 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure to afford 2-methyl-2- ( ( ( ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) propyl 2, 2, 2-trifluoroacetate (20.0 mg, 91%yield) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 457.1.

Step 3: (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2- methylpropan-2-yl) carbamate

To a stirred solution of 2-methyl-2- ( ( ( ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) propyl 2, 2, 2-trifluoroacetate (20.0 mg, 43.8 μmol) in MeOH (2.0 mL) was added K ₂CO ₃ (60.6 mg, 438 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 10%to 40%in 30 min) to give (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (6.50 mg, 41%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 361.2.

Example 147

(1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (2-cyanopropan-2- yl) carbamate

Step 1: 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (80.0 mg, 171 μmol) in TFA (8.0 mL) was warmed to 70 ℃ and stirred at that temperature for 16 h. It was concentrated under reduced pressure to give 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate which was directly used in next step without purification. LC-MS: m/z [M+H] ⁺ 411.1.

Step 2: (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (2-cyanopropan-2- yl) carbamate

To a stirred solution of 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate (50.0 mg, 122 μmol) in Pyridine (4.0 mL) was added 2-amino-2-methylpropanenitrile (20.5 mg, 244 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 45%in 40 min) to give (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (2-cyanopropan-2-yl) carbamate (5.00 mg, 12%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 356.1.

Example 148

(1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl ( (S) -1-cyanopropan-2- yl) carbamate

To a stirred solution of 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate (50.0 mg, 122 μmol) in CH ₃CN (2.0 mL) were sequentially added DIPEA (42.4 μL, 31.5 mg, 243 μmol) and (S) -3-aminobutanenitrile (20.5 mg, 244 μmol) at 20 ℃. The resulting mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 45%in 40 min) to give (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl ( (S) -1-cyanopropan-2-yl) carbamate (14.0 mg, 32%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 356.0.

Example 149

(1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: (6-chloropyrazin-2-yl) methanol

To a stirred solution of methyl 6-chloropyrazine-2-carboxylate (3.50 g, 20.3 mmol) in H ₂O (50.0 mL) was added NaBH ₄ (3.85 g, 101 mmol) in portions at 0 ℃. The reaction mixture was warmed to 20 ℃ and stirred at that temperature for 0.5 h, followed by addition of sat. aq.K ₂CO ₃ (70 mL) and EtOH (50 mL) . The resulting mixture was stirred for another 1 h and extracted with EtOAc (100 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (with EtOAc from 0 to 30%in 20 min) to give (6-chloropyrazin-2-yl) methanol (920 mg, 31%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 145.2.

Step 2: 2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-chloropyrazine

To a stirred solution of (6-chloropyrazin-2-yl) methanol (400 mg, 2.77 mmol) and Imidazole (377 mg, 5.53 mmol) in CH ₂Cl ₂ (10.0 mL) was added TBSCl (251 mg, 3.04 mmol) at 0 ℃. The reaction mixture was warmed to 20 ℃ and stirred at that temperature for 2 h before it was quenched with water (50 mL) and then extracted with CH ₂Cl ₂ (50 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (with EtOAc from 0 to 30%in 20 min) to give 2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-chloropyrazine (600 mg, 84%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 259.0.

Step 3: (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol

To a stirred solution of 2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-chloropyrazine (300 mg, 1.89 mmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (338 mg, 1.51 mmol) , Pd ₂ (dba) ₃ (173 mg, 189 μmol) , XantPhos (110 mg, 189 μmol) and Cs ₂CO ₃ (1.85 g, 5.68 mmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/EtOAc (with EtOAc from 0 to 70%in 25 min) to afford (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (130 mg, 20%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 446.1.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (100 mg, 224 μmol) in CH ₃CN (5.0 mL) were sequentially added 4-nitrophenyl carbonochloridate (136 mg, 673 μmol) , NMM (123 μL, 113 mg, 1.12 mmol) and DMAP (54.8 mg, 449 μmol) at 20 ℃. The reaction mixture was stirred at that temperature for 3 h before it was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (crude) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 611.1.

Step 5: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (crude) in CH ₃CN (5.0 mL) was added propan-2-amine (182 μL, 126 mg, 2.13 mmol) at 20 ℃. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (with EtOAc from 0 to 100%in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (90.0 mg, 79%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 531.2.

Step 6: (6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate

A stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (15.0 mg, 28.3 μmol) in TFA (2.0 mL) was warmed to 70 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure to afford (6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) pyrazin-2-yl)methyl 2, 2, 2-trifluoroacetate (crude) as a yellow oil. LC-MS: m/z [M+H] ⁺ 457.2.

Step 7: (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

To a stirred solution of (6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate (crude) in MeOH (2.0 mL) was added K ₂CO ₃ (3.02 mg, 21.9 μmol) at 20 ℃. The reaction mixture was stirred at that temperature for 6 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 70%in 30 min) to give (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (3.30 mg, 42%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 361.1.

Example 150

(1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (S) - sec-butyl) carbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl ( (S) -sec-butyl) carbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (50.0 mg, 81.9 μmol) in CH ₃CN (10.0 mL) were sequentially added DIPEA (71.3 μL, 52.9 mg, 409 μmol ) and (S) -butan-2-amine hydrochloride (12.0 mg, 164 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h, The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 70 %in 20 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (36.0 mg, 81%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 545.3.

Step 2: (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl ( (S) -sec-butyl) carbamate

A stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (35.0 mg, 66.1 μmol) in TFA (5.0 mL) at 25 ℃. The resulting mixture was warmed to 80 ℃ and stirred at that temperature for 6 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was dissolved in MeOH (5.0 mL) and then K ₂CO ₃ (4.57 mg, 33.0 μmol) was added at 25 ℃, and stirred at that temperature for 15 min. The residue was concentrated under reduced pressure and purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 30%to 70%in 40 min) to give (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (S) -sec-butyl) carbamate (14.4 mg, 58%yield) as an off-white solid. LC-MS: m/z [M+H] ⁺ 375.1.

Example 151

(1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1- methylcyclopropyl) carbamate

Step 1: (6- ( (5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate

A solution of 4-nitrophenyl (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (80.0 mg, 131 μmol) in TFA (8.0 mL) was warmed to 70 ℃ and stirred at that temperature for 16 h. It was concentrated under reduced pressure to give (6- ( (5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate which was directly used in next step without purification. LC-MS: m/z [M+H] ⁺ 537.0.

Step 2: (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl (1-methylcyclopropyl) carbamate

To a stirred solution of 4-nitrophenyl (6- ( (5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate (45.0 mg, 83.9 μmol) in CH ₃CN (2.0 mL) were sequentially added DIPEA (29.2 μL, 21.7 mg, 168 μmol) and 1-methylcyclopropan-1-amine (17.9 mg, 252 μmol) at 20 ℃. The resulting mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 45%in 40 min) to give (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate (7.90 mg, 25% yield) as a white solid. LC-MS: m/z [M+H] ⁺ 373.1.

Example 152

(1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (R) - sec-butyl) carbamate

To a stirred solution of 4-nitrophenyl (6- ( (5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate (45.0 mg, 83.9 μmol) in CH ₃CN (2.0 mL) were sequentially added Et ₃N (38.0 μL, 27.6 mg, 272 μmol) and (R) -butan-2-amine (19.9 mg, 272 μmol) at 20 ℃. The resulting mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 45%in 40 min) to give [ (1R, 3S) -3- [3- [ [6- (hydroxymethyl) pyrazin-2-yl] amino] -1H-pyrazol-5-yl] cyclopentyl] N- [ (1R) -1-methylpropyl] carbamate (11.9 mg, 38%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 374.9.

Example 153 and 154

N- (5- ( (1S, 3R) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) pyrazin-2- amine and N- (5- ( (1R, 3S) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3- yl) pyrazin-2-amine

Step 1: (cis, rac) -N- (3- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H- pyrazol-5-yl) pyrazin-2-amine

To a stirred suspension of 3-bromopyridin-2-ol (115 mg, 661 μmol) in THF (10.0 mL) were sequentially added (trans, rac) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol (199 mg, 661 μmol) , DIAD (260 μL, 267 mg, 1.32 mmol) , PPh ₃ (346 mg, 1.32 mmol) at 25 ℃ under N ₂. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40%in 20 min) to give (cis, rac) -N- (3- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) pyrazin-2-amine (280 mg, 93%yield) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 457.1.

Step 2: (cis, rac) -N- (1- (tert-butyl) -3- ( 3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) pyrazin-2-amine

To a stirred solution of (cis, rac) -N- (3- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) pyrazin-2-amine (250 mg, 547 μmol) in 1, 4-dioxane (10.0 mL) /H ₂O (1.0 mL) were sequentially added 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (460 mg, 2.74 mmol) , Pd (dppf) Cl ₂ (39.7 mg, 54.7 μmol) , K ₂CO ₃ (150 mg, 1.09 mmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 16 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20 %in 20 min) to give (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazin-2-amine (200 mg, 87%yield) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 419.2.

Step 3: (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H- pyrazol-5-yl) pyrazin-2-amine

To a stirred solution of (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazin-2-amine (200 mg, 477 μmol) in MeOH (8.0 mL) was added Pd/C (50.6 mg, 10%wt., 47.7 μmol) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 5 min before it was filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30 %in 20 min) to give (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazin-2-amine (180 mg, 90%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 421.3.

Step 4: N- (5- ( (1S, 3R) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3- yl) pyrazin-2-amine and N- (5- ( (1R, 3S) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H- pyrazol-3-yl) pyrazin-2-amine

A solution of (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazin-2-amine (180 mg, 428 μmol) in HCO ₂H (5.0 mL) was warmed to 80 ℃ and stirred at that temperature for 2 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 30%to 60%in 20 min) to give (cis, rac) -N- (5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) pyrazin-2-amine (89.3 mg, 57%yield) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 365.2. The racemic mixture was further purified by SFC (Daicel CHIRALCEL OX column, CO ₂/iPrOH=55/45, iPrOH with 0.2%NH ₃, 1.5 ml/min, 35 ℃) to afford N- (5- ( (1S, 3R) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) pyrazin-2-amine (9.0 mg, 27%yield, retention time = 1.9 min, absolute configuration arbitrarily assigned) as a yellow solid. LC-MS: m/z [M+H] ⁺ 365.2. And to give N- (5- ( (1R, 3S) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) pyrazin-2-amine (13.3 mg, 40%yield, retention time = 2.3 min, absolute configuration arbitrarily assigned) as a yellow solid. LC-MS: m/z [M+H] ⁺ 365.2.

Example 21

(1R, 3S) -3- (5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate and Example 22 (1R, 3S) -3- (5- ( (2-hydroxypyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-chloropyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

To a solution of 2, 4-dichloropyrimidine (100 mg, 671 μmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (138 mg, 447 μmol) , Pd (dtbpf) Cl ₂ (58.5 mg, 89.5 μmol) , XantPhos (103 mg, 179 μmol) and K ₃PO ₄ (94.9 mg, 447 μmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ under microwave and stirred at that temperature for 1 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 15 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-chloropyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (100 mg, 53%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 421.2.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-chloropyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (100 mg, 237 μmol) in MeOH (10 mL) was added Pd/C (5.77 mg, 47.5 μmol, 10%wt. %) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 12 h before it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressur to give (1R, 3S) -3- (1- (tert-butyl) -5-(pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (100 mg) which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 387.3.

Step 3: (1R, 3S) -3- (5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

A mixture of [ (1R, 3S) -3- [1-tert-butyl-5- (pyrimidin-4-ylamino) pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (30.0 mg, 77.6 μmol) in TFA (2.0 mL) was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 25%to 35%in 15 min) to give [ (1R, 3S) -3- [5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (15.0 mg, 58%yield) as a white solid.

LC-MS: m/z [M+H] ⁺ 331.2.

Step 4: (1R, 3S) -3- (5- ( (2-hydroxypyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

A mixture of [ (1R, 3S) -3- [1-tert-butyl-5- [ (2-chloropyrimidin-4-yl) amino] pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (40.0 mg, 95.0 μmol) in TFA (5.0 mL) was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 45%to 65%in 15 min) to give [ (1R, 3S) -3- [5- [ (2-hydroxypyrimidin-4-yl) amino] -1H-pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (14.0 mg, 42%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 347.2.

Example 155

(1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl (3-methyloxetan-3- yl) carbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentan- 1-ol

To a stirred solution of 4-chloropyrimidine (500 mg, 4.37 mmol) in 1, 4-dioxane (20.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (780 mg, 3.49 mmol) , Pd ₂ (dba) ₃ (400 mg, 437 μmol) , XantPhos (253 mg, 437 μmol) and Cs ₂CO ₃ (2.85 g, 8.73 mmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 3 h before it was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with PE/EtOAc (with EtOAc from 0 to 100%in 25 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol (270 mg, 21%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 302.2.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol (100 mg, 332 μmol) in CH ₃CN (5.0 mL) were sequentially added 4-nitrophenyl carbonochloridate (201 mg, 995 μmol) , NMM (182 μL, 168 mg, 1.66 mmol) and DMAP (81.1 mg, 664 μmol) at 20 ℃. The reaction mixture was stirred at that temperature for 1 h before it was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (crude) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺467.0.

Step 3: 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate

A stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (100 mg, 214 μmol) in TFA (2.0 mL) was warmed to 70 ℃ and stirred at that temperature for 16 h. Then it was concentrated under reduced pressure to give 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate (crude) as a yellow solid. LC-MS: m/z [M+H] ⁺ 411.1.

Step 4: (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate

To a stirred solution of 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate (crude) in CH ₃CN (2.0 mL) were sequentially added Et ₃N (40.8 μL, 29.6 mg, 292 μmol) and 3-methyloxetan-3-amine (25.7 μL, 25.5 mg, 292 μmol) at 20 ℃. The resulting mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 45%in 40 min) to give (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl (3-methyloxetan-3-yl) carbamate (3.30 mg, 10%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 359.1.

Example 156

(1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentan-1-ol

To a solution of (1R, 3S) -3- (5-amino-1-tert-butyl-pyrazol-3-yl) cyclopentanol (50.0 mg, 223 μmol) in 1, 4-dioxane (3.0 mL) was added 4-chloro-2-methyl-pyrimidine (28.7 mg, 223 μmol) , Pd ₂(dba) ₃ (41.0 mg, 44.7 μmol) , XantPhos (51.8 mg, 89.5 μmol) and Cs ₂CO ₃ (218 mg, 671 μmol) at 25 ℃. The mixture was degassed with N ₂ for 5 times, heated to 100 ℃ and stirred at 100 ℃ under the atmosphere of N ₂ for 10 h. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (20 mL) , and extracted with DCM (20 mL × 3) . The combined organic phases were washed with brine (20 mL × 2) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 100%in 15 min) to afford the product (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (60.0 mg, 84%yield) as a yellow solid. LC-MS: (ESI) m/z [M+H] ⁺ 316.2.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (60.0 mg, 190 μmol) in DCE (3.0 mL) was added (4-nitrophenyl) carbonochloridate (38.3 mg, 190 μmol) , DIPEA (73.7 mg, 570 μmol) and DMAP (4.65 mg, 38.0 μmol) at 25 ℃. The mixture was degassed with N ₂ for 5 times, then heated to 70 ℃ and stirred at 70 ℃ under the atmosphere of N ₂ for 24 h. The mixture was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 90%in 15 min) to afford the (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (40.0 mg, 43%yield) as a yellow solid. LC-MS: (ESI) m/z [M+H] ⁺481.2.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate (40.0 mg, 83.2 μmol) in NMP (1.5 mL) was added bicyclo [1.1.1] pentan-1-amine (13.8 mg, 166 μmol) and Et ₃N (25.2 mg, 249 μmol) at 25 ℃. The mixture was stirred at 25 ℃ for 2 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3) . The combined organic phases were washed with brine (20 mL × 2) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE with EtOAc from 0 to 96%in 10 min to afford the product (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate (20.0 mg, 56%yield) as a yellow solid. LC-MS: (ESI) m/z [M+H] ⁺ 425.2.

Step 4: (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate

The solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate (18.0 mg, 42.4 μmol) in FA (2.0 mL) was heated to 80 ℃ and stirred at 80 ℃ for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluting with CH ₃CN from 30%to 40%in 8 min) to afford the product (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate (4.30 mg, 27%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 369.2.

