TW202341982A - Cdk2 inhibitors and use thereof - Google Patents

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

CDK2 inhibitors and their uses [Related Applications]

This application claims priority from International Patent Application No. PCT/CN2021/141118, filed on December 24, 2021, and International Patent Application No. PCT/CN2022/080313, filed on March 11, 2022. The entire contents of the above application are incorporated herein by reference.

The present disclosure relates to a CDK2 inhibitor, its pharmaceutically acceptable salts, its stereoisomers, its uses, compositions containing the CDK2 inhibitor, and methods of using and manufacturing the CDK2 inhibitor.

Cyclin-Dependent Kinases (CDKs) are a family of protein kinases that were originally discovered for their role in regulating the cell cycle. They have been identified to play a role in regulating many other biological functions, such as transcription, mRNA processing, and neural cell differentiation.

CDKs are relatively small proteins with molecular weights ranging from approximately 34 to 40 kDa. They contain slightly more than a kinase domain and are essentially inactive when not complexed with regulatory proteins called cyclins. CDK levels remain relatively constant throughout the cell cycle, and most regulation is post-translational, most notably by binding to cyclins.

CDK2 is of particular interest because dysregulation of CDK2 activity frequently occurs in a variety of human cancers. CDK2 plays an important role in promoting G1/S transition and S phase progression. When complexed with cyclin E (CCNE), CDK2 phosphorylates members of the retinoblastoma pocket protein family (p107, p130, pRb), leading to de-repression of E2F transcription factors and the expression of G1/S transition-related genes. and the transition from G1 to S phase (Henley, SAand FADick, Cell Div, 2012, 7(1): 10). This in turn activates CDK2/cyclin A, which phosphorylates endogenous receptors to allow DNA synthesis, replication and centrosome duplication (Ekholm, SV and SIReed, Curr Opin Cell Biol, 2000, 12(6): 676- 84). It has been reported that the CDK2 pathway affects tumorigenesis mainly through amplification and/or overexpression of CCNE1 and mutations that inactivate endogenous inhibitors of CDK2 (eg, p27) respectively (Xu, X., et al ., Biochemistry, 1999, 38(27): 8713-22).

Increased copy number and overexpression of CCNE1 have been found in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcome 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, DG, et al ., Cancer, 2006, 106(9): 1925-32). It has also been reported that amplification and/or overexpression of CCNE1 contributes to trastuzumab resistance in HER2+ breast cancer and CDK4/6 inhibitor resistance in estrogen receptor-positive breast cancer (Scaltriti, M. , et al ., Proc Natl Acad Sci USA, 2011, 108(9): 3761-6; Herrera-Abreu, MT, et al ., Cancer Res, 2016, 76(8): 2301-13). Various methods of targeting CDK2 have been shown to induce cell cycle arrest and inhibition of tumor growth (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). It has been reported that inhibition of CDK2 restored sensitivity to trastuzumab treatment in drug-resistant HER2+ breast tumors in preclinical models (Scaltriti, supra).

These data provide reason to consider CDK2 as a potential target for new drug development in cancers associated with dysregulated CDK2 activity. Over the past 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 has been difficult, in part because of the close similarity between the active sites of CDK2 and other CDKs, especially CDK1, which is the only CDK essential for the cell cycle. Inhibiting CDK1 may cause many unintended side effects.

Therefore, there remains a need to discover CDK inhibitors with novel activity profiles, especially those that specifically or selectively target CDK2.

Described herein are compounds of formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof that inhibit (eg, selectively inhibit) CDK2 activity.

In one aspect, the present disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof:

其中環A和W在本文中定義。

Where rings A and W are defined in this article.

Pharmaceutical compositions comprising a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a pharmaceutically acceptable carrier or excipient are also provided.

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

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

The present disclosure further provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of (1) a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof; or (2) a compound of formula (I) comprising formula (I); A pharmaceutically acceptable composition of the compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof and a pharmaceutically acceptable carrier. In certain embodiments, the cancer is treated by inhibiting (e.g., selectively inhibiting) CDK2, such as a cancer selected from the group consisting of: ovarian cancer, breast cancer (e.g., hormone receptor positive, HER2/neu Negative progressive 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, mantle cell lymphoma , chronic myeloid leukemia and acute myeloid leukemia. In certain embodiments, the cancer exhibits abnormally upregulated CCNE1/cyclin E activity via cyclin E overexpression or duplication of the CCNE1 gene encoding cyclin E. In certain embodiments, the cancer exhibits abnormally upregulated cyclin A2 activity.

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

In certain embodiments of the methods of the invention, a compound of the invention is co-administered with any of the second therapeutic agents described herein that also treat the same cancer.

The present disclosure also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition containing the same in any of the methods described herein. in an implementation form , this article provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition containing the same for use in any method described herein. In another embodiment, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for use in any of the methods described herein.

1. Compound

In a first embodiment, the present disclosure provides compounds represented by formula (I):

其醫藥可接受鹽或其立體異構物，其中：

Its pharmaceutically acceptable salts or its stereoisomers, wherein:

Ring A is a heteroaryl group represented by:

、

、3至12員雜環基或5至10成員雜芳基；其中該 由W表示的3至12員雜環基或5至1員雜芳基視需要地被一個或多個之鹵素、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基或C_2-6炔基取代； W is

,

, 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein the 3 to 12 membered heterocyclyl or 5 to 1 membered heteroaryl represented by W is optionally replaced by one or more halogens, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl substitution;

R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl represented by R ¹ is optionally substituted by one or more halogens, CN, side oxy groups or -NH ₂ ;

R ^1' is H, C _1-6 alkyl, 3 to 12 membered carbocyclyl, 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein the C _1-6 alkyl represented by R ¹ ' The base, 3 to 12-membered carbocyclyl, 3 to 12-membered heterocyclyl or 5 to 10-membered heteroaryl is optionally substituted by one or more halogen, CN, side oxygen group or C _1-6 alkyl;

R ² is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 alkylene group, -(CH ₂ ) _{0 or 1} -3 to 12-membered carbocyclyl group, -(CH ₂ ) _{0 or 1} -3 to 12-membered heterocyclyl group, -(CH ₂ ) _{0 or 1} - 6 to 10-membered aryl, or -(CH ₂ ) _{0 or 1} -5 to 10-membered heteroaryl; _wherein the C _2-6 alkenyl, C ^2-6 alkynyl, -(CH ₂ ) _{0 or 1} -3 to 12-membered carbocyclyl, -(CH ₂ ) _{0 or 1} -3 to 12-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -6 to 10-membered aryl, or -(CH ₂ ) _{0 or 1-5} to 10-membered heteroaryl optionally substituted by one or more halogen, hydroxyl, CN or C _1-6 alkyl; or

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

R ³ is H or halogen;

； R ⁴ is

;

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

;

R ⁶ is H, halogen or C _1-6 alkyl;

in

Each ring B is independently a 3- to 12-membered carbocyclyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group;

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

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

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

The 3 to 12 membered carbocyclic group, 3 to 12 membered heterocyclic group, 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group represented by R ^4a or R ^5c is optionally replaced by one or more halogens or C _1-6 alkyl substitution; and

Each R ^* is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-6 carbon Cyclic groups and 4 to 6-membered heterocyclyl groups;

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

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

R ⁷ is H or halogen; and

Wherein the heterocyclic group contains 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; the heteroaryl group contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

In a second embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the first embodiment, wherein the compound is represented by Formula IIA:

. The definition of variables is provided in the first implementation aspect.

In a third embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the first embodiment, wherein the compound is represented by formula IIB:

。變量的定義提供於第一實施態樣。

. The definition of variables is provided in the first implementation aspect.

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

其餘變量的定義提供於第一至第三實施態樣的任一者。

The definitions of the remaining variables are provided in any one of the first to third implementation aspects.

。其餘 變量的定義提供於第一至第四實施態樣的任一者。 In a fifth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to fourth embodiments, wherein Ring A is

. The definitions of the remaining variables are provided in any one of the first to fourth implementation aspects.

。其 餘變量的定義提供於第一至第四實施態樣的任一者。 In a sixth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to fourth embodiments, wherein Ring A is

. The definitions of the remaining variables are provided in any one of the first to fourth implementation aspects.

。其 餘變量的定義提供於第一至第四實施態樣的任一者。 In a seventh embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to fourth embodiments, wherein Ring A is

. The definitions of the remaining variables are provided in any one of the first to fourth implementation aspects.

。其餘變量 的定義提供於第一至第七實施態樣的任一者。 In an eighth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to seventh embodiments, wherein W is

. The definitions of the remaining variables are provided in any one of the first to seventh implementation aspects.

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

In a tenth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first to ninth embodiments, wherein W is a 5- to 10-membered heteroaryl group (e.g., , pyridyl and pyrimidinyl), which is optionally substituted by C _1-4 alkyl (eg, isopropyl) or C _2-4 alkenyl (eg, isopropenyl). The definitions of the remaining variables are provided in the ninth implementation aspect.

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

In a twelfth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to eleventh embodiments, wherein R ² is H, C _1-6 Alkyl, C _1-6 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 alkylene, -( CH ₂ ) ₀ or ₁ -3 to 6-membered carbocyclyl, -(CH ₂ ) _{0 or 1} -3 to 6-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -phenyl, or - (CH ₂ ) _{0 or 1-5} to 6-membered heteroaryl; wherein the C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) represented by R _{2 0 or 1-3} to 6-membered carbocyclyl, -(CH ₂ ) _{0 or 1} -3 to 6-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -phenyl or -(CH ₂ ) _{0 or 1} -5 to 6-membered heteroaryl, which is optional Substituted with 1 to 3 groups selected from halogen, hydroxyl, CN and C _1-4 alkyl. The definitions of the remaining variables are provided in any one of the first to eighth implementation aspects.

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

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

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

,

,

,

,

, H,

,

,

,

,

,

其餘變量的定義提供於第一至第八、第十一至第十三實施態樣的任一者。

The definitions of the remaining variables are provided in any one of the first to eighth and eleventh to thirteenth implementation aspects.

In a sixteenth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first to eighth embodiments, wherein R ¹ and R ² are together with the connected N A 4- to 6-membered heterocyclyl group is formed; wherein the 4- to 6-membered heterocyclyl group is optionally substituted by one to three halogens (such as F) or C _1-4 alkyl. The definitions of the remaining variables are provided in any one of the first to eighth implementation aspects.

In a seventeenth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first to eighth embodiments, wherein R ¹ and R ² are connected to an N atom. Together they form a pyrrolidine group. The definitions of the remaining variables are provided in any one of the first to eighth implementation aspects.

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

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

。其餘變 量的定義提供於第一至第四及第六至第十七實施態樣的任一者。 In a twentieth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first to fourth and sixth to seventeenth embodiments, 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 to fourth and sixth to seventeenth implementation aspects.

。其餘變量的定義提供於第一至第四、第六至第十 七及第二十實施態樣的任一者。 In the twenty-first embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of the first to fourth, sixth to seventeenth and twentieth embodiments. , among which R ⁵ series

. The definitions of the remaining variables are provided in any one of the first to fourth, sixth to seventeenth and twentieth implementation aspects.

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

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

Each ring B is independently a 3- to 8-membered carbocyclyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, or a 5- to 10-membered heteroaryl group;

Each R ^4a or R ^5c is independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy C _1-4 extension Alkyl, C _2-4 alkenyl, C _2-6 alkynyl, -OR*, -SO ₂ R*, -C(O)NR*R*, -NR*SO ₂ NR*R*, -C( O)R*, -C(O)OR*, -P(O)R*R*, phenyl or 5 to 6-membered heteroaryl; where

The phenyl or 5- to 6-membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by 1 to 3 halogens or C _1-4 alkyl; and

Each R ^* is independently selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, 4 to 6 membered carbocyclyl, and 5 to 6 A group composed of membered heterocyclyl groups;

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 to twenty-second implementation aspects.

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

Each ring B is independently a 4- to 6-membered monocyclic carbocyclyl group, a 4- to 6-membered monocyclic heterocyclyl group, a phenyl group, or a 5- to 10-membered heteroaryl group;

Each R ^4a or R ^5c is independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkyne group, C _1-4 alkylene C _1-2 alkoxy group, -OR ^* , -SO ₂ R ^* , -C(O)NR ^* R ^* , C(O)OR ^* , -P(O)R ^* R ^* , phenyl or 5 to 6-membered heteroaryl; where

The phenyl or 5- to 6-membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by 1 to 2 halogens or C _1-2 alkyl; and

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

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 to twenty-third implementation aspects.

In the twenty-fifth implementation aspect, the present disclosure is based on the first to twenty-second implementation aspects Any of provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein

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

Each R ^4a is F, -CN, -OH, C _1-3 alkyl, C _1-2 hydroxyalkyl, -C _1-2 alkylene C _1-2 alkoxy, -OC _1-2 alkyl base, -SO ₂ C _1-2 alkyl, -C(O)NR*R*, C(O)OR*, -P(O)R*R*, phenyl or 5 to 6-membered heteroaryl; in

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

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

m is 0, 1 or 2. The definitions of the remaining variables are provided in the twenty-fourth implementation aspect.

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

The B ring represented in the R ⁴ group is a 6-membered heteroaryl group;

Each R ^4a is C _1-2 hydroxyalkyl; and

m is 0 or 1. The definitions of the remaining variables are provided in the twenty-fourth or twenty-fifth implementation aspect.

In a twenty-seventh embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of the first to twenty-fifth embodiments, wherein the R ⁴ group represents Ring B is a group selected from the following:

其餘變量的定義提供於第一至第二十五實施態樣的任一者。

The definitions of the remaining variables are provided in any one of the first to twenty-fifth implementation aspects.

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

,

,

,

,

, F,

,

,

,

,

,

其餘變量的定義提供於第一至第五、第八至第二十五及第二十七實施態樣的任一者。

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

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

The B ring represented in the R ⁵ group is a 5- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclyl group, a phenyl group or a 5- to 9-membered heteroaryl group;

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

n is 0, 1 or 2. The definitions of the remaining variables are provided in the twenty-fourth implementation aspect.

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

其餘變量的定義提供於第一至第二十九實施態樣。

The definitions of the remaining variables are provided in the first to twenty-ninth implementation aspects.

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

、

、

、

、 F.Cl.

,

,

,

,

其餘變量的定義提供於第一至第三十實施態樣。

The definitions of the remaining variables are provided in the first to thirtieth implementation aspects.

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

In one embodiment, the present disclosure provides compounds selected from the compounds disclosed in the Examples and Table 1, pharmaceutically acceptable salts thereof, or stereoisomers thereof.

2.Definition

As used herein, the term "halogen" refers to fluoride, chloride, bromide or iodide.

The term "alkyl" used alone or as part of a moiety such as "alkoxy" or "haloalkyl" and the like means the formula -C _n H _(2n+1) A saturated aliphatic linear or branched monovalent hydrocarbon radical. Unless otherwise indicated, alkyl groups generally have 1 to 6 carbon atoms, ie, C _1-6 alkyl. As used herein, "C _1-6 alkyl" means having 1 to 6 free radicals arranged in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like.

Optionally, the term "haloalkyl" may mean an alkyl group substituted by one or more halogen atoms. In one embodiment, the alkyl group may be substituted with one to three halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon group of _the formula _-CnH2n- . Non-limiting examples include ethylidene and propylene.

The term "haloalkylene" may mean, as appropriate, an alkylene group substituted by one or more halogen atoms. In one embodiment, the alkylene group may be substituted by one to three halogens.

The term "alkenyl" refers to an alkyl group in which one or more carbon/carbon single bonds are replaced by double bonds.

The term "alkynyl" refers to an alkyl group in which one or more carbon/carbon single bonds are replaced by a triple bond.

The term "carbocyclyl" refers to any stable non-aromatic hydrocarbon ring having 3 to 12 membered carbocyclyl groups. In one embodiment, the carbocyclyl is 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11- or A 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated or unsaturated. Any substitutable ring atom may be substituted (eg, by one or more substituents). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, adamantyl, cyclohexyl, Octyl, cyclooctenyl and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include bridged, fused, and spiro rings. In spirocarbocyclyl, two different rings share one atom. An example of a spirocarbocyclyl group is spiro[3.3]heptane. In bridged carbocyclyl groups, the rings share at least two non-adjacent atoms in common. Examples of bridged carbocyclyl groups include bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl-2-enyl, and adamantyl. In a fused ring carbocyclyl system, two or more rings can be fused together such that both rings share a common bond. Examples of two or three fused ring carbocyclyl groups include naphthyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl), indenyldiene, indenyl (indenyl ), anthracenyl, phenanthrenyldiene and decahydronaphthyl.

The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl group can have 3 to 7 ring carbons. Any substitutable ring atom can be substituted (eg, by one or more substituents). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused rings and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups 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, etc. Cycloalkyl also includes spirocyclic rings (eg, spirobicyclic rings in which two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups 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, etc.

啉基、氮雜環庚基、氧雜環庚烷基、硫雜環庚烷基、四氫吡啶 基及類似物。雜環基多環系統可在多環系統的一個或多個環包含雜原子。取代基可存在於多環系統中的一個或多個環。 The term "heterocyclyl" or "heterocycle" refers to a free radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen , tertiary nitrogen, nitrogen oxides (such as NO), oxygen and sulfur, including terine and terine (3 to 12 membered heterocyclyl). In certain embodiments, the heterocyclyl 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 to 7 membered heterocyclyl). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, if valency permits. Heterocyclyl may be monocyclic (monocyclic heterocyclyl) or polycyclic (for example, a bicyclic system (bicyclic heterocyclyl) or a tricyclic system (tricyclic heterocyclyl); polycyclic systems include fused, bridged, or spirocyclic system). Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, hexahydropyridinyl base,

Phinyl, azepanyl, oxeptanyl, thieptanyl, tetrahydropyridinyl and the like. Heterocyclyl polycyclic systems may contain heteroatoms in one or more rings of the polycyclic system. Substituents may be present on one or more rings in a polycyclic system.

Spiroheterocyclyl refers to a 5 to 12-membered polycyclic heterocyclyl having a ring connected via a common carbon atom (called a spiro atom), wherein the ring has a ring selected from nitrogen, quaternary nitrogen, nitrogen oxide (for example, NO), oxygen and sulfur, including one or more heteroatoms from the group consisting of trioxide and triane, the remaining ring atoms are C, one or more of the rings may contain one or more double bonds, but a ring has Completely engages the pi-electronic system. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:

Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl, in which each ring in the group shares a pair of adjacent carbon atoms with another ring in the group, and one or more of the rings may contain One or more double bonds, but at least one of the rings does not have a fully engaged pi-electron system, and wherein the ring has a ring selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen and sulfur, including sulfur One or more heteroatoms of the group consisting of cyclohexane and sulfide, and the remaining ring atoms are C. Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups

Bridged heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl in which any two rings share two unconnected atoms. The ring may have one or more double bonds but does not have a fully joined bond. π-electron system, and the ring has a component selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen and sulfur, including One or more heteroatoms from the group consisting of triacetyl and triacetyl are used as ring atoms, and the remaining ring atoms are C. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

Generally speaking, if valence allows, a carbocyclyl, cycloalkyl or heterocyclyl group may be unsubstituted or substituted with one or more substituents, where the substituents may be independently selected from groups such as pendant oxygen groups. group, -CN, halogen, alkyl and alkoxy, and optionally, the alkyl substitution may be further substituted.

The term "aryl" refers to a 6 to 10-membered all-carbon monocyclic or polycyclic fused ring (fused ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group, and Has a fully engaged 4-electronic system. The term "aryl" is used interchangeably with the terms "aryl ring", "carbocyclic aromatic ring", "aromatic group" and "carbocyclic aromatic group". Representative examples of aryl groups are phenyl and naphthyl.

As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring carbon atom has been replaced by a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, the heteroaryl group is based on a C _5-10 aryl group in which one or more ring carbon atoms are replaced by heteroatoms. Heteroaryl groups may be attached via ring carbon atoms or, when valence permits, via ring nitrogen atoms. Generally speaking, heteroaryl groups may be unsubstituted or substituted with one or more substituents, which are independently selected from halogen, OH, alkyl, alkoxy and amine groups (e.g., NH ₂ , NH alkyl, N (alkyl) ₂ ), if necessary, the alkyl group may be further substituted.

Examples of monocyclic 5-6 membered heteroaryl groups include furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (for example, 2-oxadiazole) base, 5-oxadiazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (for example, 3-pyrazolyl, 4-pyrazolyl) azolyl), 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 (for example, 3-pyrimidinyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , triazolyl (for example, 2-triazolyl, 5-triazolyl), tetrazolyl (for example, tetrazolyl), thienyl (for example, 2-thienyl, 3-thienyl), pyrimidinyl, Pyridyl and pyridinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuryl, indolyl, quinolyl, benzotriazolyl, benzothiazolyl, benzene Oxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl or benzisoxazolyl. A "substituted heteroaryl group" is substituted on any one or more substitutable ring atoms that are bonded to a hydrogen ring carbon atom or ring nitrogen atom.

As used herein, many moieties (eg, alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are meant to be "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise indicated, it means that any substitutable moiety of the moiety that is known to one of ordinary skill in the art may be substituted, including one or more substituents. . If more than one substituent is present, each substituent may be selected independently. Such means for substitution are well known in the art and/or are taught by this disclosure. Optional substituents may be any suitable substituents for attachment to the moiety.