Example 157

(1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate

Step 1: N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -2-methylpyrimidin-4-amine

To a solution of 4-chloro-2-methyl-pyrimidine (600 mg, 4.67 mmol) in DMF were sequentially added 2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-amine (1.58 g, 4.67 mmol) and KOt-Bu (1.57 g, 14.0 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 h before it was quenched with cold water (20 mL) and extracted with EA (20 mL × 2) . The organic layer was washed with brine, dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 10 to 80 %in 25 min) to afford N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2-methylpyrimidin-4-amine (1.10 g, 54%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 430.3.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentan-1-ol

A solution of N- [2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-yl] -2-methyl-pyrimidin-4-amine (1.1 g, 2.56 mmol) in TBAF (4.40 mL, 1.0 mol/L, 4.40 mmol) was heated to 60 ℃ and stirred at that temperature for 2 h. The mixture was cooled to 25 ℃ and quenched with cold water (20 mL) . The mixture was extracted with EA (20 mL × 3) . The EA layers were washed with brine and dried over Na ₂SO ₄. Concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80 %in 25 min) to afford (1R, 3S) -3- [1-tert-butyl-5- [ (2-methylpyrimidin-4-yl) amino] pyrazol-3-yl] cyclopentanol (710 mg, 87%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 316.3.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (710 mg, 2.25 mmol) and (4-nitrophenyl) carbonochloridate (1.81 g, 9.00 mmol) in DCM (20.0 mL) were sequentially added NMM (1.24 mL, 1.14 g, 11.3 mmol) and DMAP (136 mg, 1.13 mmol) at 25 ℃. The mixture was heated to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/CH ₂Cl ₂ (with MeOH from 0 to 15 %in 25 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (620 mg, 57%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 480.9.

Step 4: (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4- nitrophenyl) carbonate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (620 mg, 1.29 mmol) in TFA (5.0 mL) was heated to 70 ℃ and stirred at that temperature for 5 h. The mixture was concentrated under reduced pressure and the crude product was used next step without further purification. LC-MS: m/z [M+H] ⁺ 425.0.

Step 5: (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate

To a stirred solution of (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4-nitrophenyl) carbonate (50.0 mg, 118 μmol) in CH ₃CN (3.0 mL) were sequentially added 3-methyloxetan-3-amine (20.7 μL, 20.5 mg, 235 μmol, ) and Et ₃N (82.1 μL, 59.6 mg, 589 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 30%in 10 min (0.1%FA condition) ) to give (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3-methyloxetan-3-yl) carbamate (8.4 mg, 19%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 373.2.

Example 158

(1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2- methylpropan-2-yl) carbamate

Step 1: 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) nicotinonitrile

To a stirred solution of 6-chloropyridine-3-carbonitrile (500 mg, 3.61 mmol) and (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (806 mg, 3.61 mmol) in 1, 4-dioxane (10.0 mL) were sequentially added Pd ₂ (dba) ₃ (661 mg, 722 μmol) , XantPhos (835 mg, 1.44 mmol) and NaOt-Bu (867 mg, 9.02 mmol) . The mixture was heated to 90 ℃ and stirred at that temperature for 2 h under N ₂. The mixture was filtered under reduced pressure and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (with EtOAc from 30 to 90 %in 20 min) to afford 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) nicotinonitrile (500 mg, 42%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 326.3.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) nicotinonitrile (325 mg, 1.00 mmol) in CH ₂Cl ₂ (20.0 mL) were sequentially added pyridine (158 mg, 2.00 mmol) , 4-nitrophenyl carbonochloridate (404 mg, 2.00 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (with EtOAc from 0 to 60 %in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (240 mg, 49%yield) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 491.2.

Step 3: (1R, 3S) -3- (5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4- nitrophenyl) carbonate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (150 mg, 305 μmol) in TFA (3.0 mL, 4.47 g, 39.2 mmol) was warmed to 70 ℃ and stirred at that temperature for 2 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The crude product (1R, 3S) -3- (5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 435.1.

Step 4: (1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1- hydroxy-2-methylpropan-2-yl) carbamate

To a mixture of (1R, 3S) -3- (5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (40.0 mg, 92.1 μmol) and 2-amino-2-methylpropan-1-ol (43.9 μL, 41.0 mg, 460 μmol) in CH ₃CN (10.0 mL) was added Et ₃N (64.2 μL, 46.6 mg, 460 μmol) at 25 ℃. The mixture was heated to 50 ℃ and stirred at that temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 10%to 40%in 30 min) to afford (1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2-methylpropan-2-yl) carbamate (21.5 mg, 60%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 385.2.

Example 159

(1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate

To a stirred solution of (1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4-nitrophenyl) carbonate (70.0 mg, 161 μmol) in CH ₃CN (3.0 mL) were sequentially added 3-methyloxetan-3-amine (42.5 μL, 42.1 mg, 483 μmol, ) and Et ₃N (112 μL, 81.5mg, 805 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 3 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 20%to 40%in 10 min (0.1%FA condition) ) to give (1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3-methyloxetan-3-yl) carbamate (1.8 mg, 3%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 383.2.

Example 160

(1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (1r, 3R) -3- hydroxycyclobutyl) carbamate

Step 1: 2- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) isonicotinonitrile

To a stirred solution of 2-bromoisonicotinonitrile (2.00 g, 10.9 mmol) and (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (2.43 g, 10.9 mmol) in 1, 4-dioxane (100 mL) were sequentially added Pd ₂ (dba) ₃ (998 mg, 1.09 mmol) , XantPhos (1.26 g, 2.18 mmol) and Cs ₂CO ₃ (7.11 g, 21.8 mmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 16 h under N ₂ before it was cooled to 25 ℃, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 60 %in 20 min) to give 2- ( (1- (tert-butyl) -3-( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) isonicotinonitrile (2.81 g, 79%yield) as a red brown solid. LC-MS: m/z [M+H] ⁺ 326.3.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of 2- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) isonicotinonitrile (2.81 g, 8.65 mmol) in CH ₂Cl ₂ (100 mL) were sequentially added pyridine (1.37 g, 17.3 mmol) , 4-nitrophenyl carbonochloridate (3.49 g, 17.3 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 25 %in 20 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (2.85 g, 67% yield) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 491.2.

Step 3: (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4- nitrophenyl) carbonate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (100 mg, 204 μmol) in TFA (6.0 mL) was warmed to 70 ℃ and stirred at that temperature for 2 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The crude product (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4-nitrophenyl) carbonate was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 435.1.

Step 4: (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (1r, 3R) - 3-hydroxycyclobutyl) carbamate

To a stirred solution of (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4-nitrophenyl) carbonatein CH ₃CN (10.0 mL) were sequentially added (trans) -3-aminocyclobutan-1-ol hydrochloride (50.6 mg, 408 μmol) , Et ₃N (113 μL, 82.4 mg, 816 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 3 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 20%to 30%in 15 min) to give (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (1r, 3R) -3-hydroxycyclobutyl) carbamate (41.8 mg) as a light yellow solid. LC-MS: m/z [M+H] ⁺ 383.2.

Example 23

(1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) carbamate

To a solution of benzyl N- [2-tert-butyl-5- [ (1S, 3R) -3-hydroxycyclopentyl] pyrazol-3-yl] carbamate (15.0 g, 41.9 mmol) in DCM (450 mL) was added (4-nitrophenyl) carbonochloridate (12.7 g, 62.9 mmol) , pyridine (9.96 g, 126 mmol, 10.2 mL) and DMAP (1.03 g, 8.39 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure to give [ (1R, 3S) -3- [5- (benzyloxycarbonylamino) -1-tert-butyl-pyrazol-3-yl] cyclopentyl] (4-nitrophenyl) carbonate (21.0 g, 96%yield) as a white solid which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 523.1.

Step 2: benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) carbamate

To a solution of [ (1R, 3S) -3- [5- (benzyloxycarbonylamino) -1-tert-butyl-pyrazol-3-yl] cyclopentyl] (4-nitrophenyl) carbonate (22.0 g, 42.1 mmol) in DCM (230 mL) were sequentially added propan-2-amine (3.73 g, 63.1 mmol, 4.90 mL) and Et ₃N (12.8 g, 126 mmol, 17.6 mL) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40%in 30 min) to give benzyl N- [2-tert-butyl-5- [ (1S, 3R) -3- (isopropylcarbamoyloxy) cyclopentyl] pyrazol-3-yl] carbamate (15.0 g, 81%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 443.3.

Step 3: (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate 3)

To a solution of benzyl N- [2-tert-butyl-5- [ (1S, 3R) -3- (isopropylcarbamoyloxy) cyclopentyl] pyrazol-3-yl] carbamate (15.0 g, 33.9 mmol) in MeOH (160 mL) was added Pd/C (1.20 g, 1.13 mmol, 10%wt. %) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 3 h before it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30%in 30 min) to give [ (1R, 3S) -3- (5-amino-1-tert-butyl-pyrazol-3-yl) cyclopentyl] N-isopropylcarbamate (9.30 g, 89%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 309.2.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

To a solution of 5-chloropyrazolo [1, 5-a] pyrimidine (50.0 mg, 326 μmol) in 1, 4-dioxane (10 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (84.0 mg, 271 μmol) , K ₂CO ₃ (112 mg, 814 μmol) and Pd (dtbpf) Cl ₂ (35.0 mg, 54.0 μmol) at 25 ℃. The reaction mixture was warmed to 90 ℃ and stirred at that temperature for 6 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 100%in 20 min) to give [ (1R, 3S) -3- [1-tert-butyl-5- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (70.0 mg, 61%yield) as a yellow liquid. LC-MS: m/z [M+H] ⁺ 426.2.

Step 5: (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

A mixture of [ (1R, 3S) -3- [1-tert-butyl-5- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (100 mg, 235 μmol) in TFA (10 mL) was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 32%to 32%in 15 min) to give [ (1R, 3S) -3- [5- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (7.00 mg, 8%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 370.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 20.

Example 28

(1R, 3S) -3- (3- ( [3, 4'-bipyridin] -2'-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-chloropyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

To a solution of 2-bromo-4-chloropyridine (100 mg, 519 μmol) in 1, 4-dioxane (3.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (192 mg, 623 μmol) , Pd ₂ (dba) ₃ (95.2 mg, 103 μmol) , XantPhos (120 mg, 207 μmol) and Cs ₂CO ₃ (507 mg, 1.56 mmol) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 6 h. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic phases were washed with brine (10 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 43%in 20 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-chloropyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (100 mg, 45%yield) as a brown solid. LC-MS: m/z [M+H] ⁺ 420.1.

Step 2: (1R, 3S) -3- (5- ( [3, 4'-bipyridin] -2'-ylamino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-chloropyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (30.0 mg, 71.4 μmol) in 1, 4-dioxane (3.0 mL) and H ₂O (0.30 mL) were sequentially added pyridin-3-ylboronic acid (17.6 mg, 142 μmol) , Pd (OAc) ₂ (3.21 mg, 14.3 μmol) , X-Phos (6.42 mg, 13.4 μmol) , K ₂CO ₃ (29.6 mg, 214 μmol) at 25 ℃. The mixture was warmed to 110 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure, diluted with water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic phases were washed with brine (10 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM/MeOH (with MeOH from 0 to 5%in 10 min) to afford (1R, 3S) -3- (5- ( [3, 4'-bipyridin] -2'-ylamino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (25.0 mg, 76%yield) as a brown oil. LC-MS: m/z [M+H] ⁺ 463.2.

Step 3: (1R, 3S) -3- (3- ( [3, 4'-bipyridin] -2'-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (5- ( [3, 4'-bipyridin] -2'-ylamino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (20.0 mg, 43.2 μmol) in TFA (2.0 mL) was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 10%to 100%in 8 min) to afford (1R, 3S) -3- (3- ( [3, 4'-bipyridin] -2'-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (9.40 mg, 53%yield) as a green solid. LC-MS: m/z [M+H] ⁺ 407.2.

The following compounds were prepared using the similar procedure disclosed in synthetic example 28.

Example 30

(1R, 3S) -3- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

Step 1: 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) pyridine

To a suspension of (2-chloro-4-pyridyl) boronic acid (151 mg, 961 μmol) in 1, 4-dioxane (5.0 mL) and H ₂O (1.0 mL) were sequentially added 3-iodo-1-methyl-pyrazole (100 mg, 480 μmol, 51.0 μL) , Pd (dppf) Cl ₂ (70.3 mg, 96.1 μmol) and K ₂CO ₃ (199 mg, 1.44 mmol, 87.0 μL) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%to in 10 min) to give 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) pyridine (60.0 mg, 64%yield) as yellow oil. LC-MS: m/z [M+H] ⁺ 194.1.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) - 1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a suspension of 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) pyridine (37.6 mg, 194 μmol) in 1, 4-dioxane (4.0 mL) were sequentially added [ (1R, 3S) -3- (5-amino-1-tert-butyl-pyrazol-3-yl) cyclopentyl] N-isopropylcarbamate (50.0 mg, 162 μmol) , Pd ₂ (dba) ₃ (29.6 mg, 32.4 μmol) , XantPhos (37.5 mg, 64.8 μmol) and Cs ₂CO ₃ (158 mg, 486 μmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%to in 10 min) to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (30.0 mg, 39%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 466.2.

Step 3: (1R, 3S) -3- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A suspension of (1R, 3S) -3- (1- (tert-butyl) -5- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (20.0 mg, 42.9 μmol) in TFA (5.0 mL) was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 23%to 33%in 5 min) to give (1R, 3S) -3- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (3.20 mg, 18%yield) as white solid. LC-MS: m/z [M+H] ⁺ 410.2.

Example 31

(1R, 3S) -3- (3- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: (1R, 3S) -3- (1- (tert-butyl) -5- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a solution of (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (50.0 mg, 162 μmol) in DCE (4.0 mL) and AcOH (1.0 mL) were sequentially added 1-methylsulfonylpiperidin-4-one (72.0 mg, 406 μmol) and sodium triacetoxyborohydride (100 mg, 471 μmol) at 25 ℃. The mixture was stirred at that temperature for 4 h before it was treated with saturated aq. NaHCO ₃ and extracted with DCM (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM (with MeOH from 0 to 5%) in 15 min to provide (1R, 3S) -3- (1- (tert-butyl) -5- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate (40.0 mg, 52%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 470.3.

Step 2: (1R, 3S) -3- (3- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A mixture of (1R, 3S) -3- (1- (tert-butyl) -5- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (40.0 mg, 85.1 μmol) in HCO ₂H (5.0 mL) was warmed to 110 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 15%to 45%in 7 min) to provide (1R, 3S) -3- (3- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (3.10 mg, 9%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 414.3.

The following compounds were prepared using the similar procedure disclosed in synthetic example 31.

Example 33

(1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: 2-bromo-6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridine

To a stirred suspension of (6-bromo-2-pyridyl) methanol (1.00 g, 5.32 mmol) in CH ₂Cl ₂ (20 mL) were sequentially added TBSCl (1.60 g, 10.6 mmol) and imidazole (724 mg, 10.6 mmol) at 25 ℃. The mixture was stirred at that temperature for 15 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 5%in 15 min) to afford 2-bromo-6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridine (1.07 g, 66%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 302.1.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol

To a stirred solution of (6-bromo-2-pyridyl) methoxy-tert-butyl-dimethyl-silane (300 mg, 992 μmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (221 mg, 992 μmol) , Pd ₂ (dba) ₃ (90.9 mg, 99.2 μmol) , XantPhos (115 mg, 199 μmol) and Cs ₂CO ₃ (647 mg, 1.98 mmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 5 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 5 to 70 %in 15 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) - 1H-pyrazol-3-yl) cyclopentan-1-ol (390 mg, 88%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 445.3.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred suspension of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol (390 mg, 877 μmol) in CH ₂Cl ₂ (5.0 mL) were sequentially added CDI (427 mg, 2.63 mmol) and Et ₃N (367 μL, 266 mg, 2.63 mmol) at 25 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 2 h. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with CH ₂Cl ₂ (20 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 539.3.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate in CH ₃CN (5.0 mL) was added propan-2-amine (74.6 μL, 51.6 mg, 872 μmol) at 25 ℃. The reaction mixture was warmed to 70 ℃ and stirred at that temperature for 4 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 5 to 70 %in 15 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (290 mg, 62%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 530.0.

Step 5: (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (290 mg, 547 μmol) in HCO ₂H (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/CH ₂Cl ₂ (with MeOH from 0 to 15 %in 15 min) to afford (1R, 3S) -3- (3- ( (6-(hydroxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (86.1 mg, 43%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 359.9.

Example 34

(1R, 3S) -3- (3- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: 2-bromo-6- (methoxymethyl) pyridine

To a stirred suspension of (6-bromo-2-pyridyl) methanol (500 mg, 2.66 mmol) in THF (5.0 mL) was added NaH (128 mg, 60 wt. %, 3.19 mmol) at 0 ℃. The reaction mixture was stirred at that temperature for 10 min before MeI (248 μL, 566 mg, 3.99 mmol) was added. The reaction mixture was warmed to 25 ℃ and stirred at that temperature for 5 h. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (20 mL × 3) . The organic phases were washed with brine (50 mL) and dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%in 15 min) to afford 2-bromo-6- (methoxymethyl) pyridine (450 mg, 83%yield) as a colorless liquid. LC-MS: m/z [M+H] ⁺ 202.0.