When suitable substituents are not specifically enumerated, exemplary substituents include, but are not limited to: C ₁ - ₅ alkyl, C ₁ - ₅ hydroxyalkyl, C ₁ - ₅ haloalkyl, C ₁ - ₅ alkoxy , C ₁ - ₅ haloalkoxy group, halogen, hydroxyl, cyano group, amine group, -CN, -NO ₂ , -OR ^c1 , -NR ^a1 R ^b1 , -S(O) _i R ^a1 , -NR ^a1 S (O) _i R ^b1 , -S(O) _i NR ^a1 R ^b1 , -C(=O)OR ^a1 , -OC(=O)OR ^a1 , -C(=S)OR a1 , ^-O (C= S)R ^a1 , -C(=O)NR ^a1 R ^b1 , -NR ^a1 C(=O)R ^b1 , -C(=S)NR ^a1 R ^b1 , -C(=O)R ^a1 , -C( =S)R ^a1 , NR ^a1 C(=S)R ^b1 , -O(C=O)NR ^a1 R ^b1 , -NR ^a1 (C=S)OR ^b1 , -O(C=S)NR ^a1 R ^b1 , -NR ^a1 (C=O)NR ^a1 R ^b1 , -NR ^a1 (C=S)NR ^a1 R ^b1 , phenyl or 5 to 6-membered heteroaryl. Each R ^a1 and each R ^b1 are independently selected from -H and C ₁ - ₅ alkyl, optionally substituted with hydroxyl or C ₁ - ₃ alkoxy; R ^c1 is -H, C ₁ - ₅ haloalkyl Or C _{1 -5} alkyl, wherein the C _{1 -5} alkyl is optionally substituted with hydroxyl or C ₁ -C ₃ alkoxy.

」係指部分體(moiety)附接的點。 As used in this article, the notation "

” refers to the point at which a moiety is attached.

pharmaceutically acceptable salt

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

Pharmaceutically acceptable salts of compounds of any of the above chemical formulas include acid addition salts and basic salts.

Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a base group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, Benzoic acid, ethanesulfonic acid, methanesulfonic acid and succinic acid) salts. Compounds of the present teachings having acid groups, such as carboxylic acids, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. 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 of the above chemical formulas can be prepared by one or more of three methods:

(i) By reacting a compound of any of the above chemical formulas with a desired acid or base;

(ii) By removing an acid-labile or base-labile protecting group from a suitable precursor of a compound of any of the above formulas using the desired acid or base or by opening a suitable ring precursor, e.g. ester or lactam; or

(iii) Convert the salt of a compound of any of the above chemical formulas into another by reacting with a suitable acid or base or by using a suitable ion exchange column.

All three reactions typically occur in solution. The salt produced can be precipitated and collected by filtration, or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can range from completely ionised to nearly non-ionised.

Compounds of any of the above formulas and pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.

Stereoisomers and other variants

Compounds of any of the above chemical formulas may occur as one or more isomers (eg optical, geometric or tautomerism). Such variations are implicit in the compounds of any of the formulas described above as defining structural features thereof, and are therefore within the scope of the present disclosure.

Compounds with one or more chiral centers may occur in a variety of different stereoisomer forms, that is, each chiral center may have an R or S configuration or may be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomers and enantiomers of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that have two or more different chiral centers and are not mirror images of each other.

When a compound is designated by its chemical name (e.g., when the configuration is designated by an " R " or " S " chemical name) or its structure (e.g., when the configuration is designated by a "wedge" bond), it represents a single enantiomer, unless otherwise Where indicated, the optical purity of the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% (also referred to as enantiomerically pure). Optical purity is determined by dividing the weight of the specified or described mixture of enantiomers by the total weight of the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is specified or described by a structure, and the structure specified or described contains more than one stereoisomer (e.g., a pair of diastereomers), it is understood to include One of the covered stereoisomers or any mixture of covered stereoisomers. It is understood that the stereoisomer purity of a specified or described stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. In this case, stereoisomer purity is determined by dividing the total weight of the stereoisomer mixture covered by the name or structure by the total weight of all stereoisomer mixtures.

When two stereoisomers are described by their chemical nomenclature and structures, and the chemical nomenclature or structures are connected by "and/and/and", a mixture of the two stereoisomers is intended.

When two stereoisomers are described by their chemical nomenclature and structures, and the chemical nomenclature or structures are connected by "or", it means either one of the stereoisomers or the other, but not both.

When a disclosed compound having a chiral center is described by a structure that does not exhibit a configuration at the chiral center, the structure is meant to encompass compounds having an S configuration at the chiral center and an R configuration at the chiral center A compound or a compound having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is described by its chemical name without indicating an " S " or " R " configuration at the chiral center, the nomenclature is meant to encompass compounds having an S configuration at the chiral center, Compounds having an R configuration at the chiral center or compounds having a mixture of R and S configurations at the chiral center.

Racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having a chiral center is named or described without specifying the stereochemistry of the chiral center, it is understood that the name or structure covers both possible enantiomers of the compound (e.g., both pure enantiomers, rich Contains mirror images or racemates). When a compound having two or more chiral centers is named or described without specifying the stereochemistry of the chiral center, it is understood that the nomenclature or structure encompasses all possible non-mirror isomeric forms of the compound (e.g., pure non- Enantiomers, diastereomer-rich and equimolar mixtures of one or more diastereomers (eg, racemic mixtures).

The term "geometric isomer" means isomers having different orientations of substituent atoms in relation to carbon-carbon double bonds, carbocyclic rings, or bridged bicyclic ring systems. Substituent atoms (other than hydrogen) on each side of the carbon-carbon double bond can be in the E or Z configuration according to Cahn-Ingold-Prelog priority rules. In the "E" configuration, the substituent has highest priority on the opposite side of the carbon-carbon double bond. In the "Z" configuration, the substituent has the highest priority of being positioned on the same side of the carbon-carbon double bond.

The substituents around the carbon-carbon double bond can also be referred to as "cis" or "trans". "cis" means that the substituents are on the same side of the double bond, and "trans" means substitution The base positions are on opposite sides of the double bond. The arrangement of substituents around the carbocyclic ring may also be designated as "cis" or "trans". The term "cis" means that the substituents are on the same side of the ring plane, and the term "trans" means that the substituents are on opposite sides of the ring plane. Mixtures of compounds in which substituents are arranged on both the same and opposite sides of the ring plane are designated "cis/trans."

Tautomeric isomers (tautomerism) can occur when structural isomers are interconvertible through low-energy barriers. This can be achieved when compounds of any of the above chemical formulas contain, for example, imine or ketone groups in compounds containing aromatic moieties in proton tautomeric form. Or oxime group or called valence tautomerism. Therefore, a single compound can occur as more than one isomer.

In some cases of tautomerism of the disclosed compounds, tautomeric structures such as those shown below appear:

When geometric isomers are described by name or structure, it is understood that the named or described isomer occurs to a greater extent than the other isomer, that is, the named or described geometric isomer is a geometric isomer. Material purity is greater than 50% by weight, such as at least 60%, 70%, 80%, 90%, 99% or 99.9% purity. Geometric isomer purity is determined by the weight of the named or described geometric isomer in the mixture divided by the weight of all geometric isomers in the compound.

The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Traditional techniques for the preparation/isolation of individual enantiomers/diastereomers include chiral synthesis from suitable optically pure precursors or racemates (or racemates as salts or derivatives) ), use, for example, chiral high pressure liquid chromatography (HPLC for short). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or a compound of any of the formulas described above containing an acidic or basic moiety, a base or an acid. Such as in the case of 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding counterpart by methods well known to those skilled in the art. pure mirror image isomer. Chiral compounds (and chiral precursors thereof) of any of the above chemical formulas can be chromatographed, especially HPLC. In the presence of a hydrocarbon, especially heptane or hexane, containing from 0 to 50% by volume of isopropanol, especially from 2% to 20% by volume and from 0 to 5% by volume of an alkylamine, especially An asymmetric resin with a mobile phase consisting of 0.1% diethylamine was obtained enriched in the enantiomer form. Concentrates of dissolution solutions provide rich mixtures. Chiral chromatography using subcritical fluids and supercritical fluids can be applied. Methods that can be used for chiral chromatography in some embodiments of the present disclosure are well 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 in this article). The column is available from Chiral Technologies, Inc., West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

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

3. Administration and Dosage

Generally, the compounds of the present disclosure are administered in an effective amount to treat the conditions described herein. The compounds of the present disclosure may be administered as the compounds themselves, or alternatively, as pharmaceutically acceptable salts. For purposes of administration and dosage, the compound itself or a pharmaceutically acceptable salt thereof may simply refer to a compound of the present disclosure.

The compounds of the present disclosure are in the form of pharmaceutical compositions suitable for administration by any suitable route, and in dosages effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, intravaginally, parenterally, or topically.

The compounds of the present disclosure can be administered orally. Oral administration may involve swallowing, so the compound enters the gastrointestinal tract, or intrabuccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the present disclosure can also be administered directly to the bloodstream, muscles, or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

In another embodiment, the compounds of the present disclosure can also be applied topically to the skin or mucous membranes, 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 can also be administered directly to the eyes or ears.

Administration regimens for the compounds of the present disclosure and/or compositions containing the compounds are based on a variety of factors, including the patient's type, age, weight, gender, and medical condition; the severity of the condition; the route of administration; and the type of administration. activity of the compound. Therefore, administration regimens can vary widely. In one embodiment, the total daily dose of a compound of the disclosure to treat the conditions discussed herein generally ranges from about 0.001 to about 100 mg/kg (ie, mg of the compound of the disclosure per kilogram of body weight).

For oral administration, the compositions may be provided in the form of lozenges containing 0.1 to 500 mg of the active ingredient as a symptomatic adjustment of the patient's dose. Medications typically contain from about 0.01 mg to about 500 mg of active ingredient. Intravenously, doses range from about 0.01 to about 10 mg/kg/minute as a constant rate infusion.

In accordance with the present disclosure, suitable individuals include mammalian individuals, including non-human mammals such as primates, rodents (mouse, rat, hamster, rabbit, etc.). In one implementation, humans are suitable individuals. Human individuals can be of either gender and at any stage of development.

4.Pharmaceutical compositions

In another embodiment, the present disclosure includes pharmaceutical compositions. The pharmaceutical composition includes a compound presented in the present disclosure, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may 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 physiologically compatible analogs . Examples of pharmaceutically acceptable carriers include one or more of water, physiological saline, phosphate buffer, dextrose, glycerol, ethanol and the like, and combinations thereof, and the composition may include an isotonic agent, such as sugar, Sodium chloride or polyols such as mannitol or sorbitol. Pharmaceutically acceptable substances such as wetting agents or small 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 the present disclosure can be in a variety of forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the desired mode of administration and treatment.

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

Solid dosage forms for oral administration may, for example, be presented in individual units, such as hard or soft capsules, pills, cachets, buccal lozenges, or lozenges, each containing a predetermined amount of at least one compound of the present disclosure. content. In another embodiment, oral administration may be in powder or granular form. In another embodiment, the oral dosage form is sublingual, for example, a buccal lozenge. In such solid dosage forms, a compound of any of the formulas recited above is typically combined with one or more adjuvants. The capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents or may be prepared together with an enteric coating.

In another embodiment, oral administration may be in liquid dosage 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 (eg, water). The compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (eg, sweeteners), and/or perfuming agents.

In another embodiment, the present disclosure includes parenteral dosage forms.

"Parental administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Injectable preparations (i.e., sterile injectable aqueous solutions or oily suspensions) may be formulated using suitable dispersing, wetting, and/or suspending agents as known in the art.

In another embodiment, the present disclosure includes topical dosage forms.

"Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoretic device, intraocular administration, or intranasal or inhaled administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations may include active-boosting Compounds that absorb and penetrate ingredients through the skin or other affected areas. When the compounds of the present disclosure are administered via a transdermal device, the administration will be accomplished using a reservoir-type and porous membrane-type or solid-based type patch. Typical formulations for this purpose include gels, hydrogels, emulsions, solutions, creams, ointments, spreads, dressings, foams, patches, skin patches, wafers, implants implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white soft paraffin, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be included, 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 in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or otic administration may be in the form of drops of a micronized suspension or isotonic, pH-corrected, sterile physiological saline solution. Other formulations suitable for ocular or otic administration include ointments, biodegradable (ie, absorbent gel sponges, collagen) and non-biodegradable (ie, silicone) implants. agents, implants, lenses and particulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose or heteropolysaccharide compounds such as gellan gum ( gelan gum), which may be incorporated with a preservative such as benzalkonium chloride. The formulation may also be delivered by iontophoresis.

For intranasal or inhaled administration, the compounds of the present disclosure are readily extruded or aspirated by the patient in solution or suspension form, or as an aerosol spray from a self-pressurized container or nebulizer with a suitable propellant Use pump spray container for delivery. Formulations suitable for intranasal administration are generally administered as a dry powder from a dry powder inhaler (alone; or as a mixture, e.g., with a milk). Sugar in the form of a dry blend; or as particulate mixtures, e.g. mixed with phospholipids, such as phosphatidylcholine) or as an aerosol spray from pressurized containers, pumps, sprayers, atomizers (preferably Atomizers or sprayers that use electrohydrodynamics to generate a fine mist, with or without the use of suitable propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3, 3,3-Heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent such as chitosan or cyclodextrin.

In another embodiment, the present disclosure includes rectal dosage forms. Such rectal dosage forms may be, for example, in the form of suppositories. Cocoa butter is a traditional suppository base, but a variety of substitutes may reasonably be used.

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

The above considerations for effective formulation and administration procedures are well known in the art and are described in standard textbooks. Formulations of drugs are described, for example, in 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 (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

5. Treatment methods

Compounds of the present disclosure inhibit CDK2 and are therefore useful in treating diseases in which the underlying pathology is (in whole or in part) mediated by CDK2. This disease includes cancer and other diseases with disordered proliferation.

In some embodiments, the present disclosure provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, to treat the growth of cancerous tumors in an individual or patient. Compounds of formula (I) or any formula as described herein, compounds as described in any claim and described herein, or pharmaceutically acceptable salts or stereoisomers thereof, can be used to inhibit CDK2 with abnormal activation Kinase activity in cancerous tumor growth. These include, but are not limited to, diseases characterized by CCNE1 amplification or overexpression (eg, cancer), such as ovarian cancer, uterine carcinosarcoma, and breast cancer, and p27 inactivation (such as breast cancer and melanoma). Accordingly, in some embodiments of the method, the patient has been determined to have an amplification of the cyclin E1 (CCNE1) gene and/or an expression of CCNE1 that is orders of magnitude higher than that of CCNE1 in a biological sample previously obtained from the human subject. Contrast performance magnitude. Alternatively, a compound of formula (I) or any formula as described herein, or any of the claims and compounds described herein, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, may be combined with other agents or standard cancer treatments , as described below. In one embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells in vitro. The method includes contacting tumor cells in vitro with a compound of formula (I) or any formula described herein, a compound described in any claim and described herein, or a pharmaceutically acceptable salt or stereoisomer thereof . In another embodiment, the present disclosure provides a method of inhibiting the growth of tumor cells having CCNE1 amplification and overexpression in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a compound of formula (I) or any formula described herein, a compound described in any of the claims and described herein, or a pharmaceutically acceptable salt thereof or its stereoisomers.

In some embodiments, the compounds of the present disclosure selectively inhibit CDK2 more than CDK1, and the ratio of the IC ₅₀ value of the latter (CDK1) to the former (CDK2) is at least about 2, 5, 10, 15, 20, 40, 50, 60, 80, 100 or more.

In some embodiments, this article provides a method of inhibiting CDK2, comprising contacting CDK2 with a compound of Formula (I) or any of the formulas described herein, or any of the claims and described herein. compounds, or pharmaceutically acceptable salts or stereoisomers 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 formula described herein, or a compound described in any of the claims and described herein, or Its pharmaceutically acceptable salts or its stereoisomers.

In some implementations, provided herein is a method of treating cancer. The method includes administering to a patient (in need thereof) a therapeutically effective amount of a compound of formula (I) or any formula described herein, a compound of any of the claims and described herein, or a pharmaceutically acceptable amount thereof. salt or its stereoisomer. 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 some embodiments, the method further includes determining the expression status of CCNE1, p21Cip1 and/or p27Kip1.

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

In some embodiments, this article provides a method for treating a disease or disorder related to CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any formula described herein, or any of the claims. The compounds described above and described herein, or their pharmaceutically acceptable salts or their stereoisomers.

In some embodiments, the disease or disorder associated with CDK2 is associated with cyclin Amplification of the E1 (CCNE1) gene is associated with/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 cancer (see Hu, S., et al ., Mol Cancer Ther, 2015, 14(11): 2576-85) and cancers with FBW7 mutations 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 cancer, lung cancer, colorectal cancer, gastric cancer, or bone cancer, leukemia, or lymphoma.

In some embodiments, the CDK2-related disease or disorder is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma ), uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma ( mesothelioma) or sarcoma.

In some embodiments, the CDK2-related disease or disorder is lung adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

In some embodiments, the CDK2-related disease or disorder is adenocarcinoma, carcinoma, or cystadenocarcinoma.

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

In some embodiments, the disease or disorder associated with CDK2 is 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 primary disease that exhibits CDK4/6 inhibition. or acquired resistant breast cancer.

In some embodiments, the breast cancer is progressive or metastatic breast cancer. Examples of cancers treated with compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer (carcinoma of the endometrium), endometrial cancer (endometrial cancer), cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's disease Golden lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute Lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney cancer or urethra cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, Axial tumors of the spine, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos) and combinations of the above . Compounds of the present disclosure may also be used to treat metastatic cancer.

In some embodiments, cancers that may be treated 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 (eg, non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (eg, bladder), and those with high microsatellite instability Sexual cancer (MSI ^high ). Additionally, the present disclosure includes refractory or relapsed malignant tumors whose growth can be inhibited using the compounds of the present disclosure.

In some embodiments, cancers that may be treated with 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, kidney cancer, Liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood system cancer (for example, lymphoma, acute leukemia, such as acute lymphoblastic leukemia (ALL) , acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, or multiple myeloma) and combinations of these cancers.

In some embodiments, cancers that can be treated 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 tumors, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, Gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelial cancer cancer, neck cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell cancer, salivary gland cancer, sinus cancer, spinal cord cancer, tongue cancer, renal tubular cancer, urethra cancer and ureteral cancer. In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that may be treated with 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, neurological cancers, gynecological cancers, cancer and skin cancer.

Exemplary blood 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 relapsed follicular lymphoma), Hodgkin lymphoma, bone marrow Proliferative diseases (eg, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndromes (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, rhabdomyosarcoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchi adenomas, enchondromatous hamartomas, and mesothelioma.

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

Exemplary genitourinary tract cancers include 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, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma) cancer.

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

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

Exemplary neurological cancers include skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma) tumor, glioma, ependymoma, germ cell (pineal tumor), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) and cancers of the spinal cord (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma)), granular - Sheath cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) tumor), vagina (Clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tube (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications that may be treated with 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 syndrome, testicular disease carcinoma, cholangiocarcinoma, esophageal cancer, and urothelial cancer.

It is believed that the compounds of formula (I), or any embodiment thereof, may possess satisfactory pharmacological and promising biomedical properties, such as toxicological properties, metabolic and pharmacokinetic properties, solubility and permeability. It will be appreciated that measurement of appropriate biomedical properties is within the knowledge of one of ordinary skill in the art, for example, measuring cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

The terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, Sheep, horse or primate, preferably human.

The terms "treatment, treat and treating" refer to reversing, reducing or inhibiting the progression of the diseases described herein. In some embodiments, treatment (ie, therapeutic treatment) may be administered after the disease has developed or one or more signs or symptoms have been observed. In other embodiments, the treatment can be administered without signs or symptoms of disease. For example, treatment (ie, prophylactic treatment) may be administered to susceptible individuals prior to the onset of symptoms (eg, based on symptom history and/or based on pathogen exposure). Treatment can 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 a method of introducing or introducing a compound disclosed herein or a composition thereof to a patient. These methods include, but are not limited to, intra-articular (in a joint), intravenous, intramuscular , intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalational, transdermal, rectal, etc. Administration techniques that may use the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current ed.), Mack Publishing Co., Easton, Pa.

In general, the effective amount of a compound taught herein will vary depending on various factors, such as a given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the individual or host being treated, etc., but may still be determined by A person with ordinary knowledge in the relevant technical field shall make a decision based on routine procedures. One of ordinary skill can readily determine the effective amount of a compound of the present teachings by conventional methods known in the art.

The term "therapeutically effective amount" means an amount that, when administered to an individual, produces a beneficial or desired result as compared to a control group, including clinical results such as inhibition, suppression, or reduction of symptoms in the individual to be treated. Symptoms of the condition. For example, a therapeutically effective amount may be an amount effective to kill or inhibit: the growth or spread of cancer cells; the size or number of tumors; or other measures of the magnitude, stage, progression, or severity of the cancer. The exact amount required will vary from individual to individual, depending on the individual's species, age and general condition, the severity of the disease, the specific anti-cancer agent, its mode of administration, combination therapy with other treatments, etc.

6. Combination therapy

I.Cancer Therapy

Cancer cell growth and survival can be affected by dysfunction in multiple signaling pathways. Therefore, it is useful to combine different enzyme/protein/receptor inhibitors, showing different preferences in the targets subject to their modulatory activity, to treat these conditions. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance developing in a cell population and/or reduce the toxicity of the treatment.

one or more additional pharmaceutical agents, such as chemotherapeutic agents, antiestrogen agents, anti-inflammatory agents, steroids, immunosuppressive agents, immunoneoplastic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, and 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, for example, in WO Those described in 2006/056399 can be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders or conditions. Other agents, such as therapeutic antibodies, can be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders, or conditions. One or more additional agents can be administered to the patient simultaneously or sequentially.

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

The compounds disclosed herein may be used in combination with one or more other enzyme/protein/receptor inhibitor therapies to treat diseases, such as cancer and other diseases or disorders described herein. Examples of diseases and indications that may be treated with combination therapy include those described herein. Examples of cancers include solid tumors and non-solid tumors such as liquid tumors, blood cancers. Examples of infections include viral, bacterial, fungal or parasitic infections. For example, compounds of the present disclosure can be used to treat cancer in combination with one or more inhibitors of the following kinases: 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, PDGFβR, PI3K (α, β, γ, δ 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 kinase (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, compounds of the present disclosure can be used in combination with one or more of the following inhibitors to treat cancer or infection. Non-limiting examples of inhibitors that can be used in combination with the compounds of the present disclosure to treat cancer and infection include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828, INCB62079), EGFR Inhibitors (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetus cetuximab, necitumumab, or panitumumab, VEGFR inhibitors or pathway blockers (e.g., bevacizumab), paclitaxel pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib (cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olapar olaparib, rucaparib, veliparib or niraparib), JAK inhibitors (JAK1 and/or JAK2, for example, ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., icandostat (epacadostat), NLG919 or BMS-986205, MK7162), LSD1 inhibitors (such as GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (such as parsaclisib (INCB50465) or INCB50797) , PI3K-γ inhibitors such as PI3K-γ selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer; e.g., INCB081776), Glycoside receptor antagonists (e.g., A2a/A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1/2 phosphatase inhibitors, histone deacetylation HDAC inhibitors (HDAC) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromodomain and extra terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) , c-MET inhibitor (eg, capmatinib), anti-CD19 antibody (eg, tafasitamab), ALK2 inhibitor (eg, INCB00928); or combinations thereof.