Step 2: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentan-1-ol

To a stirred solution of 2-bromo-6- (methoxymethyl) pyridine (200 mg, 989 μmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1-tert-butyl-pyrazol-3-yl) cyclopentanol (221 mg, 989 μmol) , Pd ₂ (dba) ₃ (90.6 mg, 98.9 μmol) , XantPhos (114 mg, 198 μmol) and Cs ₂CO ₃ (645 mg, 1.98 mmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 5 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 5 to 70 %in 15 min) to give the desired product (1R, 3S) -3- [1-tert-butyl-5- [ [6- (methoxymethyl) -2-pyridyl] amino] pyrazol-3-yl] cyclopentanol (300 mg, 87%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 345.3.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred suspension of (1R, 3S) -3- [1-tert-butyl-5- [ [6- (methoxymethyl) -2-pyridyl] amino] pyrazol-3-yl] cyclopentanol (300 mg, 871 μmol) in CH ₂Cl ₂ (5.0 mL) were sequentially added CDI (424 mg, 2.61 mmol) and Et ₃N (364 μL, 264 mg, 2.61 mmol) at 25 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 2 h before it was quenched with ice-cold water (20 mL) and extracted with CH ₂Cl ₂ (20 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure to give (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 439.2.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate in CH ₃CN (5.0 mL) was added propan-2-amine (74.1 μL, 51.2 mg, 866 μmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 4 h before it was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 5 to 70 %in 15 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (300 mg, 80%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 430.3.

Step 5: (1R, 3S) -3- (3- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (300 mg, 698 μmol) in HCO ₂H (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/CH ₂Cl ₂ (with MeOH from 0 to 15 %in 15 min) to afford (1R, 3S) -3- (3- ( (6-(methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (240 mg, 74%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 374.0.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 34.

Example 47 (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrazin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate and Example 48 (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: 3-bromo-1H-pyrazole-5-carboxylic acid

To a stirred solution of 3-bromo-5-methyl-1H-pyrazole (1.00 g, 6.21 mmol) in HCl (10 mL, 0.1 M, 1.0 mmol) was added KMnO ₄ (2.94 g, 18.6 mmol) in H ₂O (5.0 mL) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The reaction mixture was acidified with HCl (2.0 M aq. ) to pH = 4 and extracted with EtOAc (50 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure to give 3-bromo-1H-pyrazole-5-carboxylic acid (800 mg, 67%yield) as a white solid which was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 190.9.

Step 2: 2-bromopyrazolo [1, 5-a] pyrazin-4-ol

To a stirred solution of 3-bromo-1H-pyrazole-5-carboxylic acid (800 mg, 4.19 mmol) in 1, 4-dioxane (10.0 mL) was added CDI (663 mg, 4.61 mmol) at 50 ℃. The reaction was stirred at that temperature for 30 min before 2, 2-dimethoxyethanamine (502 μL, 484 mg, 4.61 mmol) was added. The reaction mixture was stirred at that temperature for another 30 min before HCl (9.0 mL, 12.0 M aq. ) was added. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h before it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50 %in 30 min) to give 2-bromopyrazolo [1, 5-a] pyrazin-4-ol (450 mg, 50%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 213.9.

Step 3: 2, 4-dibromopyrazolo [1, 5-a] pyrazine

To a stirred solution of 2-bromopyrazolo [1, 5-a] pyrazin-4-ol (260 mg, 1.21 mmol) in toluene (5.0 mL) was added POBr ₃ (696 mg, 2.43 mmol, 247 ) at 110 ℃ and the resulting mixture was stirred at that temperature for 12 h. The reaction mixture was quenched with water (10 mL) and basified with Na ₂CO ₃ aq. to pH=8 and extracted with EtOAc (20 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20 %in 30 min) to give 2, 4-dibromopyrazolo [1, 5-a] pyrazine (300 mg, 89%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 275.8.

Step 4: 2-bromo-N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert- butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazolo [1, 5-a] pyrazin-4-amine

To a stirred solution of 2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-amine (260 mg, 0.770 mmol) in DMF (5.0 mL) were sequentially added 2, 4-dibromopyrazolo [1, 5-a] pyrazine (277 mg, 1.00 mmol) and KOt-Bu (258 mg, 2.31 mmol) at 0 ℃. The reaction mixture was stirred at that temperature for 0.5 h before it was quenched with water (30 mL) , extracted with EtOAc (30 mL × 3) . The combined organic phases were washed with brine (10 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20 %in 20 min) to give 2-bromo-N- [2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-yl] pyrazolo [1, 5-a] pyrazin-4-amine (300 mg, 73%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 533.0.

Step 5: (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentan-1-ol

A solution of 2-bromo-N- [2-tert-butyl-5- [ (1S, 3R) -3- [tert-butyl (dimethyl) silyl] oxycyclopentyl] pyrazol-3-yl] pyrazolo [1, 5-a] pyrazin-4-amine (280 mg, 524 μmol) in tetrabutylammonium fluoride (3.0 mL, 1.0 M in THF, 3.0 mmol) was warmed to 60 ℃ and stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 100 %in 30 min) to give (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4- yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentanol (220 mg, 99%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 419.0.

Step 6: (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred suspension of (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentanol (200 mg, 476 μmol) in CH ₂Cl ₂ (10.0 mL) were sequentially added CDI (205 mg, 1.43 mmol) ) and DIPEA (0.41 mL, 307 mg, 2.38 mmol) at 35 ℃. The reaction mixture was stirred at that temperature for 2 h before it was quenched with water (20 mL) and extracted with CH ₂Cl ₂ (20 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The crude product [ (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentyl] imidazole-1-carboxylate was directly used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 512.9.

Step 7: (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of [ (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentyl] imidazole-1-carboxylate in CH ₃CN (10.0 mL) were sequentially added propan-2-amine (119 μL, 82.9 mg, 1.40 mmol) and Et ₃N (195 μL, 141 mg, 1.40 mmol) at 25 °. The resulting mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40 %in 30 min) to afford [ (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (140 mg) as a yellow solid. LC-MS: m/z [M+H] ⁺ 504.0.

Step 8: (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a stirred solution of [ (1R, 3S) -3- [5- [ (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino] -1-tert-butyl-pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (60.0 mg, 118 μmol) in toluene (3.0 mL) were sequentially added tributyl (methoxymethyl) stannane (79.0 mg, 237 μmol) and Pd (PPh ₃) ₄ (13.7 mg, 11.8 μmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE 1: 1) to give [ (1R, 3S) -3- [1-tert-butyl-5- [ [2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl] amino] pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (6 mg, 10%yield) as a yellow oil and [ (1R, 3S) -3- [1-tert-butyl-5- (pyrazolo [1, 5-a] pyrazin-4-ylamino) pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (17.0 mg, 34%yield) . LC-MS: m/z [M+H] ⁺ 470.1.

Step 9: (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-5-yl) cyclopentyl isopropylcarbamate

A solution of [ (1R, 3S) -3- [1-tert-butyl-5- [ [2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl] amino] pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (9.0 mg, 19.1 μmol) in TFA (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 20%to 40%in 10 min) to give [ (1R, 3S) -3- [3- [ [2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl] amino] -1H-pyrazol-5-yl] cyclopentyl] N-isopropylcarbamate (4.0 mg, 50%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 414.0.

Step 10: (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrazin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

A solution of [ (1R, 3S) -3- [1-tert-butyl-5- (pyrazolo [1, 5-a] pyrazin-4-ylamino) pyrazol-3-yl] cyclopentyl] N-isopropylcarbamate (17.0 mg, 39.9 μmol) in TFA (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 40%to 95%in 10 min (0.1%TFA condition) ) to give (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrazin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (10.2 mg, 69%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 370.1.

Example 49

(1R, 3S) -3- (3- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

Step 1: 6-bromo-N-methylpicolinamide

To a solution of 6-bromopicolinic acid (200 mg, 990 μmol) in DCM (8.0 mL) were sequentially added methanamine hydrochloride (133 mg, 1.98 mmol) , EDCI (379 mg, 1.98 mmol) , HOBt (267 mg, 1.98 mmol) and DIPEA (383 mg, 2.97 mmol, 516 μL) at 25 ℃. The reaction mixture was stirred at that temperature for 3 h before it was diluted with water (50 mL) and extracted with DCM (50 mL × 3) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 32%in 20 min) to afford 6-bromo-N-methylpicolinamide (200 mg, 94%yield) as a colorless liquid. LC-MS: m/z [M+H] ⁺ 215.0.

Step 2: 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) -N- methylpicolinamide

To a solution of 6-bromo-N-methyl-pyridine-2-carboxamide (100 mg, 465 μmol) in 1, 4-dioxane (5.0 mL) were sequentially added (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol (124 mg, 558 μmol) , Pd ₂ (dba) ₃ (85.1 mg, 93.0 μmol) , XantPhos (107 mg, 186 μmol) and Cs ₂CO ₃ (454 mg, 1.40 mmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (50 mL × 3) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with DCM from 0 to 6%in 15 min) to afford 6-( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) -N-methylpicolinamide (140 mg, 84%yield) as a green solid. LC-MS: m/z [M+H] ⁺ 358.2.

Step 3: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a solution of 6- [ [2-tert-butyl-5- [ (1S, 3R) -3-hydroxycyclopentyl] pyrazol-3-yl] amino] -N-methyl-pyridine-2-carboxamide (100 mg, 279 μmol) in DCM (4.0 mL) were sequentially added CDI (136 mg, 839 μmol) and DIPEA (180 mg, 1.40 mmol, 243 μL) at 25 ℃. The mixture was warmed to 35 ℃ and stirred at that temperature for 2 h. The mixture was cooled, diluted with water (30 mL) and extracted with DCM (30 mL × 3) . The combined organic phases were washed with brine (30 mL × 2) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 85%in 15 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate (50.0 mg, 39%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 452.2.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate (50.0 mg, 110 μmol) in CH ₃CN (2.0 mL) were sequentially added propan-2-amine (65.4 mg, 1.11 mmol, 95.0 μL) and DIPEA (143 mg, 1.11 mmol, 193 μL) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 20 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 68%in 15 min) to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (40.0 mg, 81%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 443.3.

Step 5: (1R, 3S) -3- (3- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (40.0 mg, 90.3 μmol) in TFA (2.0 mL) was warmed to 70 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 30%to 100%in 8 min) to afford ( (1R, 3S) -3- (3- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (11.4 mg, 32%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 387.2.

Example 50 (1R, 3S) -3- (3- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate, Example 51 (1R, 3S) -3- (5- ( (6- (isopropylcarbamoyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate, and Example 52 6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) picolinic acid

Step 1: methyl 6-bromopicolinateisopropylcarbamate

To a solution of 6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol) in DCM (10.0 mL) was added DMF (10.0 mg, 136 μmol, 10.5 μL) and oxalyl chloride (943 mg, 7.43 mmol, 648 μL) at 0 ℃. The resulting mixture was warmed to 25 ℃ and stirred at that temperature for 1 h before Methanol (5.0 mL) was added. The mixture was stirred at that temperature for 5 min before it was concentrated under reduced pressure. The residue was diluted with H ₂O (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layers were washed with brine (50 mL) and dried over Na ₂SO ₄, filtered and concentrated under reduced pressure to provide methyl 6-bromopyridine-2-carboxylate (514 mg, 96%yield) . LC-MS: m/z [M+H] ⁺ 216.0/218.0.

Step 2: methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) picolinate

To a solution of (1R, 3S) -3- (5-amino-1-tert-butyl-pyrazol-3-yl) cyclopentanol (250 mg, 1.12 mmol) in 1-4, dioxane (10 mL) were sequentially added methyl 6-bromopyridine-2-carboxylate (375 mg, 1.73 mmol) , Pd ₂ (dba) ₃ (82.0 mg, 89.4 μmol) , XantPhos (52.0 mg, 89.8 μmol) and Cs ₂CO ₃ (750 mg, 2.30 mmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was diluted with H ₂O (30 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 15 min to provide methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) picolinate (188 mg, 46%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 359.2.

Step 3: methyl 6- ( (3- ( (1S, 3R) -3- ( (1H-imidazole-1-carbonyl) oxy) cyclopentyl) -1- (tert- butyl) -1H-pyrazol-5-yl) amino) picolinate

To a solution of methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) picolinate (188 mg, 523 μmol) in DCM (6.0 mL) were sequentially added CDI (475 mg, 2.93 mmol) and DIPEA (375 mg, 2.9 mmol, 0.502 mL) at 25 ℃. The reaction mixture was warmed to 40 ℃ and stirred at that temperature for 2 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure to obtain methyl 6- ( (3- ( (1S, 3R) -3- ( (1H-imidazole-1-carbonyl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) amino) picolinate (140 mg) which was directly used in the next step without purification. LC-MS: m/z [M+H] ⁺ 453.2.

Step 4: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate

To a solution of methyl 6- ( (3- ( (1S, 3R) -3- ( (1H-imidazole-1-carbonyl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) amino) picolinate (140 mg, 309 μmol) in CH ₃CN (5.0 mL) were sequentially added propan-2-amine (100 mg, 1.69 mmol, 0.15 mL) and DIPEA (120 mg, 928 μmol, 0.16 mL) at 25 ℃. The reaction mixture was heated to 80 ℃ and stirred at that temperature for 6 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was diluted with H ₂O (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 15 min to provide methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) amino) picolinate (100 mg, 73%yield) as a white solid and (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (30.0 mg, 20%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 444.2 and 471.3.

Step 5: 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) amino) picolinic acid

To a solution of methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) amino) picolinate (80.0 mg, 180 μmol) in MeOH (6.0 mL) and H ₂O (1.0 mL) was added NaOH (40.0 mg, 1.00 mmol) at 25 ℃. The mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure. The residue was diluted with H ₂O (2.0 mL) and acidified with aq. HCl (2.0 M) to pH = 5 before it was filtered and dried to provide 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) amino) picolinic acid (70.0 mg, 91%yield) as a colorless solid. LC-MS: m/z [M+H] ⁺ 430.2.

Step 6: (1R, 3S) -3- (1- (tert-butyl) -5- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

To a solution of 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) amino) picolinic acid (40.0 mg, 93.1 μmol) in THF (5.0 mL) was added HATU (70.0 mg, 184 μmol) , DIPEA (36.0 mg, 278 μmol, 48.5 μL) and NH ₄Cl (15.0 mg, 280 μmol) at 25 ℃. The mixture was stirred at that temperature for 12 h before it was concentrated under reduced pressure. The residue was diluted with H ₂O (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 10%) in 12 min to provide (1R, 3S) -3- (1- (tert-butyl) -5- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (35.0 mg, 87%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 429.2.

Step 7: (1R, 3S) -3- (3- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate

A mixture of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (35.0 mg, 81.6 μmol) in TFA (4.0 mL) was warmed to 70 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 21%to 31%in 8 min) to provide (1R, 3S) -3- (3- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (6.00 mg, 19%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 373.1.

Step 8: 6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) picolinic acid

A solution of 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) amino) picolinic acid (20.0 mg, 46.5 μmol) in TFA (4.0 mL) was warmed to 70 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 18%to 28%in 8 min) to provide 6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) picolinic acid (6.00 mg, 34%yield) as a blue solid. LC-MS: m/z [M+H] ⁺ 374.2.

Step 9: (1R, 3S) -3- (5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate

A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (25.0 mg, 53.1 μmol) in TFA (4.0 mL) was warmed to 70 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 20%to 50%in 7 min) to provide (1R, 3S) -3- (5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (15.0 mg, 68%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 415.3.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 49.

Example 60

(cis, rac) -N-isopropyl-2- ( (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-5-yl) cyclopentyl) acetamide

Step 1: ethyl (E) -2- (3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentylidene) acetate

To a stirred solution of benzyl N- [2-tert-butyl-5- (3-oxocyclopentyl) pyrazol-3-yl] carbamate (1.00 g, 2.81 mmol) in THF (20.0 mL) was added NaH (203 mg, 60 wt. %in mineral oil, 8.44 mmol) at 0 ℃. The reaction mixture was stirred for 30 min before a solution of ethyl 2-diethoxyphosphorylacetate (1.68 mL, 1.89 g, 8.44 mmol) in THF (5.0 mL) was added at 0 ℃. The reaction mixture was warmed to 25 ℃ and stirred for 5 h at that temperature. The reaction mixture was quenched with aq. saturated NH ₄Cl (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 25 %in 25 min) to give ethyl (E) -2- (3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentylidene) acetate (1.1 g, 91%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 426.1.

Step 2: ethyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate

To a stirred solution of ethyl (E) -2- (3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentylidene) acetate (1.10 g, 2.59 mmol) in THF (5.0 mL) and EtOAc (5.0 mL) was added Pd/C (550 mg, 10%wt., 0.519 mmol) . The reaction mixture was stirred under hydrogen atmosphere (balloon) at 25 ℃ for 3 h. The reaction mixture was filtered through a pad of Celite before the filtrate was concentrated under reduced pressure to obtain the crude ethyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 294.1.

Step 3: ethyl 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl) acetate

To a stirred solution of ethyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate in DMF (5.0 mL) were sequentially added 4-bromo-2-methyl-pyrazolo [1, 5-a] pyrazine (281.8 mg, 1.33 mmol) and KOt-Bu (343.5 mg, 3.07 mmol) at 0 ℃. The resulting mixture was stirred at that temperature for 0.5 h before it was quenched with water (10 mL) and then extracted with EtOAc (20 mL × 3) . The combined organic phases were washed with brine (20 mL) and dried over Na ₂SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%in 25 min) to give ethyl 2- [3- [1-tert-butyl-5- [ (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino] pyrazol-3-yl] cyclopentyl] acetate (100 mg, 9%for two steps) as a yellow oil. LC-MS: m/z [M+H] ⁺ 425.1.

Step 4: 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl) acetic acid

To a stirred solution of ethyl 2- [3- [1-tert-butyl-5- [ (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino] pyrazol-3-yl] cyclopentyl] acetate (70.0 mg, 0.164 mmol) in THF (2.0 mL) and water (2.0 mL) was added LiOH ^. H ₂O (13.8 mg, 0.329 mmol) at 25 ℃ and the reaction mixture was stirred at that temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove most of THF. The mixture was acidified with aq. HCl (2.0 M) to pH = 3 before it was extracted with EtOAc (10 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl) acetic acid as a yellow oil which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 397.1.

Step 5: 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl) -N-isopropylacetamide

To a stirred solution of 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl) acetic acid (60.0 mg, 0.151 mmol) in CH ₂Cl ₂ (3.0 mL) were added sequentially DIPEA (52.5 μL, 39.0 mg, 0.302 mmol) , HATU (115 mg, 0.302 mmol) and propan-2-amine (12.9 μL, 8.90 mg, 0.151 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was quenched with water (5.0 mL) and then extracted with CH ₂Cl ₂ (15 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with CH ₃OH/CH ₂Cl ₂ (with CH ₃OH from 0 to 8 %in 25 min) to afford 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl) -N-isopropylacetamide (65.0 mg, 98 %yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 438.1.

Step 6: (cis, rac) -N-isopropyl-2- ( (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-5-yl) cyclopentyl) acetamide

A solution of 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl) -N-isopropylacetamide (60.0 mg, 65.0 μmol) in HCO ₂H (2.0 mL) was warmed to 50 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by SFC (Daicel CHIRALCEL AD-H column, CO ₂/EtOH = 60/40, EtOH with 0.2%NH ₄OH, 2.5 mL/min, 40 ℃) to afford (cis, rac) -N-isopropyl-2- ( (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl) acetamide (4.0 mg, 7.6%yield) . LC-MS: m/z [M+H] ⁺ 370.0.

Example 61

3- (methoxymethyl) -1-methyl-N- (5- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H- pyrazol-3-yl) -1H-pyrazole-5-carboxamide

Step 1: ethyl 3- (bromomethyl) -1-methyl-1H-pyrazole-5-carboxylate

To a stirred solution of ethyl 2, 5-dimethylpyrazole-3-carboxylate (2.00 g, 11.8 mmol) in CCl ₄ (20 mL) were sequentially added BPO (147 mg, 2.38 mmol) and NBS (2.00 g, 11.8 mmol) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 16 h. The mixture was cooled to 25 ℃ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 2%) in 30 min to give crude product (1.8 g crude) which was further slurried with PE (5.0 mL) to give ethyl 3- (bromomethyl) -1-methyl-1H-pyrazole-5-carboxylate (880 mg, 30%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 247.0.

Step 2: 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylic acid

To a suspension of ethyl 3- (bromomethyl) -1-methyl-1H-pyrazole-5-carboxylate (757 mg, 3.06 mmol) in MeOH (10 mL) was added K ₂CO ₃ (2.00 g, 15.3 mmol) at 25 ℃. The mixture was stirred at that temperature for 12 h before it was treated with ice-cold water (20 mL) . The mixture was acidified with aq. HCl (1.0 M) to pH = 3 before it was extracted with EtOAc (20 mL × 3) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to afford 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylic acid (470 mg, 90%yield) as a white solid which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 171.1.

Step 3: benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol- 5-yl) carbamate

To a suspension of benzyl N- [2-tert-butyl-5- [ (1S, 3R) -3-hydroxycyclopentyl] pyrazol-3-yl] carbamate (250 mg, 0.70 mmol) in dioxane (4.0 mL) were sequentially added 2-chloropyrimidine (160 mg, 1.40 mmol) and NaH (279 mg, 6.99 mmol, 60%wt. %) at 0 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃, quenched with water (50 mL) and extracted with DCM (50 mL × 3) . The combined organic layers were washed with brine (50 mL × 2) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatograph eluting with EtOAc/PE (with EtOAc from 0 to 50%) in 20 min to give benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (200 mg, 66%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 436.2.

Step 4: 1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-amine

To a stirred solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (150 mg, 0.34 mmol) in MeOH (6.0 mL) was added Pd/C (42.0 mg, 39.6 μmol, 10%wt. %) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 1 h. The reaction mixture was filtered through a pad of Celite before the filtrate was concentrated under reduced pressure to give 1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-amine (100 mg, 96%yield) as a yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 302.2.

Step 5: N- (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) - 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of 1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-amine (80.0 mg, 0.27 mmol) in pyridine (5.0 mL) were sequentially added 5- (methoxymethyl) -2-methyl-pyrazole-3-carboxylic acid (90.0 mg, 0.53 mmol) and POCl ₃ (122 mg, 0.80 mmol, 74.2 μL) at -5 ℃. The reaction mixture was stirred at that temperature for 3 h before it was quenched with H ₂O (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatograph eluting with EtOAc/PE (with EtOAc from 0 to 50%) in 25 min to give N- (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (52.0 mg, 43%yield) LC-MS: m/z [M+H] ⁺ 454.2.

Step 6: 3- (methoxymethyl) -1-methyl-N- (5- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) - 1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide

A mixture of N- (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (45.0 mg, 0.10 mmol) in HCO ₂H (3.0 mL) was warmed to 80 ℃ and stirred at that temperature for 4 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with CH ₃CN in H ₂O with CH ₃CN from 25%to 55%in 8 min) to give 3- (methoxymethyl) -1-methyl-N- (5- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide (9.70 mg, 25%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 398.2.

Example 62

(rac) -3- (methoxymethyl) -1-methyl-N- (5- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) - 1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide

Step 1: (trans, rac) -3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentyl methanesulfonate

To a stirred solution of ( trans, rac) -benzyl (1- (tert-butyl) -3- (3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (600 mg, 1.68 mmol) in DCM (10 mL) were sequentially added Et ₃N (700 μL, 510 mg, 5.04 mmol) and methanesulfonyl chloride (288 mg, 2.52 mmol, 195 μL) at 0 ℃. The mixture was stirred at that temperature for 2 h before it was quenched with H ₂O (20 mL) and extracted with EtOAc (30 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%) in 25 min to give ( trans, rac) -3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl methanesulfonate (700 mg, 95%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 436.2.

Step 2: (cis, rac) -benzyl (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) carbamate

To a stirred solution of 1-methylpyrazol-3-ol (315 mg, 3.21 mmol) in THF (10 mL) was added NaH (257 mg, 6.43 mmol, 60%wt. %) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h before (trans, rac) -3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl methanesulfonate (700 mg, 1.61 mmol) was added. The mixture was warmed to 80 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃, diluted with water (30 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (40 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 20 min to give (cis, rac) -benzyl (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (80.0 mg, 11%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 438.1.

Step 3: (cis, rac) -1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H- pyrazol-5-amine

To a solution of ( cis, rac) -benzyl (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (80.0 mg, 0.18 mmol) in MeOH (5.0 mL) was added Pd/C (11.1 mg, 10.4 μmol, 10%wt. %) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 3 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 20 min to give ( cis, rac) -1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-amine (45.0 mg, 81%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 607.3.

Step 4: (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide

To a solution of (cis, rac) -1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-amine (40.0 mg, 0.13 mmol) in pyridine (6.0 mL) were sequentially added 5- (methoxymethyl) -2-methyl-pyrazole-3-carboxylic acid (44.8 mg, 0.26 mmol) and POCl ₃ (60.6 mg, 0.40 mmol, 40.9 μL) at 0 ℃. The mixture was stirred at that temperature for 6 h before it was quenched with saturated NaHCO ₃ solution (50 mL) and extracted with EtOAc (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 20 min to give (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -3-(methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (30.0 mg, 49%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 456.2.

Step 5: (cis, rac) -3- (methoxymethyl) -1-methyl-N- (5- (3- ( (1-methyl-1H-pyrazol-3- yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide

A mixture of (cis, rac) -N- [2-tert-butyl-5- [3- (1-methylpyrazol-3-yl) oxycyclopentyl] pyrazol-3-yl]-5- (methoxymethyl) -2-methyl-pyrazole-3-carboxamide (25.0 mg, 0.05 mmol) in TFA (5.0 mL) was warmed to 80 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with CH ₃CN in water with CH ₃CN from 50%to 80%in 12 min to give (cis, rac) -3-(methoxymethyl) -1-methyl-N- (5- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide (1.00 mg, 4 %yield) as a white solid. LC-MS: m/z [M+H] ⁺ 400.2.

Exampel 63 Intentionally left blank

Example 64 and 65

(1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (arbitrarily assigned) and (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) - 1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (arbitrarily assigned)

Step 1: 5-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine

To a stirred suspension of NaH (1.10 g, 27.4 mmol, 60% wt. %) in DMF (30 mL) was added a solution of 5-bromo-1H-pyrrolo [2, 3-b] pyridine (3.00 g, 15.2 mmol) in DMF (15 mL) at 0 ℃. The mixture was stirred at that temperature for 1 h before a solution of 4-methylbenzenesulfonyl chloride (2.90 g, 15.2 mmol) in DMF (15 mL) was added. The reaction mixture was warmed to 25 ℃ and stirred at that temperature for 3 h. The mixture was quenched with saturated NaHCO ₃ solution (100 ml) and extracted with DCM (100 mL × 2) . The combined organic layers were washed with saturated NaCl solution (50 mL × 2) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%in 15 min) to afford 5-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine (4.50 g, 84%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 353.2.

Step 2: 5-bromo-2-iodo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine

To a solution of 5-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine (6.00 g, 17.08 mmol) in THF (60 mL) was added LDA (6.40 mL, 25.6 mmol, 2.0 M in THF) at -50 ℃ over a period of 10 min. The mixture was stirred at that temperature for 1 h before a solution of I ₂ (7.37 g, 29.0 mmol) in THF (20 ml) was added at -65 ℃ over a period of 20 min. The reaction mixture was warmed to 10 ℃ and stirred at that temperature for 1 h. The mixture was quenched with water (100 ml) and extracted with EtOAc (100 mL × 2) . The combined organic layers were washed with brine (50 mL × 2) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 7%in 15 min) to afford 5-bromo-2-iodo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine (2.33 g, 22%yield) as a crude yellow solid. LC-MS: m/z [M+H] ⁺ 476.2.

Step 3: 5-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridine (Intermediate 4)

To a suspension of -bromo-2-iodo-1-tosyl-1H-pyrrolo [2, 3-b] pyridine (1.76 g, 2.58 mmol) and (1-methyl-1H-pyrazol-5-yl) boronic acid (487 mg, 3.87 mmol) in DME (15 mL) and water (2.0 mL) were sequentially added Pd (PPh ₃) ₄ (298 mg, 258 μmol) and Na ₂CO ₃ (820 mg, 7.73 mmol ) at 25 ℃. The mixture was warmed to 60 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃, diluted with water (50 mL) and extracted with EtOAc (50 mL ×2) . The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 31%in 20 min) to afford 5-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridine (501 mg, 45%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 431.0.

Step 4: 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-one

To a stirred solution of 5-bromo-2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridine (300 mg, 695 μmol) in dioxane (5.0 mL) and water (1.0 mL) were sequentially added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (434 mg, 2.09 mmol) , K ₂CO ₃ (288 mg, 2.09 mmol) and Pd (dppf) Cl ₂ (50.8 mg, 69.5 μmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The reaction was diluted with water (20 mL) and extracted with DCM (20 mL × 3) . The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40%in 15 min) to give 3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-one (170 mg, 56%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 433.1.

Step 5: (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentan-1-ol (Intermediate 5)

To a solution of 3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-ol (100 mg, 230 μmol) in MeOH (5.0 mL) was added PtO ₂ (27.2 mg, 230 μmol) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30%in 15 min) to give (cis, rac) -3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentanol (30.0 mg, 29%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 437.1.

Step 6: (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred solution of (cis, rac) -3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentanol (30.0 mg, 68.7 μmol) in DCM (2.0 mL) was added Et ₃N (34.7 mg, 343μmol, 47.8 μL) and CDI (29.6 mg, 206 μmol) at 25 ℃. The reaction was warmed to 35 ℃ and stirred at that temperature for 2 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 10 min) to give (cis, rac) - [3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] imidazole-1-carboxylate (30.0 mg, 82%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 531.1.

Step 7: (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a stirring solution of (cis, rac) - [3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] imidazole-1-carboxylate (30.0 mg, 56.5 μmol) in DCM (3.0 mL) were sequentially added Et ₃N (28.6 mg, 282 μmol, 39.4 μL) and propan-2-amine (10.0 mg, 169 μmol, 14.5 μL) at 25 ℃. The reaction was warmed to 35 ℃ and stirred at that temperature for 16 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 10 min) to give (cis, rac) - [3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (28.0 mg, 94%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 522.2.

Step 8: (1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate and (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a stirring solution of (cis, rac) - [3- [2- (2-methylpyrazol-3-yl) -1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (30.0 mg, 57.5 μmol) in THF (2.0 mL) and water (2.0 mL) was added KOH (32.7 mg, 575 μmol) at 25 ℃. The reaction was warmed to 100 ℃ and stirred at that temperature for 24 h. The reaction mixture was cooled, diluted with water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by SFC (REGIS CHIRAL (S, S) -Whelk O1, CO ₂/MeOH = 50/50, MeOH with 0.1%DEA, 1.5 ml/min, 37 ℃) to give (1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (Retention Time = 3.1 min, absolute configuration arbitrarily assigned, 1.00 mg, 10%yield) as a white solid, LC-MS: m/z [M+H] ⁺ 368.2, and (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (Retention Time = 3.4 min, absolute configuration arbitrarily assigned, 1.00 mg, 10%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 368.2.

Example 66

(cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl cyclopropylcarbamate

Step 1: (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl (4-nitrophenyl) carbonate

To a solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (100 mg, 229 μmol) in DCE (10.0 mL) were sequentially added (4-nitrophenyl) carbonochloridate (230 mg, 1.15 mmol) and Et ₃N (115 mg, 1.15 mmol, 159 μL) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was diluted with H ₂O (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH/DCM (with MeOH from 0 to 5%) in 10 min to provide the (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5- yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl (4-nitrophenyl) carbonate (100 mg, 73%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 602.2.

Step 2: (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl cyclopropylcarbamate

To a solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl (4-nitrophenyl) carbonate (50.0 mg, 83.1 μmol) in CH ₃CN (10 mL) was added cyclopropanamine (14.0 mg, 249 μmol, 17.2 μL) and Et ₃N (25.0 mg, 249 μmol, 34.7 μL) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure to give (cis, rac) -3- (2-(1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl cyclopropylcarbamate (40.0 mg) which was used directly in the next step without purification. LC-MS: m/z [M+H] ⁺ 520.2.

Step 3: (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl cyclopropylcarbamate

To a mixture of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl cyclopropylcarbamate (40.0 mg, 76.9 μmol) in THF (5.0 mL) and H ₂O (5.0 mL) was added KOH (43.0 mg, 769 μmol) at 25 ℃. The reaction mixture was warmed to 110 ℃ and stirred at that temperature for 12 h. The mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 34%to 44%in 8 min) to provide (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl cyclopropylcarbamate (5.0 mg, 17%yield) as a colorless solid. LC-MS: m/z [M+H] ⁺ 366.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 66.

Example 75

(cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- (pyrimidin-2-yloxy) cyclopentyl) -1H- pyrrolo [2, 3-b] pyridine

To a solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (50.0 mg, 114 μmol) in DMF (5.0 mL) was added NaH (27.0 mg, 687 μmol, 60%wt. %) at 0 ℃. stirred at that temperature for 0.5 h before 2-chloropyrimidine (65.0 mg, 572 μmol) was added. The mixture was warmed to 25 ℃ and stirred at that temperature for 12 h. The mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (30 mL×2) . The combined organic layers were washed by brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluting with CH ₃CN in water with CH ₃CN from 45%to 100%in 8 min) to provide (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrrolo [2, 3-b] pyridine (3.00 mg, 7%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 361.1.

Example 76

(cis, rac) - 3- (3-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a suspension of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 109 μmol) in CHCl ₃ (8.0 mL) was added NCS (17.4 mg, 130 μmol, 10.6 μL) at 25 ℃. The reaction mixture was warmed to 60 ℃ and stirred at that temperature for 10 h. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 45%to 75%in 8 min) to give (cis, rac) -3- (3-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (11.3 mg, 26%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 402.1.

Example 77

(cis, rac) - 3- (3-methyl-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) - 3- (3-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a stirred solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 109 μmol) in THF (3.0 mL) was added NBS (20.3 mg, 114 μmol) at 25 ℃. The mixture was stirred at that temperature for 1 h before it was concentrated under reduced pressure. The residue was purified by PTLC (EtOAc/PE = 1/1) to give (cis, rac) -3- (3-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (35.0 mg, 72%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 446.1.