In some embodiments, a compound or salt described herein is administered with a PI3K6 inhibitor. In some embodiments, a compound or salt described herein is administered with a JAK inhibitor. In some embodiments, a compound or salt described herein is administered with a JAK1 or JAK2 inhibitor (eg, baricitinib or ruxolitinib). In some embodiments, a compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, a compound or salt described herein is administered with a JAK1 inhibitor that is selective over JAK2. Exemplary antibodies for combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab Bevacizumab (AVASTINTM, e.g., anti-VEGF), panibumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-EGFR) ( For example, anti-CD20) and antibodies against 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: cytostatics, cisplatin, doxorubicin, taxotere, taxol ), etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilone (epothilones), tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123 , BMS 214662, IRESSATM (gefitinib), TARCEVATM (erlotinib (gefitinib)), EGFR antibody, intron, ara-C, adriamycin (adriamycin), cytoxan, gemcitabine ( gemcitabine), uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene Melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine ), floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxa Oxaliplatin, leucovirin, ELOXATIN ^TM (oxaliplatin), pentostatine, vinblastine, vincristine, vindesine, Bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin mithramycin), deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17 α -ethinylestradiol 17.alpha.-ethinylestradiol), diethylstilbestrol, testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone (testolactone), megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene ), hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, Mitoxantrone, Levamisole, navelbene, anastrazole, letrozole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN ^TM (trastuzumab), BEXXAR ^TM (tositumomab) , Vanke ^TM (bortezomib), ZEVALIN ^TM (ibritumomab tiuxetan), TRISENOX ^TM (arsenic trioxide), XELODA ^TM (capecitabine), vinorelbine ( vinorelbine), porfimer, ERBITUX ^TM (cetuximab), thiotepa, altretamine, melphalan, trastuzumab ( trastuzumab), lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225 (cetuximab) Antibody), 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 also be used in combination with other methods of treating cancer, such as through chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapies include interleukin therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, Antibody drug conjugates, receptive T cell infusion, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy and immunomodulatory small molecule drugs, including thalidomide or JAK1 /2 inhibitors, PI3Kd inhibitors, etc. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, alkaline Altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene ), baricitinib, bleomycin, bortezomib, busulfan intravenous, busulfan oral, callusterone (calusterone), capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin , cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium), dasatinib, daunorubicin, decitabine (decitabine), denileukin (denileukin), denileukin diftitox (denileukin diftitox), dexrazoxane (dexrazoxane), docetaxel (docetaxel), doxorubicin (doxorubicin), drostatin propionate (dromostanolone propionate), eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etopol Etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil , fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, acetic acid group Histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate (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, penstatin, pipobroman, plicamycin ), procarbazine, quinac Quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib (sunitinib), sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide ), thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab ), tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat ) and zoledronate.

Other examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, alfa Doxorubicin, Cyclophosphamide, vincristine, etoposide, carmustine, etc.

Exemplary steroids include corticosteroids such as dexamethasone or prednisone. Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC ^™ ), nilotinib, dasatinib, bosutinib, and ponatinib ponatinib, and pharmaceutically acceptable salts. Other examples of suitable Bcr-Abl inhibitors include compounds of the type and kind disclosed in US Patent No. 5,521,184, WO 04/005281, and US Patent Application No. 60/578,491, and pharmaceutically acceptable salts thereof.

Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, Maleate, sorafenib, quizartinib, grams crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds as disclosed in WO 03/037347, WO 03/099771 and WO 04/046120, and pharmaceutically acceptable salts thereof.

Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include, e.g. The compounds disclosed in WO 00/09495 and WO 05/028444 and their pharmaceutically acceptable salts.

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

Exemplary suitable CDK4/6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, as well as pharmaceutical agents thereof. Take it with a grain of salt. Other exemplary suitable CDK4/6 inhibitors include compounds as disclosed in WO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074 and WO 12/061156, and their pharmaceutical uses. Take it with a grain of salt.

In some embodiments, the compounds disclosed herein can be used in combination with one or more kinase inhibitors, including imatinib, particularly in the treatment of patients who are resistant to imatinib or other kinase inhibitors. patient.

In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents to treat cancer and can improve the therapeutic response compared to the use of the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, the compounds of the present disclosure can be used in combination with the chemotherapeutic agents provided herein. For example, other agents used to treat multiple myeloma may include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (Boron Tezomib). Other agents used to treat 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 alkylating agents 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). The desired result when using the CDK2 inhibitors of the present disclosure in combination with other agents is a synergistic effect.

The agents may be combined with the compounds of the present disclosure in single or sequential dosage forms, or the agents may be administered as separate dosage forms simultaneously or sequentially.

Compounds of the present disclosure may be used in combination with one or more other inhibitors or one or more therapies to treat infection. Examples of infections include viral, bacterial, fungal or parasitic infections.

In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, wherein the dexamethasone is administered intermittently rather than continuously.

A compound of formula (I) or any formula as described herein, a compound as described in any claim and contained herein, or a salt thereof, may be combined with another immunogenic agent, such as cancer cells, purified tumor antigens ( Contains recombinant proteins, peptides and carbohydrate molecules), cells and genes encoding immune-stimulating cytokines cells transfected with the subgene. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigen, Trp-2, MARTI and/or tyrosinase, or transfected to express the interleukin GM- CSF tumor cells.

A compound of formula (I) or any formula as described herein, a compound as described in any claim and contained herein, or a salt thereof, may be used in conjunction with a vaccination regimen for the treatment of cancer. In some embodiments, the tumor cells are transduce to express GM-CSF. In some embodiments, the tumor vaccine includes proteins from viruses associated with human cancer such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, a compound of Formula (I) or any formula as described herein, a compound as claimed in any claim and described herein, or a salt thereof, can be immunologically combined with dendritic cells to activate effective anti- tumor response.

Compounds of the present disclosure may be used in combination with bispecific macrocyclic peptides that target effector cells expressing Feα or Fγ receptors to tumor cells. Compounds of the present disclosure may also be combined with macrocyclic peptides that activate the host immune response.

In some further embodiments, compounds of the present disclosure in combination with other therapeutic agents can be administered to patients before, during, and/or after bone marrow transplantation or stem cell transplantation.

The compounds of the present disclosure can be used in combination with bone marrow transplantation to treat tumors of various hematopoietic origins.

Compounds of formula (I) or any formula as described herein, compounds as described in any of the claims and contained herein, or salts thereof, may be used in combination with vaccines to stimulate immune responses to pathogens, toxins and autoantigens. Examples of pathogens in particular that may be targeted by this treatment approach include those that are not currently Pathogens for which vaccines are not effective, or for which conventional vaccines are not fully effective. These include, but are not limited to, HIV, Hepatitis (A, B and C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa Bacteria.

Viruses causing infections that can be treated by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex Herpes viruses, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes viruses (such as VZV, HSV-1, HAV-6, HSV-II and CMV, Epstein Barr ) viruses, flaviviruses, echovirus, rhinovirus, Coxsackie virus, cornovirus, respiratory syncytial virus, mumps 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.

Pathogens that cause infections that can be treated by the method of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, and 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 that can cause infections that can be treated by the method of the present disclosure include, but are not limited to, Candida (Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, Kojima Koji mold, Koji mold, etc.), Mucor genus (Mucor, Rhizopus and Rhizopus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis), Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites that can cause infections that can be treated by the method of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, and Naegleria fowleri. ), Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax ), Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Brazil Nippostrongylus brasiliensis.

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

The safety and effective methods of administration of most of these chemotherapeutic agents are known to those of ordinary skill in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, eg , 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if fully presented .

II. Immune checkpoint therapy

Compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors to treat diseases, such as cancer or infection. Exemplary immune checkpoint inhibitors include inhibitors directed against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginine enzyme, 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 the group consisting of: CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is selected from the following inhibitory checkpoint molecules: A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3 , TIGIT and VISTA. In some embodiments, compounds provided herein can be used in combination with one or more drugs selected from the group consisting of KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

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

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

In some embodiments, the inhibitor of the immune checkpoint molecule is an antibody to PD-1, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody system contains 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 a nivolumab monoclonal antibody or a pembrolizumab monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is a pembrolizumab monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody system MGA012. In some embodiments, the anti-PD-1 monoclonal antibody is SHR-1210. Other anti-cancer agents include antibody therapies such as 4-1BB (eg, urelumab and utomilumab).

In some embodiments, the inhibitor of the immune checkpoint molecule is an antibody to PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody system is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody system is MPDL3280A or MEDI4736. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, for example, a 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 the 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 the 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 the immune checkpoint molecule is a TIM3 inhibitor, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody system is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of the immune checkpoint molecule is a GITR inhibitor, 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 the immune checkpoint molecule is an OX40 agonist, for example, an anti-OX40 agonist antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody system 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 the immune checkpoint molecule is a CD20 inhibitor, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is an obinutuzumab or rituximab antibody. 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, compounds of the present disclosure may 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, additional compounds, inhibitors, agents, and the like can be combined with the compounds of the present disclosure in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

7. Treatment package

One aspect of the invention relates to a kit, convenient and effective for carrying out the method or use according to the invention. Generally, the pharmaceutical package or set contains one or more containers containing one or more ingredients of the pharmaceutical composition of the invention. Such sets are particularly suitable for delivering solid oral dosage forms such as tablets or capsules. Such kits preferably contain multiple unit doses, and may also contain cards with dose guides for their intended use. If desired, memory aids may be provided, such as in the form of numbers, letters, or other markings, or in the form of calendar inserts, designating the days in the treatment plan when doses may be administered. Optionally, notices associated with such containers may be in the form of regulations governing the manufacture, use, or sale of medicinal products for human administration that reflect the establishment by which they are manufactured, used, or sold for human administration. of approval.

The following representative examples contain important additional information, examples, and guidance that may be applicable to various implementations of the invention and their equivalents. These examples are intended to help illustrate the invention and are not intended to, and should not be construed as, limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those of ordinary skill in the art upon reading this document, including the following examples and References to scientific and patent documents cited in this article.

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

Furthermore, for the purposes of this invention, chemical elements are those found in the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover). In addition, general principles of organic chemistry and specific functional moieties and reactivity are described in "Organic Chemistry" (Thomas Sorrell, University Science Books, Sausalito: 1999) and "Organic Chemistry" (Morrison & Boyd (3rd edition)) .