Step 2: (cis, rac) - 3- (3-methyl-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a stirred solution of (cis, rac) -3- (3-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (35.0 mg, 78.4 μmol) in 1, 4-dioxane (2.0 mL) and water (0.4 mL) were sequentially added methylboronic acid (14.1 mg, 235 μmol) , Pd (dppf) Cl ₂·CH ₂Cl ₂ (5.1 mg, 7.8 μmol) and K ₂CO ₃ (21.7 mg, 157 μmol) at 25 ℃. The mixture was warmed to 120 ℃ under microwave and stirred at that temperature for 1 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluting with CH ₃CN in water with CH ₃CN from 31%to 41%in 9 min) to give (cis, rac) -3- (3-methyl-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (1.2 mg, 4%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 382.2.

Example 78

(cis, rac) - 3- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: 5-bromo-2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridine

To a solution of 5-bromo-2-methyl-1H-pyrrolo [2, 3-b] pyridine (1.00 g, 4.74 mmol) in DMF (20 mL) was added NaH (125 mg, 5.21 mmol, 60%wt. %) at 0 ℃. The mixture was stirred at that temperature for 30 min before 4-methylbenzenesulfonyl chloride (993 mg, 5.21 mmol) was added. The reaction mixture was warmed to 25 ℃ and stirred at that temperature for 1 h. The mixture was quenched with saturated NaHCO ₃ solution (20 ml) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with saturated NaCl solution (50 mL × 2) and dried over anhydrous Na ₂SO ₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%) in 15 min to give 5-bromo-2-methyl-1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridine (1.54 g, 80%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 365.0.

Step 2: 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one

To a solution of 5-bromo-2-methyl-1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridine (1.20 g, 3.29 mmol) in 1, 4-dioxane (12 mL) and water (2.0 mL) were sequentially added K ₂CO ₃ (1.36 g, 9.86 mmol) , 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (2.05 g, 9.86 mmol) and Pd (dppf) Cl ₂ (268 mg, 328 μmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc/PE (with EtOAc from 0 to 70%) in 15 min to give 3- [2-methyl-1- (p-tolyl-sulfonyl) pyrrolo [2, 3- b] pyridin-5-yl] cyclopent-2-en-1-one (700 mg, 55%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 367.0.

Step 3: (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol

To a solution of 3- [2-methyl-1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-one (700 mg, 1.91 mmol) in MeOH (10 mL) was added PtO ₂ (43.3 mg, 191 μmol) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 53%to 95%in 8 min) to afford (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (380 mg, 53%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 371.1.

Step 4: (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H- imidazole-1-carboxylate

To a solution of (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (60.0 mg, 161 μmol) in DCM (2.0 mL) were sequentially added CDI (78.7 mg, 485 μmol) and Et ₃N (81.9 mg, 809 μmol, 112 μL) at 25 ℃. The mixture was warmed to 35 ℃ and stirred at that temperature for 18 h. The mixture was concentrated under reduced pressure to give (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (65.0 mg, 73%yield) as a yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 465.1.

Step 5: (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarba-mate

To a solution of (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (65.0 mg, 111 μmol) in CH ₃CN (2.0 mL) were sequentially added propan-2-amine (132 mg, 2.24 mmol, 192 μL) and Et ₃N (33.9 mg, 335 μmol, 46.6 μL) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=3: 1) to give (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarba-mate (40.0 mg, 70%yield) as a pale-yellow solid. LC-MS: m/z [M+H] ⁺ 456.1.

Step 6: (cis, rac) - 3- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarba-mate (150 mg, 329 μmol) in 1, 4-dioxane (1.0 mL) and water (1.0 mL) was added KOH (554 mg, 9.88 mmol) at 25 ℃. The mixture was warmed to 110 ℃ and stirred at that temperature for 6 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1: 1) to give (cis, rac) -3- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropyl-carbamate (32.0 mg, 30%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 302.1.

Example 79

(cis, rac) -3- (3-chloro-2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropyl-carbamate (25.0 mg, 82.9 μmol) in DCE (1.0 mL) was added NCS (12.1 mg, 91.2 μmol) at 25 ℃. The mixture was stirred at that temperature for 0.5 h before it was concentrated under reduced pressure. The residue was purified by prep-TLC (PE: EtOAc=5: 1) to give (cis, rac) -3-(3-chloro-2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (2.10 mg, 7%yield) as a pale-yellow solid. LC-MS: m/z [M+H] ⁺ 336.1.

Example 80

(cis, rac) - 3- (2-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: 5-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

To a stirring solution of 5-bromo-1H-pyrrolo [2, 3-b] pyridine (5.00 g, 25.4 mmol) in DMF (30 mL) was added NaH (1.22 g, 30.5 mmol, 60%wt. %) portionwise at 0 ℃. The mixture was stirred at that temperature for 10 min before 2- (chloromethoxy) ethyl-trimethyl-silane (6.35 g, 38.0 mmol, 6.74 mL) was added. The mixture was warmed to 25 ℃ and stirred at that temperature for 17 h. The reaction was quenched with aqueous NH ₄Cl (120 mL) and extracted with EtOAc (25 mL × 2) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%in 20 min) to give 5-bromo-1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (6.60 g, 79%yield) as a brown oil. LC-MS: m/z [M+H] ⁺ 327.0.

Step 2: 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent- 2-en-1-one

To a stirring solution of 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (5.72 g, 27.5 mmol) in 1, 4-dioxane/H ₂O=5: 1 (60 mL) were sequentially added 5-bromo-1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (3.00 g, 9.17 mmol) , K ₂CO ₃ (2.53 g, 18.3 mmol) and Pd (dppf) Cl ₂·CH ₂Cl ₂ (374 mg, 458 μmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃, diluted with brine (200 mL) and extracted with EtOAc (80 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%in 20 min) to give 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (2.50 g, 83%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 329.1.

Step 3: (rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-ol

To a stirring solution of 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (2.50 g, 7.61 mmol) in MeOH (20 mL) and THF (10 mL) was added NaBH ₄ (432 mg, 11.4 mmol) portionwise at 0 ℃. The mixture was stirred at that temperature for 30 min before another batch of NaBH ₄ (288 mg, 7.61 mmol) was added portionwise. The mixture was stirred at 0 ℃ for 30 min, quenched with aqueous NaCl (50 mL) and extracted with EtOAc (25 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure to give (rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-ol (2.50 g, 99%yield) as a brown oil which was used directly into the next step without further purification. LC-MS: m/z [M+H] ⁺ 331.1.

Step 4: (cis, rac) - 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentan-1-ol (Intermediate 6)

To a stirred solution of of (rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-ol (2.50 g, 7.56 mmol) in methanol (30 mL) was added PtO ₂ (300 mg, 1.32 mmol) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at 25 ℃ for 17 h. The reaction mixture was filtered through a pad of Celite before the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 25%in 15 min) to give (cis, rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (523 mg, 21%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 333.2.

Step 5: (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentan-1-ol

To a stirring solution of (cis, rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (550 mg, 1.65 mmol) in THF (35 mL) was added n-BuLi (1.98 mL, 2.5 M in hexanes, 4.95 mmol) at -65 ℃. The mixture was stirred at that temperature for 2 h before a solution of I ₂ (756 mg, 2.98 mmol) in THF (15 mL) was added. The mixture was warmed to 25 ℃ and stirred at thar temperature for 1 h. The mixture was quenched with saturated aqueous NH ₄Cl (50 mL) and extracted with EtOAc (15 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 25%in 15 min) to give (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (361 mg, 48%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 459.0.

Step 6: (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirred solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (340 mg, 742 μmol) in DCM (10 mL) were sequentially added Et ₃N (515 μL, 375 mg, 3.71 mmol) and CDI (510 mg, 3.15 mmol) at 25 ℃. The mixture was warmed to 35 ℃ stirred at that temperature for 2 h. The reaction was concentrated under reduced pressure to give (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (400 mg, 98%yield) as a yellow solid which was used directly into the next step without further purification. LC-MS: m/z [M+H] ⁺ 553.0.

Step 7: (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate (Intermediate 7)

To a stirring solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (340 mg, 615 μmol) in CH ₃CN (1.0 mL) were sequentially added propan-2-amine (529 μL, 364 mg, 6.15 mmol) and Et ₃N (427 μL, 311 mg, 3.08 mmol) at 25 ℃. The mixture was warmed to 70 ℃and stirred at that temperature for 16 h in a Schlenk pressure tube. The reaction was cooled, diluted with H ₂O (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%in 15 min) to give (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (300 mg, 90%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 544.1.

Step 8: (cis, rac) - 3- (2-phenyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a stirred solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (50.0 mg, 91.9 μmol) in 1, 4-dioxane/H ₂O=5: 1 (3.0 mL) were sequentially added phenylboronic acid (33.7 mg, 276 μmol) , K ₂CO ₃ (38.1 mg, 276 μmol) and Pd (dppf) Cl ₂·CH ₂Cl ₂ (15.1 mg, 18.4 μmol) at 25 ℃. The mixture was warmed to 100 ℃ under microwave and stirred at that temperature for 0.5 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EtOAc = 3: 1) to give (cis, rac) -3- (2-phenyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (30.0 mg, 66%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 494.2.

Step 9: (cis, rac) - 3- (2-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (2-phenyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (30.0 mg, 60.8 μmol) in HCO ₂H (2.0 mL) and methanol (1.0 mL) was warmed to 100 ℃ and stirred at that temperature for 4 h in a Schlenk pressure tube. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water with CH ₃CN from 10%to 20%in 8 min to give (cis, rac) -_3- (2-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (7.60 mg, 34%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 364.2.

Example 81

(cis, rac) - 3- (2- (1-methyl-1H-indazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) - 3- (2- (1-methyl-1H-indazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 73.6 μmol) in 1, 4-dioxane (5.0 mL) and H ₂O (0.50 mL) were sequentially added (1-methylindazol-5-yl) boronic acid (25.9 mg, 147 μmol) , Pd (dppf) Cl ₂ (9.50 mg, 14.7 μmol) and K ₂CO ₃ (30.5 mg, 220 μmol) . The mixture was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 25 min) to give (cis, rac) -3- (2- (1-methyl-1H-indazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate (30.0 mg, 74%yield) as yellow solid. LC-MS: m/z [M+H] ⁺ 548.2.

Step 2: (cis, rac) - 3- (2- (1-methyl-1H-indazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (2- (1-methyl-1H-indazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (25.0 mg, 45.6 μmol) in EtOH (2.0 mL) and HCl (2.0 mL, 2.0 M aq. ) was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 45%to 75%in 8 min) to give (cis, rac) -3- (2- (1-methyl-1H-indazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (2.50 mg, 13%yield) as yellow solid. LC-MS: m/z [M+H] ⁺ 418.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 80.

Example 95

(cis, rac) - 3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) boronic acid

To a solution of 5-bromo-3- (methoxymethyl) -1-methyl-pyrazole (200 mg, 975 μmol) in 1, 4-dioxane (15 mL) were sequentially added Pd (dppf) Cl ₂ (71.3 mg, 97.5 μmol) , AcOK (287 mg, 2.93 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (371 mg, 1.46 mmol) at 25℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 12 h. The reaction mixture was cooled to 25 ℃, filtered and concentrated under reduced pressure to give (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) boronic acid (150 mg, 90%yield) as brown oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 171.2.

Step 2: (cis, rac) - 3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- [2-iodo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (50.0 mg, 91.9 μmol) in 1, 4-dioxane (10 mL) and H ₂O (1.0 mL) were sequentially added Pd (dtbpf) Cl ₂ (11.8 mg, 18.4 μmol) , K ₂CO ₃ (38.1 mg, 275 μmol, 16.6 μL) and [5- (methoxymethyl) -2-methyl-pyrazol-3-yl] boronic acid (31.2 mg, 183 μmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 3 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 25 min) to give (cis, rac) -3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1-( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 80%yield) as yellow oil. LC-MS: m/z [M+H] ⁺ 542.2.

Step 3: (cis, rac) - 3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (30.0 mg, 55.3 μmol) in EtOH (2.0 mL) was added HCl (2.0 mL, 4.0 M aq.) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residuet was purified by prep-HPLC (CH ₃CN from 30%to 60%in 8 min) to give (cis, rac) -3- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (5.20 mg, 23%yield) as white solid. LC-MS: m/z [M+H] ⁺ 412.2.

Example 96 (cis, rac) - 3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate and Example 97 (cis, rac) - 3- (2- (1, 1- dioxidotetrahydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) - 3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (157 mg, 290 μmol) in 1, 4-dioxane (2.0 mL) and H ₂O (0.50 mL) were sequentially added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-thiopyran 1, 1-dioxide (50.0 mg, 193 μmol) , Pd (dtbpf) Cl ₂ (25.0 mg, 38.7 μmol) and K ₂CO ₃ (26.7 mg, 193 μmol) at 25 ℃. The reaction mixture was warmed to 100 ℃ under microwave and stirred at that temperature for 3 h. The mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL) and extracted with DCM (30 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 52%in 20 min) to afford (cis, rac) -3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (100 mg, 94%yield) as an orange gum. LC-MS: m/z [M+H] ⁺ 548.2.

Step 2: (cis, rac) - 3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (25.0 mg, 45.6 μmol) in HCO ₂H (1.0 mL) and MeOH (0.5 mL) was warmed to 100 ℃ and stirred at that temperature for 6 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluting with CH ₃CN from 40%to 100%in 8 min) to afford (cis, rac) -3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (3.10 mg, 16%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 418.2

Step 3: (cis, rac) -3- (2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (2- (1, 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (50.0 mg, 91.2 μmol) in MeOH (5.0 mL) was added Pd/C (9.71 mg, 9.12 μmol, 10%wt. %) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 2 h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford (cis, rac) -3- (2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (45.0 mg, 89%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 550.2.

Step 4: (cis, rac) - 3- (2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 72.7 μmol) in HCO ₂H (1.0 mL) and MeOH (0.50 mL) was warmed to 100 ℃ and stirred at that temperature for 6 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 26%to 100%in 8 min) to afford (cis, rac) -3- (2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (10.6 mg, 34%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 420.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 96 or 97.

Example 104

(cis, rac) -3- (2-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamat

To a solution of [ (cis, rac) -3- [2-iodo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin- 5-yl] cyclopentyl] N-isopropylcarbamate (40.0 mg, 73.6 μmol) in EtOH (1.0 mL) was added HCl (1.0 mL, 3.0 M aq. ) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 4 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH3CN from 37%to 95%in 10 min) to give (cis, rac) -3- (2-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamat (7.00 mg, 29 %yield) as a white solid. LC-MS: m/z [M+H] ⁺ 322.1.

Example 105

(cis, rac) -3- (2-iodo-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

A mixture of [ (cis, rac) -3- [2-iodo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (40.0 mg, 73.0 μmol) in HCO ₂H (1.0 mL) and MeOH (1.0 mL) was warmed to 100 ℃ and stirred at that temperature for 2 h. The reaction was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 37%to 95%in 10 min) to give (cis, rac) -3- (2-iodo-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (2.00 mg, 7%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 414.0.

Example 106

(cis, rac) - 3- (2- (1-isopropyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamatepyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) - 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -2- ( (trimethylsilyl) ethynyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a suspension of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (75.0 mg, 138 μmol) in THF (10 mL) were sequentially added Et ₃N (69.8 mg, 690 μmol, 96.2 μL) , ethynyltrimethylsilane (40.7 mg, 414 μmol, 58.5 μL) , Pd (PPh ₃) Cl ₂ (14.5 mg, 20.7 μmol) and CuI (6.57 mg, 34.5 μmol) at 25 ℃. The mixture was warmed to 70 ℃ and stirred at that temperature for 12 h. The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%in 15 min) to afford (cis, rac) -3- (1- ( (2-(trimethylsilyl) ethoxy) methyl) -2- ( (trimethylsilyl) ethynyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (62.0 mg, 87%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 514.3.

Step 2: (cis, rac) - 3- (2-ethynyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -2- ( (trimethylsilyl) ethynyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (60.0 mg, 117 μmol) in MeOH (2.0 mL) was added K ₂CO ₃ (48.4 mg, 350 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL × 2) . The mixture was washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 15%in 20 min) to afford (cis, rac) -3- (2-ethynyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (45.0 mg, 87%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 442.2.

Step 3: (cis, rac) - (2- ( (1-methyl-1H-pyrazol-5-yl) ethynyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a suspension of (cis, rac) -3- (2-ethynyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (45.0 mg, 101 μmol) in DMF (0.40 mL) and Et ₃N (2.0 mL) were sequentially added 5-iodo-1-methyl-1H-pyrazole (15.0 mg, 72.1 μmol) , Pd (PPh ₃) ₂Cl ₂ (7.59 mg, 10.8 μmol) and CuI (2.06 mg, 10.8 μmol) at 25 ℃. The suspension was warmed to 70 ℃ and stirred at that temperature for 2 h. The mixture was cooled, diluted with water (50 mL) and extracted with EtOAc (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 12%in 20 min) to afford (cis, rac) -3- (2- ( (1-methyl-1H-pyrazol-5-yl) ethynyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (42.0 mg, 70%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 552.2.

Step 4: (cis, rac) - 3- (2- ( (1-methyl-1H-pyrazol-5-yl) ethynyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To solution of (cis, rac) -3- (2- ( (1-methyl-1H-pyrazol-5-yl) ethynyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (40.0 mg, 76.7 μmol) in Methanol (1.00 mL) was added formic acid (2.0 mL) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 16 h. The mixture was cooled and concentrated reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 50%to 100%in 15 min) to afford (cis, rac) -3- (2- ( (1-methyl-1H-pyrazol-5-yl) ethynyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (1.50 mg, 5%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 392.2.

Example 107

(cis, rac) - 3- (2- (Morpholinomethyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) -methyl5- (-3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-2-carboxylate

To a solution of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (200 mg, 353 μmol) in MeOH (4.0 mL) were sequentially added Pd (dppf) Cl ₂ (103 mg, 141 μmol) and Et ₃N (4.0 mL) was added at 25 ℃. The reaction mixture was warmed to 70 ℃ and stirred under CO atmosphere (balloon) at that temperature for 5 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30%) in 15 min to give methyl (cis, rac) -5- (3-( (isopropylcarbamoyl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-2-carboxylate (200 mg, 95%yield) as a brown oil. LC-MS: m/z [M+H] ⁺ 476.2.

Step 2: (cis, rac) -3- (2- (hydroxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -methyl -5- [3- (isopropylcarbamoyloxy) cyclopentyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridine-2-carboxylate (88.0 mg, 185 μmol) in THF (5.0 mL) was added LiAlH ₄ (370 μL, 370 μmol, 1.0 M in THF ) at 0 ℃. The reaction mixture was stirred at that temperature 1 h before it was quenched with water (20 mL) and extracted with DCM (50 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give (cis, rac) - [3- [2- (hydroxymethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (80.0 mg, 96%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 448.3.

Step 3: (cis, rac) - 3- (2- (chloromethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- [2- (hydroxymethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (80.0 mg, 179 μmol) in CH ₂Cl ₂ (3.0 mL) was added Et ₃N (54.3 mg, 536 μmol, 74.7 μL) and Methanesulfonyl chloride (30.7 mg, 268 μmol, 20.8 μL) at 25 ℃. The reaction mixture was stirred at that temperature for 1 h. The mixture was concentrated under reduced pressure to give (cis, rac) - [3- [2- (chloromethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (80.0 mg, 96%yield) as a yellow oil which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 466.1.

Step 4: (cis, rac) - 3- (2- (morpholinomethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- [2- (chloromethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (80.0 mg, 172 μmol) in DCM (4.0 mL) was added Et ₃N (52.1 mg, 515 μmol, 71.8 μL) and morpholine (22.4 mg, 257 μmol, 22.5 μL) at 25 ℃. The reaction mixture was stirred at that temperature for 1 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%) in 15 min to give (cis, rac) - [3- [2- (morpholinomethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (75.0 mg, 84%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 517.2.

Step 5: (cis, rac) - (1R, 3S) -3- (2- (morpholinomethyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- [2- (morpholinomethyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (70.0 mg, 135 μmol) in MeOH (1.5 mL) was added formic acid (3.0 mL) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 15%to 100%in 8 min) to give (cis, rac) - [3- [2- (morpholinomethyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (14.5 mg, 28%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 387.2.

Example 108

(cis, rac) - 3- (2- (dimethylcarbamoyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) -5- (3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-2-carboxylic acid

To a solution of (cis, rac) -methyl 5- (3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-2-carboxylate (80.0 mg, 168 μmol) in MeOH (1.0 mL) and THF (1.0 mL) was added NaOH (757 μL, 2.0 M in H ₂O) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h before it was diluted with water (20 mL) . The mixture was acidified with aq. HCl (2.0 M) to pH = 4 before it was extracted with CH ₂Cl ₂ (50 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give (cis, rac) -5- [3- (isopropylcarbamoyloxy) cyclopentyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridine-2-carboxylic acid (75.0 mg, 96%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 462.2.

Step 2: (cis, rac) -3- (2- (dimethylcarbamoyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -5- (3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-2-carboxylic acid (60.0 mg, 130 μmol) in THF (4.0 mL) were sequentially added HATU (74.1 mg, 195 μmol) , dimethylamine (29.3 mg, 650 μmol, 37.8 μL) and DIPEA (84.0 mg, 650 μmol, 113 μL) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h. The mixture was quenched with water (20 mL) and then extracted with EtOAc (50 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%) in 15 min to give (cis, rac) -3- (2- (dimethylcarbamoyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (60.0 mg, 94%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 397.1.

Step 3: (cis, rac) - 3- (2- (dimethylcarbamoyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- [2- (dimethylcarbamoyl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (30.0 mg, 61.4 μmol) in MeOH (1.0 mL) was added HCO ₂H (2.0 mL) at 25 ℃. The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 0%to 100%in 8 min) to give (cis, rac) - [3- [2- (dimethylcarbamoyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] N-isopropylcarbamate (12.0 mg, 54%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 359.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 108.

Example 113

(cis, rac) -3- (3-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: 3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one

To a solution of 5-bromo-1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridine (6.00 g, 17.0 mmol) in dioxane (100 mL) and water (20 mL) were sequentially added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (10.6 g, 51.2 mmol) , K ₂CO ₃ (7.08 g, 51.2 mmol) and Pd (dppf) Cl ₂ (1.25 g, 1.71 mmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The reaction mixture was cooled to 25 ℃, diluted with water (50 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 15 min) to give 3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-one (5.00 g, 83%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 353.0.

Step 2: (rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-ol

To a stirring solution of 3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-one (3.00 g, 8.51 mmol) in THF (50 mL) was added LiBHEt ₃ (1.80 g, 17.0 mmol) at -60 ℃. The resulting mixture was warmed to 25 ℃ and stirred at that temperature for 2 h. The reaction was diluted with water (100 mL) and then extracted with EtOAc (120 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure to give (rac) -3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-ol (2.50 g, 82%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 355.1.

Step 3: (cis, rac) - 3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (Intermediate 8)

To a stirring solution of (rac) -3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopent-2-en-1-ol (2.50 g, 7.05 mmol) in MeOH (50 mL) was added PtO ₂ (320 mg, 1.41 mmol) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at 25 ℃ for 16 h before it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 45%to 75%in 8 min) to give (cis, rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (600 mg, 25%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 357.1.

Step 4: (cis, rac) - 3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1- carboxylate

To a stirring solution of (cis, rac) -3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentanol (200 mg, 561 μmol) in DCM (10 mL) were sequentially added Et ₃N (283 mg, 2.81 mmol, 391 μL) and CDI (272 mg, 1.68 mmol) at 25 ℃. The mixture was stirred at that temperature for 2 h before it was concentrated under reduced pressure to give (cis, rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (250 mg, 95%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 451.0.

Step 5: (rac) - (1R, 3S) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a stirring solution of (cis, rac) - [3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] imidazole-1-carboxylate (200 mg, 443 μmol) in CH ₃CN (5.0 mL) was added propan-2-amine (262 mg, 4.44 mmol, 379 μL) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80%in 15 min) to give (cis, rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (180 mg, 92%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 442.2.

Step 6: (cis, rac) - 3- (3-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (600 mg, 1.36 mmol) in DCE (10 mL) was added NBS (242 mg, 1.36 mmol) at 25 ℃. The reaction mixture was warmed to 60 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 37%in 15 min) to give (cis, rac) -3- (3-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (620 mg, 88%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 520.0.

Step 7: (cis, rac) - 3- (3-phenyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (3-bromo-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (50.0 mg, 96.1 μmol) in dioxane (2.0 mL) were sequentially added phenylboronic acid (23.2 mg, 192 μmol) , Pd (dppf) Cl ₂ (14.1 mg, 19.2 μmol) , K ₂CO ₃ (40.4 mg, 288 μmol) and H ₂O (0.40 mL) . The reaction mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The mixture was cooled, diluted with water (30 mL) and extracted with DCM (30 mL × 3) . The combined organic layers were washed with brine (30 mL × 2) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc/PE (with EtOAc from 0 to 27%in 10 min) to afford (cis, rac) -3- (3-phenyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (41.0 mg, 82%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 518.2.

Step 8: (cis, rac) -3- (3-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (3-phenyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (35.0 mg, 67.6 μmol) in MeOH (1.5 mL) was added NaOH (22.0 mg, 541 μmol) in H ₂O (0.10 mL) at 25 ℃. The reaction mixture was warmed to 75 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 55%to 100%in 8 min) to afford (cis, rac) -3- (3-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (8.2 mg, 33%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 364.2.

The following compounds were prepared using the similar procedure disclosed in synthetic Example 113.

Example 130

(cis, rac) - 3- (1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Step 1: (cis, rac) - 3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1- carboxylate

To a solution of (cis, rac) -3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentanol (700 mg, 1.96 mmol) in DCM (10 mL) were sequentially added Et ₃N (993 mg, 9.82 mmol, 1.37 mL) and CDI (955 mg, 5.89 mmol) at 25 ℃. The reaction mixture was warmed to 35 ℃ and stirred at that temperature for 2 h. The mixture was concentrated under reduced pressure to give (cis, rac) - [3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] imidazole-1-carboxylate (880 mg, 99%yield) as a brown oil which was used directly in the next step without further purification. LC-MS: m/z [M+H] ⁺ 451.1.

Step 2: (cis, rac) - 3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- [1- (p-tolylsulfonyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentyl] imidazole-1-carboxylate (880 mg, 1.95 mmol) in CH ₃CN (10 mL) were sequentially added propan-2-amine (1.73 g, 29.3 mmol, 2.51 mL) and Et ₃N (988 mg, 9.77 mmol, 1.36 mL) at 25 ℃. The reaction mixture was warmed to 70 ℃ and stirred at that temperature for 4 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40%in 15 min) to give (cis, rac) - (1R, 3S) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (700 mg, 81%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 442.1.

Step 3: (cis, rac) - 3- (1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (100 mg, 226 μmol) in THF (1.0 mL) and H ₂O (1.0 mL) was added KOH (127 mg, 2.26 mmol) at 25 ℃. The reaction mixture was warmed to 110 ℃ and stirred at that temperture for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 10%to 100%in 8 min) to give (cis, rac) -3- (1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (35.0 mg, 53%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 288.1.

Example 131

(cis, rac) - 3- (3-bromo-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - [3- (1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl] N-isopropylcarbamate (10.0 mg, 34.8 μmol) in DCM (2.0 mL) was added NBS (6.81 mg, 38.2 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 2 h, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 55%to 100%in 8 min) to give (cis, rac) - [3- (3-bromo-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl] N-isopropylcarbamate (4.00 mg, 31%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 366.0.

Example 132

(cis, rac) - (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) - (1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl] N-isopropylcarbamate (30.0 mg, 104 μmol) in CHCl ₃ (2.0 mL) was added NCS (13.9 mg, 104 μmol) at 25 ℃. The reaction mixture was warmed to 60 ℃ and stirred at that temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 55%to 100%in 8 min) to give (cis, rac) - [3- (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl] N-isopropylcarbamate (18.3 mg, 54 %yield) as a white solid. LC-MS: m/z [M+H] ⁺ 322.2.

Example 133

(cis, rac) - 3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

Step 1: 5-bromo-4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridine

To a stirred solution of 5-bromo-4-fluoro-1H-pyrrolo [2, 3-b] pyridine (900 mg, 4.19 mmol) in THF (30 mL) was added KHMDS (5.44 mL, 1.0 M, 5.44 mmol) at 0 ℃. The mixture was stirred at that temperature for 10 min SEMCl (1.05 g, 6.28 mmol, 1.11 mL) was added . The mixture was warmed to 25 ℃ and stirred at that temperature for 2 h. The mixture was diluted with aqueous NH ₄Cl (50 mL) and extracted with EtOAc (30 ml × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 10%in 20 min) to give 5-bromo-4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (1.20 g, 83%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 345.0.

Step 2: 3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-one

To a stirring solution of 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (1.99 g, 9.56 mmol) in 1, 4-dioxane/H ₂O=5: 1 (60 mL) were sequentially added 5-bromo-4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (1.10 g, 3.19 mmol) , Pd (dppf) Cl ₂ (260 mg, 0.32 mmol) and Na ₂CO ₃ (675 mg, 6.37 mmol) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃, diluted with brine (200 mL) and extracted with EtOAc (60 mL × 3) . The combined organic layers were dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30%in 20 min) to give 3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (760 mg, 69%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 347.1.

Step 3: (cis+trans, rac) -3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentan-1-ol

To a stirred solution of 3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (760 mg, 2.19 mmol) in MeOH (30 mL) were sequentially added NaBH ₄ (498 mg, 13.2 mmol) and NiCl ₂ (28.4 mg, 0.220 mmol) at 0 ℃. The mixture was stirred at that temperature for 30 min before it was quenched with aqueous NaCl (50 mL) . The mixture was extracted with EtOAc (25 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 40%in 20 min) to give (cis+trans, rac) -3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (600 mg, 78%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 351.2.

Step 4: (cis+trans, rac) -3- (4-fluoro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol

To a solution of (cis+trans, rac) -3- (4-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (400 mg, 1.14 mmol) in THF (40 mL) was added n-BuLi (1.42 mL, 2.4 M in hexane, 3.42 mmol) at -65 ℃. The mixture was stirred at -65 ℃ for 1 h before a solution of iodine (579 mg, 2.28 mmol) in THF was added. The mixture was warmed to 25 ℃ and stirred at that temperature for 2 h. The mixture was quenched with aqueous Na ₂S ₂O ₃ (500 mL) and the aqueous layer was extracted with EtOAc (100 mL × 3) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to afford (cis+trans, rac) -3- (4-fluoro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (310 mg, 57%yield) as a brown oil. LC-MS: m/z [M+H] ⁺ 477.0.

Step 5: (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol

To a solution of (cis+trans, rac) -3- (4-fluoro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (300 mg, 629 μmol) in dioxane/H ₂O =5: 1 (10 mL) were sequentially added K ₂CO ₃ (261 mg, 1.89 mmol) , Pd (dppf) Cl ₂ (103 mg, 126 μmol) and 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (393 mg, 1.89 mmol) at 25 ℃. The mixture was warmed to 100 ℃ under microwave and stirred at that temperature for 0.5 h. The mixture was cooled , diluted with water (20 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to afford (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (152 mg, 56%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 431.2.

Step 6: (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl (4- nitrophenyl) carbonate

To a solution of (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (150 mg, 348 μmol) in DCE (10 mL) were sequentially added 4-nitrophenyl carbonochloridate (211 mg, 1.05 mmol) , DMAP (42.6 mg, 348 μmol) and DIPEA (135 mg, 1.05 mmol, 182 μL) at 25 ℃. The mixture was warmed to 85 ℃ and stirred at that temperature for 8 h. The mixture was cooled, diluted with water (30 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to give (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl (4-nitrophenyl) carbonate (230 mg) as a brown solid which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 596.2.

Step 7: 3- ( (cis+trans, rac) -4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl (4-nitrophenyl) carbonate (230 mg, 309 μmol) in CH ₃CN (10 mL) were sequentially added propan-2-amine (183 mg, 3.09 mmol, 264 μL) and DIPEA (120 mg, 927 μmol, 161 μL) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 30%in 20 min) to afford (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (120 mg, 75%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 516.2.

Step 8: (cis, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

To a solution of (cis+trans, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (110 mg, 213 μmol) in1, 4-dioxane (5.0 mL) were sequentially added HCl (5.0 mL, 4.0 M in 1, 4-dioxane) and H ₂O (5.0 ml) at 25 ℃. The mixture was stirred at that temperature for 48 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 30%to 60%in 8 min) and further purified by SFC (Daicel CHIRALCEL OZ column, CO2/MeOH=85/15, MeOH with 0.2%NH3, 2.0 ml/min, 35 ℃) to afford (cis, rac) -3- (4-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (21.8 mg, 27%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 386.2.

Example 134

(cis, rac) - 3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

Step 1: 5-bromo-4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridine

To a solution of 5-bromo-4-chloro-1H-pyrrolo [2, 3-b] pyridine (900 mg, 3.89 mmol) in DMF (15 mL) was added NaH (202 mg, 5.05 mmol, 60%wt. %) at 0 ℃. The mixture was stirred at that temperature for 1 h before 2- (chloromethoxy) ethyl-trimethyl-silane (972 mg, 5.83 mmol, 1.03 mL) was added. The mixture was stirred at 0 ℃ for 10 min before it was quenched with water (50 mL) and extracted with EtOAc (20 mL×2) . The combined layers were dried with anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 7%) in 15 min to give 5-bromo-4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (1.26 g, 89%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 363.0.

Step 2: 3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-one

To a solution of 5-bromo-4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (1.33 g, 3.68 mmol) in dioxane (15 mL) and water (2.5 mL) were sequentially added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (1.53 g, 7.35 mmol) , K ₂CO ₃ (1.52 g, 11 mmol) and Pd (dppf) Cl ₂ (300 mg, 367 μmol) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 4 h. The mixture was cooled, diluted in water (20 mL) and extracted with EtOAc (100 mL×3) . The combined organic layers were dried with anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 7%) in 20 min to give 3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (680 mg, 50%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 363.0.