8. Preparation

Compounds of any of the above formulas can be prepared by the following general and specific methods using the common general knowledge of those skilled in the art of synthetic organic chemistry. This 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); Compendium of Organic Synthetic Methods (Vol. I-XII (published by Wiley-Interscience)). The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

When preparing compounds of any of the above formulas, it should be noted that some preparation methods described herein may require protection of remote functional groups (for example, primary amines, secondary amines, carboxyl groups in any of the above precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation method. The need for such protection can be readily determined by those of ordinary skill in the art. The use of such protection/deprotection is also within the skill of 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, some compounds contain primary amine or carboxylic acid functional groups that, if unprotected, can interfere with reactions at other sites on the molecule. Therefore, such functional groups can be protected by appropriate protecting groups, This protecting group can be removed in a subsequent step. Protecting groups suitable for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenyl for amines. Methoxycarbonyl (Fmoc) and lower alkyl esters or benzyl esters of carboxylic acids), which are generally not chemically reactive under the reaction conditions and can usually be used without chemically changing other functions of any of the above compounds. case was removed.

The concepts described below are intended to provide a general description of methods for preparing the compounds of the present disclosure. Some compounds of the present disclosure may contain single or multiple chiral centers with stereochemical designation (R) or (S). As will be apparent to one of ordinary skill in the art, all synthetic transformations can be performed in a similar manner, whether the material is enantiomer-rich or racemic. Furthermore, resolution embodiments of desired optically active materials can be performed at any desired point in the sequence using well-known methods as described herein and in chemical documents.

Abbreviation

General steps. Unless otherwise stated, all reactions were performed under anhydrous conditions using dry solvents under nitrogen. The reaction progress was monitored using low-resolution mass spectrometry (LC-MS) and recorded on a Waters ACQUITY UPLC equipped with an SQ detector 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 ₃ CN; 5% solvent B changes to 95% solvent B in 1.0 minutes, holds for 1.0 minutes, equilibrates to 5% solvent B in 0.5 minutes; flow rate: 1.8 mL/min; column temperature 40°C. Purification of the final product was performed by Prep-HPLC on Waters Prep-HPLC with QDA detector using an Xbridge C18 column (5 μm, 150 × 19 mm) and using gradient elution. Purchased (1-(tert-butyl)-3-((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)benzylcarbamate from PharmaBlock ester, (1-(tert-butyl)-3-((1R,3 S )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)carbamate benzyl ester and methanesulfonate Acid (trans, racemic)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester .

Intermediates

Intermediate 1

Step 1: (1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1 H -pyra Azol-5-yl)carbamic acid benzyl ester

(1-(tert-Butyl)-3-((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazole-5 in CH ₂ Cl ₂ (100 mL) at 20 °C To a suspension of benzyl carbamate (6.00g, 16.8mmol), imidazole (1.71g, 25.2mmol) and TBDPSCl (6.93g, 25.2mmol) were added sequentially. The mixture was stirred at this temperature for 6 hours, then quenched with water (50 mL) and extracted with _CH2Cl2 (100 _mL ×3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 8% EtOAc in 15 min) to give (1-(tert-butyl)-3-((( 1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)carbamic acid benzyl ester (9.30g, 92% yield). LC-MS: m/z[M+H] ⁺ 595.8.

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

(1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy) in CH ₃ CN (200 mL) at 25°C ) Cyclopentyl) -1H -pyrazol-5-yl)carbamic acid benzyl ester (6.00g, 16.8mmol) was added to a suspension of fluorine reagent (Selectfluor) (7.92g, 22.4mmol). The mixture was stirred at this temperature for 1 hour and then quenched with water (200 mL). The mixture was concentrated under reduced pressure to remove most of the _CH3CN and extracted with EtOAc (100 mL×3). The combined organic phases were dried over _{anhydrous Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 15% EtOAc in 15 min) to afford (1-(tert-butyl)-3-((( 1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-fluoro-1 H -pyrazol-5-yl)carbamic acid benzyl ester ( 3.70g, 55% yield). LC-MS: m/z[M+H] ⁺ 614.3.

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

(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)) in THF (50.0 mL) and EtOAc (50.0 mL) at 25°C )oxy)cyclopentyl)-4-fluoro-1H-pyrazol-5-yl)carbamic acid benzyl ester (3.70g, 6.03mmol) was added to a stirred solution of Pd/C (1.28g, 5% wt .%, 6.75 mmol). The mixture was stirred for 2 hours at this temperature under _H2 atmosphere (balloon) and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain (1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl) as a yellow oil )-4-fluoro- 1H -pyrazol-5-amine (2.44g, 84% yield), which was used in the next step without further purification. LC-MS: m/z [M+H] ⁺ 480.3.

Synthesis Example

Example 1

Isopropylcarbamic acid (1 R ,3 S )-3-(3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino)-1 H -pyra Azol-5-yl)cyclopentyl ester 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) at 25 °C was added CDI (3.42 g, 23.8 mmol ). The mixture was stirred at this temperature for 0.5 hours, then 2,2-dimethoxyethylamine (2.18 mL, 2.10 g, 20.0 mmol) was added at 25°C. The solution was stirred at this temperature for 0.5 hours, then HCl (1.0 mL, 12.0 M aq., 12.0 mmol) was added and the mixture was warmed to 100°C and stirred at this temperature for 48 hours. The reaction mixture was cooled to 25°C, quenched with water (50 _mL ), then extracted with EtOAc (50 mL x 2), dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 2-methyl- 5H -pyrazolo[1,5- a ]pyrazin-4-one as a brown oil (2.00 g, 68% yield). LC-MS: m/z[M+H] ⁺ 150.1.

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

Stirring of 2-methyl-5 H -pyrazolo[1,5- a ]pyrazin-4-one (500 mg, 3.35 mmol) and DMF (0.1 mL) in toluene (10.0 mL) at 25 °C solution, add POBr3 (0.511mL, 1.44g, 5.03mmol). The reaction mixture was warmed to 90°C and stirred at this temperature for 12 hours, then cooled, quenched with water at 0°C and extracted with EtOAc (50 mL×3). The combined organic phases _were washed with saturated aqueous _Na2CO3 (10 _mL ) and brine (10 mL), dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 60% EtOAc in 30 min) to give 4-bromo-2-methyl-pyrazolo[1, 5-a]pyrazine (180 mg, 25% yield). LC-MS: m/z[M+H] ⁺ 211.9.

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

2-tert-Butyl-5-[(1 S ,3 R )-3-[tert-butyl(dimethyl)silyl]oxycyclopentyl in DMF (5.0 mL) at 0°C ] Pyrazol-3-amine (200 mg, 592 mmol) was stirred, and 4-bromo-2-methylpyrazolo[1,5- a ]pyrazine (163 mg, 770 μmol) and KOt-Bu (199 mg ,1.78mmol). The reaction mixture was stirred at this temperature for 1 hour, then quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases _were washed with brine (10 mL), dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 30% EtOAc in 20 min) to give N -(1-(tert-butyl)-3-( (1 S ,3 R )-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)-2-methylpyrazolo[1 ,5- a ]pyrazin-4-amine (180 mg, 65% yield). LC-MS: m/z[M+H] ⁺ 469.3.

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

N -(1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldimethylsilyl))oxy in THF (5.0 mL) at 20°C To a stirred solution of cyclopentyl) -1H -pyrazol-5-yl)-2-methylpyrazolo[1,5- a ]pyrazin-4-amine (180 mg, 384 μmol), TBAF ( 1.92 mL, 1.0 M in THF, 1.92 mmol). The reaction mixture was warmed to 40°C and stirred at this temperature for 16 hours, then quenched with water (5 mL) and extracted with EtOAc (5 mL×2). The combined organic phases _were washed with brine (10 mL), dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 60% EtOAc in 20 min) to give (1 R ,3 S )-3-(1-(No. Tributyl)-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentan-1-ol (100 mg, 73% yield). LC-MS: m/z[M+H] ⁺ 355.0.

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

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

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

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrazolo[1,5- a ] A solution of pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (40.0 mg, 91.0 μmol) was warmed to 70°C and stirred at this temperature for 2 hours, then Cool to 25°C and concentrate under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (20 mL), washed with saturated NaHCO ₃ aqueous solution (5 mL), and extracted with CH ₂ Cl ₂ (5 mL×2). The combined organic phases _were washed with brine (10 mL), dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE=1:1) to obtain white solid isopropylcarbamic acid (1 R ,3 S )-3-(3-((2-methylpyrazolo[ 1,5- a ]pyrazin-4-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (10.0 mg, 29% yield). LC-MS: m/z[M+H] ⁺ 384.2

Example 2

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

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

1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)oxy) ring in DMF (5.0 mL) at 0°C To a stirring solution of pentyl)-4-fluoro- 1H -pyrazole-5-amine (220 mg, 1.04 mmol), 4-bromo-2-methylpyrazolo[1,5- a ]pyrazine was added sequentially (385 mg, 800 μmol) and KOt-Bu (270 mg, 2.41 mmol). The reaction mixture was stirred at this temperature for 30 minutes, then quenched with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases _were washed with brine (20 mL), dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 10% EtOAc in 15 min) to give N -(1-(tert-butyl)-3-( (1 S ,3 R )-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-fluoro-1 H -pyrazol-5-yl)-2-methylpyra Azolo[1,5- a ]pyrazin-4-amine (250 mg, 39% yield). LC-MS: m/z[M+H] ⁺ 611.3.

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

N -(1-(tert-butyl)-3-((1 S ,3 R )-3-((tert-butyldiphenylsilyl))oxy in THF (5.0 mL) at 25°C A stirred solution of cyclopentyl)-4-fluoro-1 H -pyrazol-5-yl)-2-methylpyrazolo[1,5- a ]pyrazin-4-amine (300 mg, 491 μmol) , add TBAF (385mg, 1.47mmol). The reaction mixture was warmed to 40°C and stirred at this temperature for 16 hours. The reaction mixture was cooled, diluted with EtOAc (50 mL) and washed with saturated aqueous _NH4Cl (40 mL) and brine (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 minutes) to give (1 R ,3 S )-3-(1-(No. Tributyl)-4-fluoro-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl -1-ol (180 mg, 98% yield). LC-MS: m/z[M+H] ⁺ 373.1.

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

(1 R ,3 S )-3-(1-(tert-butyl)-4-fluoro-5-((2-methylpyrazolo) in CH ₂ Cl ₂ (10.0 mL) at 25 °C To a stirred solution of [1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopent-1-ol (180 mg, 483 μmol), CDI (209 mg, 1.45mmol), DMAP (59.0mg, 483μmol) and Et3N (202μL, 147mg, 1.45mmol). The reaction mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-4 as a yellow oil). -Fluoro-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (220 mg, 98 % yield), which was used directly in the next step without further purification. LC-MS: m/z [methyl ester + H] ⁺ 431.2.