Step 3: (cis+trans, rac) -3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentan-1-ol

To a solution of 3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one (680 mg, 1.87 mmol) in MeOH (10 mL) were sequentially added NiCl ₂ (24.2 mg, 187 μmol) and NaBH ₄ (425 mg, 11.2 mmol) at 0 ℃. The mixture was stirred at that temperature for 30 min before it was quenched with water (4.0 mL) and extracted with EtOAc (50 mL×2) . The combined layers were dried with anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to give 3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (301 mg, 43%yield) as a yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 367.1.

Step 4: (cis, rac) - 3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol

To a solution of 3- (4-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (250 mg, 681 μmol) in THF (4.0 mL) was added n-BuLi (0.85 mL, 2.4 M in hexane, 2.04 mmol) at -65 ℃. The mixture was stirred at -65 ℃ for 1 h before I ₂ (345 mg, 1.36 mmol) was added. The mixture was warmed to 25 ℃ and stirred at that temperature for 1 h. The mixture was quenched with aq. NH ₄Cl (4.0 mL) and extracted with EtOAc (50 mL×2) . The combined organic layers were dried with anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (with CH ₃CN from 85%to 90%in 7 min) to afford (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (80.0 mg, 23%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 493.0.

Step 5: (cis, rac) - 3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate

To a stirring solution of (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (25.0 mg, 50.7 μmol) in THF (1.0 mL) were sequentially added DIPEA (32.7 mg, 253 μmol, 44.1 μL) and CDI (24.6 mg, 152 μmol) at 25 ℃. The mixture was warmed to 40 ℃ and stirred at that temperature for 16 h. The mixture was cooled, and concentrated under reduced pressure to give (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (28.0 mg, 56%yield) as a yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 587.0.

Step 6: (cis, rac) - 3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate (25.0 mg, 42.6 μmol) in acetonitrile (1.0 mL) were sequentially added isopropylamine (50.3 mg, 851 μmol, 73.1 μL) and DIPEA (16.5 mg, 127 μmol, 17.5 μL) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure to give (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (15.0 mg, 61%yield) as a pale-yellow solid which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺579.0.

Step 7: (cis, rac) -3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (4-chloro-2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (60.0 mg, 103 μmol) in 1, 4-dioxane (4.0 mL) and water (2.0 mL) were sequentially added (2-methylpyrazol-3-yl) boronic acid (26.1 mg, 207 μmol) , Pd (dppf) Cl ₂ (8.48 mg, 10.3 μmol) and K ₂CO ₃ (43.0 mg, 311 μmol) at 25 ℃. The mixture was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled to 25 ℃, diluted with brine (20 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified with prep-TLC (PE: EtOAc=3: 1) to give (cis, rac) -3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (28.0 mg, 50%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 532.2.

Step 8: (cis, rac) - 3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (30.0 mg, 56.3 μmol) in Methanol (1.0 mL) and formic acid (51.8 mg, 1.13 mmol, 42.5 μL) was warmed to 100 ℃ and stirred at that temperature for 6 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified with prep-HPLC (with CH ₃CN from 30%to 100%in 8 min) to afford (cis, rac) -3- (4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate (11.4 mg, 50%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 402.1.

Example 135 (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and Example 136 (cis, rac) -3- (7- (1-methyl-1H-pyrazol-5- yl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate

Step 1: 2-bromo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazine

To a stirred solution of 2-bromo-5H-pyrrolo [2, 3-b] pyrazine (2.00 g, 10.1 mmol) in THF (25 mL) was added NaH (1.62 g, 40.4 mmol, 60%wt. %) at 0 ℃. The mixture was stirred at that temperature for 30 min before 2- (chloromethoxy) ethyl-trimethyl-silane (5.05 g, 30.3 mmol, 5.36 mL) was added. The reaction mixture was warmed to 25 ℃ and stirred at that temperature for 12 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2) . The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 15 min) to give 2-bromo-5- ( (2-(trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazine (3.30 g, 99%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 328.0.

Step 2: 3- (5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopent- 2-en-1-one

To a solution of 2-bromo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazine (3.20 g, 9.75 mmol) and in 1, 4-dioxane (30 mL) and water (1 mL) were sequentially added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (6.08 g, 29.2 mmol) , Pd (dppf) Cl ₂ (927 mg, 1.27 mmol) and K ₂CO ₃ (4.04 g, 29.2 mmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to afford 3- [5- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyrazin-2-yl] cyclopent-2-en-1-one (2.80 g, 87%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 300.2.

Step 3: (cis, rac) -3- (5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2- yl) cyclopentan-1-ol

To a stirred solution of 3- [5- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyrazin-2-yl] cyclopent-2-en-1-one (2.70 g, 8.20 mmol) in Methanol (20 mL) and DCM (20 mL) was added NaBH ₄ (930 mg, 24.6 mmol) at 0 ℃. The mixture was warmed to 25 ℃ and stirred at that temperature for 5 h. The mixture was quenched with saturated aqueous NaHCO ₃ (100 mL) and extracted with EtOAc (150 mL × 2) . The combined organic layers were dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to afford (cis, rac) -3- (5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol (1.50 g, 55%yield) as a yellow oil; LC-MS: m/z [M+H] ⁺ 334.2.

Step 4: (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3- b] pyrazin-2-yl) cyclopentan-1-ol and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol

To a solution of (cis, rac) -3- (5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol (1.50 g, 4.50 mmol) in THF (25 mL) was added n-BuLi (3.75 mL, 2.4 M in THF, 9.00 mmol) at -70 ℃. The reaction mixture was stirred at that temperature for 1 h before I ₂ (1.48 g, 5.85 mmol) was added. The reaction mixture was warmed to 0 ℃ and stirred at that temperature for 1 h. The mixture was quenched with saturated NaHCO ₃ solution (80 mL) and extracted with EtOAc (80 mL × 2) . The combined organic layers were dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 20 min) to afford (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol (mixture, 200 mg, 10%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 460.1.

Step 5: (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3- b] pyrazin-2-yl) cyclopentyl 1H-imidazole-1-carboxylate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl 1H-imidazole- 1-carboxylate

To a solution of (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentan-1-ol (200 mg, 435 μmol) in DCM (10 mL) were sequentially added DIPEA (281 mg, 2.18 mmol, 379 μL) and CDI (212 mg, 1.31 mmol) at 20 ℃. The mixture warmed to 35℃ and stirred at that temperature for 12 h. The mixture was concentrated under reduced pressure to afford (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl 1H-imidazole-1-carboxylate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl 1H-imidazole-1-carboxylate (mixture, 230 mg) as a yellow gum which was used in the next step without further purificaiton. LC-MS: m/z [M+H] ⁺ 554.0.

Step 6: (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3- b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl 1H-imidazole-1-carboxylate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl 1H-imidazole-1-carboxylate (230 mg) in CH ₃CN (8.0 mL) were sequentially added propan-2-amine (1.34 g, 22.6 mmol, 2.00 mL) and DIPEA (1.48 g, 11.5 mmol, 2.00 mL) at 25℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 15 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc=1: 1) to afford (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (mixture, 160 mg, 71%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 545.1.

Step 7: (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) - 5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7- (1- methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin- 2-yl) cyclopentyl isopropylcarbamate

To a solution of (cis, rac) -3- (6-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7-iodo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (60.0 mg, 110 μmol) in 1, 4-dioxane (5.0 mL) and Water (0.20 mL) were sequentially added 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (45.9 mg, 220 μmol) , Pd (dppf) Cl ₂ (16.1 mg, 22.0 μmol) and K ₂CO ₃ (45.7 mg, 331 μmol) . The mixture was warmed to 100 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50%in 15 min) to afford (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, ra-c) 3- (7- (1-methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (mixture, 50.0 mg, 91%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 499.2.

Step 8: (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5H-pyrrolo [2, 3-b] pyrazin-2- yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7- (1-methyl-1H-pyrazol-5-yl) -5H- pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate

A solution of (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate and (cis, rac) -3- (7- (1-methyl-1H-pyrazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (50.0 mg, 100 μmol) in Methanol (2.0 mL) and HCO ₂H (3.0 mL) was warmed to 100 ℃ and stirred at that temperature for 8 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 28%to 58%in 8 min) to afford (cis, rac) -3- (6- (1-methyl-1H-pyrazol-5-yl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (5.00 mg, 14%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 369.2. And to afford (cis, rac) -3- (7- (1-methyl-1H-pyrazol-5-yl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) cyclopentyl isopropylcarbamate (4.00 mg, 11%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 369.2.

Example 137

(1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (arbitrarily assigned) and Example 138 (1S, 3R) -3- (2- (1-methyl-1H- pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (arbitrarily assigned)

Step 1: 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridine

To a stirred solution of 1-methyl-1H-pyrazole-5-carbaldehyde (2.00 g, 18.5 mmol) in AcOH (40.0 mL) was added 5-bromopyridine-2, 3-diamine (3.42 g, 18.2 mmol) at 25 ℃. The reaction mixture was warmed to 120 ℃ and stirred at that temperature for 16 h. The mixture was cooled to 25 ℃ and the precipitates were collected by filtration and dried to afford 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridine (1.10 g, 22%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 277.9.

Step 2: 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2 (trimethylsilyl) ethoxy) methyl) -3H- imidazo [4, 5-b] pyridine

To a stirred solution of NaH (174 mg, 60 wt. %in mineral oil, 4.35 mmol) in THF (10.0 mL) solution was added a solution of 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridine (1.10 g, 3.96 mmol) in THF (20.0 mL) dropwise at 0 ℃. The mixture was stirred at that temperature for 0.5 h before a solution of SEMCl (700 μL, 659 mg, 3.96 mmol) in THF (20.0 mL) was added. The resulting mixture was warmed to 25 ℃ and stirred at that temperature for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (50 mL × 2) . The combined organic phases were washed with brine (10 mL) , dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 50 % in 25 min) to afford 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridine (900 mg, 56%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 408.0.

Step 3: 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H- imidazo [4, 5-b] pyridin-6-yl) cyclopent-2-en-1-one

To a stirred solution of 6-bromo-2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridine (900 mg, 2.20 mmol) in 1, 4-dioxane (30.0 mL) were sequentially added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (459 mg, 2.20 mmol) , Pd (dtbpf) Cl ₂ (143 mg, 220 μmol) and K ₂CO ₃ (912 mg, 6.61 mmol) at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at that temperature for 2 h. The reaction mixture was cooled to 25 ℃, diluted with water (25 mL) and extracted with EtOAc (30 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80 %in 25 min) to give 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopent-2-en-1-one (450 mg, 50%yield) as a brown solid. LC-MS: m/z [M+H] ⁺ 410.1.

Step 4: 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H- imidazo [4, 5-b] pyridin-6-yl) cyclopentan-1-ol

To a stirred solution of 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopent-2-en-1-one (400 mg, 977 μmol) in MeOH (10.0 mL) were sequentially added NiCl ₂ (12.7 mg, 97.7 μmol) and NaBH ₄ (148 mg, 3.91 mmol) in portions at 25 ℃. The reaction mixture was stirred at that temperature for 2 h. The mixture was quenched with saturated aqueous of NH ₄Cl (50 mL) and extracted with EtOAc (50 mL × 2) . The combined organic phases were washed with brine (30 mL) and dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80 %in 25 min) to afford the 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentan-1-ol (220 mg, 55%yield) as a light-yellow solid. LC-MS: m/z [M+H] ⁺ 414.3.

Step 5: 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H- imidazo [4, 5-b] pyridin-6-yl) cyclopentyl (4-nitrophenyl) carbonate

To a stirred solution of 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentan-1-ol (200 mg, 484 μmol) in CH ₃CN (10.0 mL) were sequentially added 4-nitrophenyl carbonochloridate (292 mg, 1.45 mmol) , DMAP (118 mg, 967 μmol) and NMM (266 μL, 245 mg, 2.42 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 3 h before it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 70 %in 25 min) to afford 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl (4-nitrophenyl) carbonate (100 mg, 36%yield) as a light-yellow solid. LC-MS: m/z [M+H] ⁺ 579.2.

Step 6: 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H- imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate

To a stirred solution of 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl (4-nitrophenyl) carbonate (100 mg, 173 μmol) in CH ₃CN (10.0 mL) were sequentially added propan-2-amine (44.4 μL, 30.6 mg, 518 μmol, ) and Et ₃N (72.3 μL, 52.5 mg, 518 μmol) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 2) . The combined organic phases were washed with brine (30 mL) and dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 80 %in 25 min) to afford the 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (80.0 mg, 93%yield) as a light-yellow solid. LC-MS: m/z [M+H] ⁺ 499.1.

Step 7: (1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6- yl) cyclopentyl isopropylcarbamate + (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) -3H- imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate

To a stirred solution of 3- (2- (1-methyl-1H-pyrazol-5-yl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (80.0 mg, 160 μmol) in 1, 4-dioxane (5.0 mL) was added HCl (5.0 mL, 4.0 M in 1, 4-dioxane, 20.0 mmol) at 25 ℃. The reaction mixture was stirred at that temperature for 16 h before it was concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with CH ₃CN in water (with CH ₃CN from 5%to 70%in 30 min) to afford 3- (2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (20.0 mg, 34%yield, trans + cis) which was further separated by SFC (Daicel CHIRALCEL AD-H column, CO ₂/MeOH = 60/40, MeOH with 0.2%NH ₄OH, 2.5 mL/min, 40℃ ) to obtain (1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (Retention Time = 8.8 min, absolute configuration arbitrarily assigned, 2.1 mg, 1.2%yield) as a white solid, LC-MS: m/z [M+H] ⁺ 369.2, and (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-b] pyridin-6-yl) cyclopentyl isopropylcarbamate (Retention Time = 11.1 min, absolute configuration arbitrarily assigned, 2.1 mg, 1.2%yield) as a white solid, LC-MS: m/z [M+H] ⁺ 369.2.

Example 139 (cis, rac) -5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H- pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridine and Example 140 (cis, rac) -2- (1-methyl-1H- pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1H-pyrrolo [2, 3- b] pyridine

Step 1: (cis, rac) - - (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentan-1-ol

To a stirred solution of (cis, rac) -3- [1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl] cyclopentanol (6.00 g, 18.0 mmol) in THF (150 mL) was added n-BuLi (21.6 mL, 2.50 M, 54.0 mmol) at -65 ℃. The mixture was stirred at that temperature for 2 h before a solution of I ₂ (4.58 g, 18.0 mmol) in THF (50 mL) was added. The mixture was warmed to 25 ℃ and stirred at that temperature for 1 h. The mixture was quenched with saturated aqueous NH ₄Cl (120 mL) . The aqueous layer was extracted with EtOAc (40 mL × 3) . The combined organic layers were washed with Na ₂S ₂O ₃ (30 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 20%in 20 min) to give (cis, rac) -3- (2-iodo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridin-5-yl) cyclopentanol (3.50 g, 42%yield) as a brown solid. LC-MS: m/z [M+H] ⁺ 549.1.

Step 2: (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol

To a suspension of (cis, rac) -3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (1.50 g, 3.27 mmol) in DME (30 mL) and H ₂O (6.0 mL) were sequentially added (1-methyl-1H-pyrazol-5-yl) boronic acid (824 mg, 6.54 mmol) , Pd (PPh ₃) ₄ (378 mg, 327 μmol) and Na ₂CO ₃ (1.04 g, 9.82 mmol) at 25 ℃. The mixture was warmed to 60 ℃ and stirred at that temperature for 5 h. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (50 mL × 5) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 46%in 40 min) to afford (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (1.30 g, 96%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 413.2.

Step 3: (cis, rac) -5- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5- yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

To a suspension of NaH (29.1 mg, 727 μmol, 60%wt. %) in DMF (5.0 mL) was added (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (100 mg, 242 μmol) at 0 ℃. The mixture was stirred at that temperature for 30 min before was 3-bromo-2-fluoropyridine (59.7 mg, 339 μmol) added at 0 ℃. The reaction was warmed to 80 ℃ and stirred at that temperature for 3 h. The mixture was cooled, quenched with NH ₄Cl solution (20 mL) and extracted with DCM (20 mL × 3) . The combined organic phases were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 23%in 20 min) to afford (cis, rac) -5- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (100 mg, 72%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 570.2.

Step 4: (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2- yl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

To a solution of (cis, rac) -5- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (100 mg, 175 μmol) in 1, 4-dioxane (5.0 mL) and H ₂O (1.0 mL) were sequentially added 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (59.1 mg, 351 μmol) , Pd (dppf) Cl ₂ (25.7 mg, 35.1 μmol) , Na ₂CO ₃ (55.9 mg, 527 μmol) at 25 ℃. The mixture was warmed to 100 ℃ and stirred at that temperature for 2 h. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with DCM (30 mL × 3) . The combined organic phases were washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/PE (with EtOAc from 0 to 28%in 20 min) to afford (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- ( (1S, 3R) -3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (80.0 mg, 85%yield) as a colorless oil. LC-MS: m/z [M+H] ⁺ 530.2.

Step 5: (cis, rac) -5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H- pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

To a solution of (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (40.0 mg, 75.5 μmol) in MeOH (2.0 mL) were sequentially added Pd/C (8.0 mg, 7.5 μmol, 10%wt. ) at 25 ℃. The reaction mixture was stirred under hydrogen atmosphere (balloon) at that temperature for 6 h before it was filtered through a pad of Celite and concentrated under reduced pressure to afford (cis, rac) -5- (- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (40.0 mg, 99%yield) as a yellow oil which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 532.2.

Step 6: (cis, rac) -5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H- pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridine

A solution of (cis, rac) -5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (30.0 mg, 56.4 μmol) in HCO ₂H (2.0 mL) and MeOH (1.0 mL) was warmed to 100 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting (with CH ₃CN from 45%to 100%in 13 min) to afford (cis, rac) -5- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridine (3.40 mg, 15%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 402.2.

Step 7: (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2- yl) oxy) cyclopentyl) -1H-pyrrolo [2, 3-b] pyridine

A solution of (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (30.0 mg, 56.6 μmol) in HCO ₂H (2.0 mL) and MeOH (1.0 mL) was warmed to 100 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting (with CH ₃CN from 45%to 100%in 13 min) to afford (cis, rac) -2- (1-methyl-1H-pyrazol-5-yl) -5- (3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) -1H-pyrrolo [2, 3-b] pyridine (3.50 mg, 15%yield) as a white solid. LC-MS: m/z [M+H] ⁺ 400.2.

Example 142

Step 1: (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 3-methylbutanoate

To a solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol (77.0 mg, 186 μmol) and pyridine (148 mg, 1.87 mmol, 151 μL) in DCM (2.0 mL) was added 3- methylbutanoyl chloride (113 mg, 933 μmol, 114 μL) at 0 ℃. The mixture was warmed to 25 ℃ and stirred at that temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 2) . The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=2: 1) to afford (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 3-methylbutanoate (32.0 mg, 35%yield) as a yellow oil. LC-MS: m/z [M+H] ⁺ 497.3.

Step 2: (cis, rac) - (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 3- methylbutanoate

A solution of (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 3-methylbutanoate (27.0 mg, 54.4 μmol) in HCO ₂H (1.0 mL) was warmed to 90 ℃ and stirred at that temperature for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (with CH ₃CN from 35%to 100%in 13 min) to afford (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 3-methylbutanoate (6.10 mg, 31%yield) as a yellow solid. LC-MS: m/z [M+H] ⁺ 367.2.

Biological Example 1. Assay for Inhibition of CDK2/Cyclin E1

The homogeneous time-resolved fluorescence (HTRF) assay was performed to detect CDK2/Cyclin E1 catalyzed phosphorylation of peptide substrate in assay buffer containing 50 mM HEPES, PH=7.5, 10 mM MgCl2, 1mM EGTA, 2 mM DTT, 0.01%Tween, 0.1%BSA. The enzymatic reaction was carried out in a 10 μL volume containing 2 nM CDK2/Cyclin E1 enzyme (Merk, 14-475) , 80 μM ATP, 20 nM LANCE Ultra ULight ^TM-eIF4E-binding protein 1 (Thr37/46) Peptide (PerkinElmer, TRF0128-M) and 1 %DMSO (or the test compound at appropriate dilutions in DMSO) in the assay buffer. All the components were added to the 384-well plate (PerkinElmer, 6008280) , and incubated at Room Temperature for 4 hours. The reaction was terminated by addition of 10 μL detection buffer (PerkinElmer, CR97-100) containing 20 mM EDTA and 4 nM

Ultra Europium-anti-phospho-eIF4E-bindingprotein 1 (Thr37/46) (PerkinElmer, TRF0216-M) antibody. Then incubate the plate at Room Temperature for 1 hour. Plate was read using Envision Reader (PerkinElmer, EnVision Multilabel Reader) . The IC ₅₀ values of the test compound were determined by fitting the inhibition curves by 4 parameter sigmoidal dose-response model using the GraphPad Prism 8 software.

Biological Example 2. Assay for Inhibition of CDK1/Cyclin A2

The homogeneous time-resolved fluorescence (HTRF) assay was performed to detect CDK1/Cyclin A2 catalyzed phosphorylation of peptide substrate in assay buffer containing 50 mM HEPES, PH=7.5, 10 mM MgCl2, 1mM EGTA, 2 mM DTT, 0.01%Tween, 0.1%BSA. The enzymatic reaction was carried out in a 10 μL volume containing 0.4 nM CDK1/Cyclin A2 enzyme (SignalChem, C22-18G) , 10 μM ATP, 20 nM LANCE Ultra ULight ^TM-eIF4E-binding protein 1 (Thr37/46) Peptide (PerkinElmer, TRF0128-M) ) and 1 %DMSO (or the test compound at appropriate dilutions in DMSO) in the assay buffer. All the components were added to the 384-well plate (PerkinElmer, 6008280) , and incubated at Room Temperature for 2 hours. The reaction was terminated by addition of 10 μL detection buffer (PerkinElmer, CR97-100) containing 20 mM EDTA and 4 nM

The IC ₅₀ values of each exemplified compound against CDK2 and the ratio of CDK1/CDK2 are provided in the the Table 2. The IC ₅₀ values are indicated as "+" for < 50 nM; "++" for ≥ 50 nM and < 200 nM; "+++" for ≥ 200 nM and < 1000 nM; and "++++" for ≥ 1000 nM, respectively. The ratio of CDK1/CDK2 are indicated as “+” for < 5 folds; “++” for ≥ 5 folds and < 20 folds; “+++” for ≥ 20 folds and < 50 folds; “++++” for ≥ 50 folds.

Biological Example 3. Anti-proliferation Assay in OVCAR3 Cell

OVCAR3 cells (ATCC, HTB-161) were plated at 5000 cells/well in 96-well plates respectively, and were incubated in RPMI 1640 medium (Gibco, 31800105) with 10%FBS at 37℃, 5%CO ₂. After overnight incubation, baseline values were measured of the samples from one plate using CyQUANT reagent (Invitrogen, C35011) following manufacturer’s recommendations. Cells were incubated with the detection reagent for 1 hour at 37℃, and then the fluorescence was measured with excitation at 485 nm and emission at 535 nm using Envision Multilabel Plate Reader (PerkinElmer) . Other plates were dosed with tested compounds in a 3-fold dilution scheme. On day 6 after compound addition, CyQUANT reagent was added and the fluorescence was measured using Envision. The IC ₅₀ values of the test compound’s anti-proliferation activity was determined from the baseline subtracted viability readout curve using GraphPad Prism 5 software.

The cellular data obtained from biological examples 3 are listed in the Table A below. The IC ₅₀ values are indicated as "+" for < 50 nM; "++" for ≥ 50 nM and < 200 nM; "+++" for ≥ 200 nM and < 1000 nM; and "++++" for ≥ 1000 nM, respectively.

Table 2

Claims

A compound of Formula I:

a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:

ring A is heteroaryl represented by

W is
3-12 membered heterocyclyl, or 5-10 membered heteroaryl; wherein said 3-12 membered heterocyclyl or 5-10 membered heteroaryl represented by W is optionally substituted by one or more halogen, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, or C _2-6alkynyl;

R ¹ is H or C _1-6alkyl; wherein said C _1-6alkyl represented by R ¹ is optionally substituted with one or more halogen, -OH, CN, oxo, or –NH ₂;

R ^1' is H, C _1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said C _1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl represented by R ^1' is optionally substituted with one or more halogen, CN, oxo, or C _1-6alkyl;

R ² is H, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, C _2-6alkynyl, C _1-6hydroxylalkyl, C _1- ₆alkoxylC _1-6alkylene, – (CH ₂) _0 or 1-3-12 membered carbocyclyl, – (CH ₂) _0 or 1-3-12 membered heterocyclyl, – (CH ₂) _0 or 1-6-10 membered aryl, or – (CH ₂) _0 or 1-5-10 membered heteroaryl; wherein said C _2-6alkenyl, C _2-6alkynyl, – (CH ₂) _0 or 1-3-12 membered carbocyclyl, – (CH ₂) _0 or 1-3-12 membered heterocyclyl, – (CH ₂) _0 or 1-6-10 membered aryl, or – (CH ₂) _0 or 1-5-10 membered heteroaryl represented by R ² is optionally substituted by one or more halogen, hydroxyl, CN, or C _1-6alkyl; or

R ¹ and R ², together with the attached N atom, form a 3-8 membered heterocyclyl; wherein said 3-8 membered heterocyclyl is optionally substituted by one or more R ^#; wherein each R ^#is independently F, hydroxyl, C _1-4 alkyl, C _1-4alkoxyl, or CN;

R ³ is H or halogen;

R ⁴ is

R ⁵ is H, halogen, C _1-6alkyl, C (O) OR ^5a, C (O) NR ^5aR ^5b, or

R ⁶ is H, halogen, or C _1-6alkyl;

wherein

each ring B is independently 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

U is a bond, -CH ₂-, -C≡C-, or –C (O) NH-;

R ^5a and R ^5b are independently H or C _1-6alkyl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-6alkyl, C _1-6haloalkyl, C _1-6hydroxylalkyl, C _1-6alkoxylC _1-6alkylene, C _2-6alkenyl,

C _2-6alkynyl, -C (O) R ^*, -C (O) OR ^*,

-C (O) NR ^*R ^*, -OR ^*, -SO ₂R ^*, -NR ^*R ^*, -NR ^*C (O) R ^*, -NR ^*C (O) OR ^*, -NR ^*SO ₂R ^*, -NR ^*SO ₂NR ^*R ^*, -P (O) R ^*R ^*, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein

said 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one or more halogen or C _1-6alkyl; and

each R ^* is independently selected from the group consisting of hydrogen, C _1-6alkyl, C _1-6haloalkyl, C _2-6alkenyl, C _2-6alkynyl, 3-6 membered carbocyclyl, and 4-6 membered heterocyclyl;

n is 0, 1, 2, 3, 4, or 5 (as appropriate) ;

m is 0, 1, 2, 3, 4, or 5 (as appropriate) ;

R ⁷ is H or halogen; and

wherein said heterocyclyl comprises 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur; and said heteroaryl comprises 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.
The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is represented by Formula IIA:
The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is represented by Formula IIB:
The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is selected from the group consisting of:
The compound of any one of claims 1-4, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
The compound of any one of claims 1-4, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
The compound of any one of claims 1-4, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
The compound of any one of claims 1-7, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is
The compound of any one of claims 1-7, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-10 membered heteroaryl optionally substituted by 1 to 3 C _1-4alkyl, C _1-4haloalkyl, C _2-4alkenyl, or C _2-4alkynyl.
The compound of claim 9, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-6 membered heteroaryl (e.g. pyridinyl, pyrimidinyl) optionally substituted by

C _1-4alkyl (e.g., isopropyl) or C _2-4alkenyl (e.g., isopropenyl) .
The compound of any one of claims 1-8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ is H.
The compound of any one of claims 1-8 and 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ² is H, C _1-6alkyl, C _1-6haloalkyl, C _1- ₆hydroxylalkyl, C _1-6alkoxylC _1-6alkylene, C _2-4alkenyl, C _2-4alkynyl, – (CH ₂) _0 or 1-3-6 membered carbocyclyl, – (CH ₂) _0 or 1-3-6 membered heterocyclyl, – (CH ₂) _0 or 1-phenyl, or – (CH ₂) _0 or 1-5-6 membered heteroaryl; wherein said C _2-4alkenyl, C _2-4alkynyl, – (CH ₂) _0 or 1-3-6 membered carbocyclyl, – (CH ₂) _0 or 1-3-6 membered heterocyclyl, – (CH ₂) _0 or 1-phenyl, or – (CH ₂) _0 or 1-5-6 membered heteroaryl represented by R ² is optionally substituted by one to three groups selected from halogen, hydroxyl, CN, and C _1-4alkyl.
The compound of any one of claims 1-8, 11, and 12, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is H, C _1-5alkyl, C _1-5haloalkyl, C _1-4hydroxylalkyl, C _1-4alkoxylC _1-4alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH ₂) -phenyl; wherein said 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH ₂) -phenyl represented by R ² is optionally substituted by one or two groups selected from halogen, hydroxyl, CN, and C _1-4alkyl.
The compound of any one of claims 1-8 and 11-13, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is C _1-4alkyl, C _1-4hydroxylalkyl, or cyclopropyl; wherein said cyclopropyl represented by R ² is optionally substituted by C _1-2alkyl.
The compound of any one of claims 1-8 and 11-13, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ² is selected from the group consisting of:
The compound of any one of claims 1-8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ and R ², together with the attached N, form a 4-6 membered heterocyclyl; wherein said 4-6 membered heterocyclyl is optionally substituted by one to three halogen (e.g. F) or C _1-4alkyl.
The compound of any one of claims 1-8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ¹ and R ², together with the attached N, form a pyrrolidinyl group.
The compound of any one of claims 1-5 and 8-17, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ³ is H or F.
The compound of any one of claims 1-5 and 8-18, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ³ is H.
The compound of any one of claims 1-4 and 6-17, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ⁵ is H, halogen, CH ₃, isopropyl, C (O) OH, C (O) N (CH ₃) ₂, or
The compound of any one of claims 1-4, 6-17, and 20, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R ⁵ is
The compound of any one of claims 1-4, 6-17, 20, and 21, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein U is a bond.
The compound of any one of claims 1-22, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

each ring B is independently 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4hydroxylalkyl, C _1-4alkoxylC _1-4alkylene, C _2-4alkenyl, C _2-6alkynyl, -OR ^*, -SO ₂R ^*, -C (O) NR ^*R ^*, -NR ^*SO ₂NR ^*R ^*, -C (O) R ^*, -C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one to three halogen or C _1-4alkyl; and

each R ^* is independently selected from the group consisting of hydrogen, C _1-4alkyl, C _1-4haloalkyl, C _2-4alkenyl, C _2-4alkynyl, 4-6 membered carbocyclyl, and 5-6 membered heterocyclyl;

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3.
The compound of any one of claims 1-23, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

each ring B is independently 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl;

each R ^4a or R ^5c is independently halogen, -CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4hydroxylalkyl, C _2-4alkenyl, C _2-4alkynyl, -C _1-4alkyleneC _1-2alkoxy, -OR ^*, -SO ₂R ^*, -C (O) NR ^*R ^*, C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by one to two halogen or C _1-2alkyl; and

each R ^* is independently selected from the group consisting of hydrogen, C _1-4alkyl, and C _1-4haloalkyl;

m is 0, 1, or 2; and

n is 0, 1, or 2.
The compound of claim 24, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁴ is 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;

each R ^4a is F, -CN, -OH, C _1-3alkyl, C _1-2hydroxylalkyl, -C _1-2alkyleneC _1-2alkoxy, -OC _1-2alkyl, -SO ₂C _1-2alkyl, -C (O) NR ^*R ^*, C (O) OR ^*, -P (O) R ^*R ^*, phenyl, or 5-6 membered heteroaryl; wherein

said phenyl or 5-6 membered heteroaryl represented by R ^4a is optionally substituted by halogen or C _1-2alkyl;

each R ^* is independently selected from the group consisting of hydrogen or C _1-3alkyl; and

m is 0, 1, or 2.
The compound of claim 24 or claim 25, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁴ is 6 membered heteroaryl;

each R ^4a is C _1-2hydroxylalkyl; and

m is 0 or 1.
The compound of any one of claims 1-25, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R ⁴ is selected from the group consisting of
The compound of any one of claims 1-5, 8-25, and 27 a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^4a is selected from the group consisting of
The compound of claim 24, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

ring B represented in the group of R ⁵ is 5-6 membered monocyclic carbocyclyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;

each R ^5c is halogen, -CN, C _1-3alkyl, C _1-3haloalkyl, C _1-3alkoxy, C _1-3haloalkoxy, C _1-2alkoxylC _1-2alkylene, -SO ₂C _1-3alkyl, or -SO ₂C _1-3haloalkyl; and

n is 0, 1, or 2.
The compound of any one of claims 1-29, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R ⁵ is selected from the group consisting of
The compound of any one of claims 1-30, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^5c is selected from the group consisting of
The compound of any one of claims 1-7 and 18-31, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R ^1' is H or C _1-4alkyl (e.g., isopropyl) .
A compound of Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-33, a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
A method of treating a disease or condition modulated at least in part by CDK2 in a subject, comprising administering to the subject in need thereof, the compound of any one of claims 1-33, a pharmaceutically acceptable salt, or a stereoisomer thereof, or the pharmaceutical composition of claim 34.
A method of inhibiting CDK2 in a patient, comprising administering to the patient the compound of any one of claims 1-33, a pharmaceutically acceptable salt, or a stereoisomer thereof, or the pharmaceutical composition of claim 34.
A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-33, a pharmaceutically acceptable salt, or a stereoisomer thereof, or the pharmaceutical composition of claim 34; wherein the disease or disorder is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1.
The method of any one of claims 35-37, wherein the disease or disorder is cancer.