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

1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-4-fluoro-5-() in CH ₃ CN (6.0 mL) at 25 °C A stirred solution of (2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (220 mg, 472 μmol), Propan-2-amine (202 μL, 139 mg, 2.36 mmol) and Et3N (197 μL, 143 mg, 1.41 mmol) were added sequentially. The reaction mixture was warmed to 40°C and stirred at this temperature for 4 hours. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 80% EtOAc in 20 min) to give isopropylcarbamic acid (1-(tert-butyl)) as a yellow oil -4-Fluoro-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (198 mg , 92% yield). LC-MS: m/z[M+H] ⁺ 458.1.

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

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-4-fluoro-5-((2-methylpyrazolo)) in HCO ₂ H (5.0 mL) A stirred solution of [1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (180 mg, 393 μmol) was warmed to 50°C and stirred at this temperature 16:00. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 5% to 70% _CH3CN in 30 min) to give isopropylcarbamic acid ( 1R , 3S ) as a white solid )-3-(4-fluoro-3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino)-1 H -pyrazol-5-yl)cyclopenta ester (28.1 mg, 18% yield). LC-MS: m/z[M+H] ⁺ 402.1.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 1.

Example 11

(1-Methylcyclobutyl)carbamic acid (1 R ,3 S )-3-(3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino )-1 H -pyrazol-5-yl)cyclopentyl) ester

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

( ₁ R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrazolo[1,5- a ] To a stirred solution of pyrazin-4-yl)amine) -1H -pyrazol-3-yl)cyclopent-1-ol (40.0 mg, 113 μmol), DMAP (13.8 mg, 113 μmol), and NMM (37.2 μL, 34.2 mg, 339 μmol) and (4-nitrophenyl)carbonate (68.2 mg, 339 μmol). The reaction mixture was stirred at this temperature for 3 hours, and the filtrate was concentrated under reduced pressure to obtain carbonic acid (1 R , 3 S )-3-(1-(tert-butyl)-5-((2-methylpyrazolo)) as a yellow oil. [1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (50.0 mg, 85% yield) , which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 520.2.

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

To a stirred suspension of 1-methylcyclobutylamine hydrochloride (81.9 mg, 674 μmol) in CH ₃ CN (1.0 mL) at 20° C. was added sequentially Et ₃ N (268 μL, 195 mg, 1.92 mmol) and Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrazolo[1,5- a ]pyra) in CH ₃ CN (1.0 mL) Azin-4-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (50.0 mg, 96.2 μmol). The reaction mixture was stirred at this temperature for 16 hours, then it was poured into _H2O (5 mL) and extracted with EtOAc (15 mL×3). The combined _organic phases were washed with brine (5 mL), dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE=1:1) to obtain (1-methylcyclobutyl)carbamic acid ( 1R , 3S )-3-(1-(tert-butyl) as a yellow oil yl)-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (25.0 mg, 56% yield). LC-MS: m/z[M+H] ⁺ 466.3.

Step 3: (1-methylcyclobutyl)carbamic acid (1 R ,3 S )-3-(3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl) )Amino)-1 H -pyrazol-5-yl)cyclopentyl ester

( ₁ -methylcyclobutyl)carbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrazole)) in HCO 2 H (2.0 mL) The solution of [1,5- a ]pyrazin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (20.0 mg, 43.0 μmol) was heated to 50°C. Stir for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC with CH ₃ CN in water (from 25% to 65% CH ₃ CN in 30 min) to give (1-methylcyclobutyl)carbamic acid as a white solid (1 R ,3 S )-3-(3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino)-1 H -pyrazol-5-yl) Cyclopentyl ester. LC-MS: m/z[M+H] ⁺ 410.2.

The following compounds were prepared using similar procedures as disclosed in Synthesis Example 11.

Example 20

Isopropylcarbamic acid (1 R ,3 S )-3-(3-(pyrazin-2-ylamine)-1 H -pyrazol-5-yl)cyclopentyl ester

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

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

Step 2: Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazin-2-ylamino)-1 H -pyrazole-3- cyclopentyl ester

(1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazin-2-ylamino)-1 H - in CH ₃ CN (20.0 mL) at 25 °C To a stirring solution of pyrazol-3-yl)cyclopent-1-ol (60.0 mg, 199 μmol), NMM (109 μL, 100 mg, 995 μmol) and (4-nitrophenyl) carbonate (120 mg, 597μmol) and DMAP (48.7mg, 398μmol). The reaction mixture was stirred at 25°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 minutes) to give the desired product isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazin-2-ylamino)-1 H -pyrazol-3-yl)cyclopentyl ester (30.0 mg, 39% yield ). LC-MS: m/z[M+H] ⁺ 387.2.

Step 3: Isopropylcarbamate (1 R ,3 S )-3-(3-(pyrazin-2-ylamine)-1 H -pyrazol-5-yl)cyclopentyl ester

(1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazin-2-ylamino)-1 H -pyrazole-3 in HCO 2 H ( _10.0 mL) A solution of cyclopentylisopropylcarbamate (30.0 mg, 77.6 μmol) was warmed to 50°C and stirred at this temperature for 12 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC with CH ₃ CN in water (from 0% to 70% CH ₃ CN in 50 min) to give isopropylcarbamic acid (1 R ,3 S )-3-(3-(pyrazin-2-ylamino)-1 H -pyrazol-5-yl)cyclopentyl ester (13.0 mg, 51% yield). LC-MS: m/z[M+H] ⁺ 331.2.

Example 143

(1-Hydroxy-2-methylpropan-2-yl)carbamic acid (1 R ,3 S )-3-(3-(pyrazin-2-ylamino)-1 H -pyrazole-5- cyclopentyl ester

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

Carbonic acid [(1 R ,3 S )-3-[1-tert-butyl-5-(pyrazin-2-ylamino)pyrazole-3 in CH ₃ CN (2.0 mL) at 25 °C To a stirring solution of -]cyclopentyl ester] (4-nitrophenyl ester) (70.0 mg, 150 μmol), Et ₃ N (105 μL, 75.9 mg, 750 μmol) and 2-amino-2-methyl were added in sequence. Propan-1-ol (143 μL, 134 mg, 1.50 mmol). The reaction mixture was stirred at this temperature for 12 hours. The mixture was treated with water (5.0 mL) and extracted with EtOAc (100 mL×3). The combined organic phases _were washed with brine (10 mL), dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc) to give (1-hydroxy-2-methylpropan-2-yl)carbamic acid (1 R ,3 S )-3-(1-(tert-butyl) as a yellow oil )-5-(pyrazin-2-ylamino)-1 H -pyrazol-3-yl)cyclopentyl ester (25.0 mg, 40% yield). LC-MS: m/z[M+H] ⁺ 417.3.

Step 2: 2,2,2-trifluoroacetic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamine)-1 H -pyrazol-5-yl)cyclopentylcyclopentyl base)oxy)carbonyl)amino)propyl ester

(1-Hydroxy-2-methylpropan-2-yl)carbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazine) in TFA (1.0 mL) A solution of -2-ylamine) -1H -pyrazol-3-yl)cyclopentyl ester (20.0 mg, 48.0 μmol) was warmed to 70°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 25°C and then concentrated under reduced pressure to obtain 2,2,2-trifluoroacetic acid 2-methyl-2-((((1 R ,3 S )-3-(3-(pyridine)) as a yellow oil. Azin-2-ylamino)-1 H -pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propyl ester (20.0 mg, 91% yield), which was used without further purification for the next step. LC-MS: m/z[M+H] ⁺ 457.1.

Step 3: (1-Hydroxy-2-methylpropan-2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamino)-1 H -pyrazole- 5-yl)cyclopentyl ester

2,2,2-trifluoroacetic acid 2-methyl-2-((((1 R ,3 S )-3-(3-(pyrazine-)) in MeOH (2.0 mL) at 25°C. To a stirred solution of 2-ylamino)-1 H -pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propyl ester, K ₂ CO ₃ (60.6 mg, 438 μmol) was added. The reaction mixture was stirred at this temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 10% to 40% _CH3CN in 30 min) to give (1-hydroxy-2-methylpropan- 2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamine)-1 H -pyrazol-5-yl)cyclopentyl ester (6.50 mg, 41% yield). LC-MS: m/z[M+H] ⁺ 361.2.

Example 147

(2-cyanoprop-2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamine)-1 H -pyrazol-5-yl)cyclopentyl ester

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

Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrazin-2-ylamino)-1 H -pyrazol-3-yl) in TFA (8.0 mL) The solution of cyclopentyl ester (4-nitrophenyl ester) (80.0 mg, 171 μmol) was heated to 70° C. and stirred at this temperature for 16 hours. It was concentrated under reduced pressure to obtain 4-nitrophenyl carbonate ((1 R ,3 S )-3-(3-(pyrazin-2-ylamine)-1 H -pyrazol-5-yl) ring amyl ester), which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 411.1.

Step 2: (2-cyanoprop-2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamine)-1 H -pyrazol-5-yl) Cyclopentyl ester

4-nitrophenyl carbonate ((1 R ,3 S )-3-(3-(pyrazin-2-ylamino)-1 H -pyrazole) in pyridine (4.0 mL) at 25 °C -To a stirred solution of -5-yl)cyclopentyl ester) (50.0 mg, 122 μmol), 2-amino-2-methylpropionitrile (20.5 mg, 244 μmol) was added. The reaction mixture was stirred at this temperature for 16 hours and then filtered under reduced pressure. The residue was purified by Prep-HPLC, eluating with _CH3CN in water (from 5% to 45% _CH3CN in 40 min) to give carbonic acid ( 1R , 3S )-3 as a white solid -(3-pyrazin-2-ylamino)-1 H -pyrazol-5-yl)cyclopentyl ester (5.00 mg, 12% yield). LC-MS: m/z[M+H] ⁺ 356.1.

Example 148

(( S )-1-cyanopropan-2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-ylamine)-1 H -pyrazol-5-yl )cyclopentyl ester

4-nitrophenyl carbonate ((1 R ,3 S )-3-(3-(pyrazin-2-ylamino)-1 H -pyridine) in CH ₃ CN (2.0 mL) at 20 °C To a stirred solution of azol-5-yl cyclopentyl ester) (50.0 mg, 122 μmol), DIPEA (42.4 μL, 31.5 mg, 243 μmol) and ( S )-3-aminobutyronitrile (20.5 mg, 244 μmol) were added in sequence. ). The resulting mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 5% to 45% _CH3CN in 40 min) to give (( S )-1-cyanopropane as a yellow solid -2-yl)carbamic acid (1 R ,3 S )-3-(3-pyrazin-2-yllamino)-1 H -pyrazol-5-yl)cyclopentyl ester (14.0 mg, 32 % yield). LC-MS: m/z[M+H] ⁺ 356.0.

Example 149

Isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazol-5-yl) ring Amyl ester

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

To a stirred solution of 6-chloropyrazine-2-carboxylic acid methyl ester (3.50 g, 20.3 mmol) in _H2O (50.0 mL) at 0°C was added _NaBH4 (3.85 g, 101 mmol) portionwise. The reaction mixture was warmed to 20°C and stirred at _this temperature for 0.5 hours, then saturated aqueous _K2CO3 (70 mL) and EtOH (50 mL) were added. The resulting mixture was stirred for another 1 hour and extracted with EtOAc (100 mL×2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/petroleum ether (from 0% to 30% EtOAc in 20 min) to afford (6-chloropyrazin-2-yl)methanol (6-chloropyrazin-2-yl)methanol (from 0% to 30% EtOAc in 20 min) as a yellow oil 920 mg, 31% yield). 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 ₂ Cl ₂ (10.0 mL) was added TBSCl (251 mg, 3.04mmol). The reaction mixture was warmed to 20°C and stirred at this temperature for 2 hours, then quenched with water (50 mL) and extracted with CH ₂ Cl ₂ (50 mL×2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/petroleum ether (from 0% to 30% EtOAc in 20 min) to give 2-((tert-butyldimethylsilica) as a yellow oil (yl)oxy)methyl)-6-chloropyrazine (600 mg, 84% yield). LC-MS: m/z[M+H] ⁺ 259.0.

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

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

Step 4: Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine) Azin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester)

(1 R ,3 S )-3-(5-amino-1-(tert-butyl)-1 H -pyrazol-3-yl) ring in CH ₃ CN (5.0 mL) at 20 °C To a stirred solution of pentan-1-ol (100 mg, 224 μmol), 4-nitrobenzyl chloride (136 mg, 673 μmol), NMM (123 μL, 113 mg, 1.12 mmol) and DMAP (54.8 mg, 449 μmol) were added sequentially. The reaction mixture was stirred at this temperature for 3 hours and then concentrated under reduced pressure to obtain carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((( tert-Butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (as received), which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 611.1.

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

Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethyl)) in CH ₃ CN (5.0 mL) at 20°C Stirring of silyl)oxy)methyl)pyrazin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (original state) Propan-2-amine (182 μL, 126 mg, 2.13 mmol) was added to the solution. The reaction mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/oleyl ether (from 0% to 10% EtOAc in 20 min) to give isopropylcarbamic acid (1 R ,3 S ) as a yellow oil. -3-(1-(tert-butyl)-5-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (90.0 mg, 79% yield). LC-MS: m/z[M+H] ⁺ 531.2.

Step 6: 2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-((isopropylaminoformyl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethyl)) in TFA (2.0 mL) A stirred solution of silyl)oxy)methyl)pyrazin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (15.0 mg, 28.3 μmol) was heated to 70°C, and Stir at this temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-((isopropylaminoformyl)oxy)) as a yellow oil Cyclopentyl) -1H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester (as is). LC-MS: m/z[M+H] ⁺ 457.2.

Step 7: Isopropylcarbamate (1 R ,3 S )-3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazol-5-yl) ring Amyl ester

2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-((isopropylaminoformyl)) in MeOH (2.0 mL) at 20°C Oxy)cyclopentyl) -1H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester (as is) was stirred and K ₂ CO ₃ (3.02 mg, 21.9 μmol) was added. The reaction mixture was stirred at this temperature for 6 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 5% to 70% _CH3CN in 30 min) to give isopropylcarbamic acid ( 1R , 3 S )-3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (3.30 mg, 42% yield). LC-MS: m/z[M+H] ⁺ 361.1.

Example 150

(( S )-Dibutyl)carbamic acid (1 R ,3 S )-3(3--((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyra Azol-5-yl)cyclopentyl ester

Step 1: (( S )-Second butyl)carbamic acid (1 R ,3 S )-3-(1-(tertiary butyl)-5-((6-(((tertiary butyl dibutyl)) Methylsilyl)oxy)methyl)pyrazin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester

Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethyl)) in CH ₃ CN (10.0 mL) at 25°C Silyl)oxy)methyl)pyrazin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (50.0 mg, 81.9 μmol ), DIPEA (71.3 μL, 52.9 mg, 409 μmol) and ( S )-butan-2-amine hydrochloride (12.0 mg, 164 μmol) were added in sequence. The reaction mixture was stirred at this temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and EtOAc/PE elution (from 0% to 70% EtOAc in 20 min) to give (1-hydroxy-2-methylpropan-2-yl) as a colorless oil Carbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl ) cyclopentyl ester (36.0 mg, 81% yield). LC-MS: m/z[M+H] ⁺ 545.3.

Step 2: (( S )-Second butyl)carbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester

(1-Hydroxy-2-methylprop-2-yl)carbamic acid (1 R ,3 S )-3-(1-(tert-butyl)- in TFA (5.0 mL) at 25°C Stirred solution of 5-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (35.0 mg, 66.1 μmol). The reaction mixture was heated to 80°C and stirred at this temperature for 6 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was dissolved in MeOH (5.0 mL) at 25°C, then K ₂ CO ₃ (4.57 mg, 33.0 μmol) was added and stirred at this temperature for 15 min. The residue was concentrated under reduced pressure and purified by Prep-HPLC, eluting with CH ₃ CN in water (from 30% to 70% CH ₃ CN in 40 min) to give (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl (( S )-second butyl ) carbamate (14.4 mg, 58% yield). LC-MS: m/z[M+H] ⁺ 375.1.

Example 151

(1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyrazole -5-yl)cyclopentyl ester

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

(1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethylsilyl))oxy)carbonate in TFA (8.0 mL) )Methyl)pyrazin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (80.0 mg, 131 μmol) solution was heated to 70°C , stirred at this temperature for 16 hours. Concentrate it under reduced pressure to obtain 2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-((4-nitrophenoxy)carbonyl)oxy) ring Pentyl)-1 H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester was used in the next step without further purification. LC-MS: m/z[M+H] ⁺ 537.0.

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

2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-(((4-nitrophenoxy)) in CH ₃ CN (2.0 mL) at 20 °C yl)carbonyl)oxy)cyclopentyl) -1H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester, add DIPEA (29.2 μL, 21.7 mg, 168 μmol) and 1-methylcyclopropan-1-amine (17.9 mg, 252 μmol). The resulting mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 5% to 45% _CH3CN in 40 min) to give (1-methylcyclopropyl)amine as a white solid (1 R ,3 S )-3-(3-((6-(hydroxymethyl) pyrazin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester ( 7.90 mg, 25% yield). LC-MS: m/z[M+H]+ 373.1.

Example 152

(( R )-Second-butyl)carbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyrazin-2-yl)amino)-1 H -pyra Azol-5-yl)cyclopentyl ester

2,2,2-trifluoroacetic acid (6-((5-((1 S ,3 R ))-3-(((4-nitrophenoxy)) in CH ₃ CN (2.0 mL) at 20 °C yl)carbonyl)oxy)cyclopentyl) -1H -pyrazol-3-yl)amino)pyrazin-2-yl)methyl ester (45.0 mg, 83.9 μmol) was stirred and Et3N was added sequentially. (38.0 μL, 27.6 mg, 272 μmol) and ( R )-butan-2-amine (19.9 mg, 272 μmol). The resulting mixture was stirred at this temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 5% to 45% _CH3CN in 40 min) to give N -[( 1R )-1- as a yellow solid Methylpropyl]carbamic acid [(1 R ,3 S )-3-[3-[[6-(hydroxymethyl)pyrazin-2-yl]amino]-1 H -pyrazole-5- base] cyclopentyl ester] N -] 11.9 mg, 38% yield). LC-MS: m/z[M+H] ⁺ 374.9.

Examples 153 and 154

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

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

To a stirred solution of 2-bromopyrazine (115 mg, 661 μmol) in THF (10.0 mL) at 25°C and in a nitrogen atmosphere, ( trans , rac )-3-(1-(tert-butyl)) was added sequentially -5-(pyrazin-2-ylamino)-1 H -pyrazol-3-yl)cyclopentan-1-ol (199 mg, 661 μmol), DIAD (260 μL, 267 mg, 1.32 mmol) and PPh ₃ (346 mg , 1.32mmol). The reaction mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 20 minutes) to give ( cis , rac ) -N- (3-(3) as a pale yellow solid -((3-bromopyridin-2-yl)oxy)cyclopentyl)-1-(tert-butyl) -1H -pyrazol-5-yl)pyrazin-2-amine (280 mg, 93% yield). 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)cyclic Pentyl) -1H -pyrazol-5-yl)pyrazin-2-amine

( cis , rac )- N -(3-(3-((3-bromopyridin-2-yl) in 1,4-dioxane (10.0 mL)/H ₂ O (1.0 mL) at 25°C )oxy)cyclopentyl)-1-(tert-butyl) -1H -pyrazol-5-yl)pyrazin-2-amine (250mg, 547μmol) to a stirred solution, add 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) and K ₂ CO ₃ (150 mg, 1.09 μmol). The reaction mixture was heated to 80°C, stirred at this temperature for 16 hours, then cooled to 25°C, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 20 minutes) to give ( cis , rac ) -N- (1-tertiary) as a pale yellow solid. Butyl)-3-(3-((3-(prop-1-en-2-yl)pyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)pyrazine -2-Amine (200 mg, 87% yield). LC-MS: m/z[M+H] ⁺ 419.2.

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

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

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

( cis , rac )- N -(1-(tert-butyl)-3-(3-((3-isopropylpyridin-2-yl)oxy)oxy) ring in HCO ₂ H (5.0 mL) A solution of pentyl) -1H -pyrazol-5-yl)pyrazin-2-amine (180 mg, 428 μmol) was heated to 80°C, stirred at this temperature for 2 hours, then cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC with CH ₃ CN in water (from 30% to 60% CH ₃ CN in 20 min) to give (c is , rac ) -N -( as a yellow solid 5-(3-((3-isopropylpyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)pyrazin-2-amine (89.3 mg, 57% yield ). 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 plus 0.2% NH ₃ , 1.5 ml/min, 35°C) to obtain yellow solid N- (5 -((1S,3 R )-3-((3-isopropylpyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)pyrazin-2-amine (9.0 mg, 27% yield, lag time = 1.9 min, arbitrary assignment absolute configuration). LC-MS: m/z[M+H] ⁺ 365.2. And obtain yellow solid N- (5-((1 R ,3 S )-3-((3-isopropylpyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazole-3- pyrazin-2-amine (13.3 mg, 40% yield, lag time = 2.3 min, arbitrary assigned absolute configuration). LC-MS: m/z[M+H]+ 365.2.

Example 21

Isopropylcarbamic acid (1 R ,3 S )-3-(5-(pyrimidin-4-ylamino)-1 H -pyrazol-3-yl)cyclopentyl ester and Example 22 isopropyl Carbamic acid (1 R ,3 S )-3-(5-((2-hydroxypyrimidin-4-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester

Step 1: Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-chloropyrimidin-4-yl)amino)-1 H -pyridine Azol-3-yl)cyclopentyl ester

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

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

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-chloropyrimidin-4-yl)) in MeOH (10 mL) at 25°C To a solution of amino) -1H -pyrazol-3-yl)cyclopentyl ester (100 mg, 237 μmol), Pd/C (5.77 mg, 47.5 μmol, 10% wt.%) was added. The reaction mixture was stirred at this temperature under hydrogen atmosphere (balloon) for 12 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain isopropyl carbamate (1 R , 3 S )-3-(1-(tert-butyl)-5-(pyrimidin-4-ylamine)-1 H -pyrazole -3-yl)cyclopentyl (100 mg), which was used in the next step without further purification. LC-MS: m/z[M+H] ⁺ 387.3.

Step 3: Isopropylcarbamate (1 R ,3 S )-3-(5-(pyrimidin-4-ylamine)-1 H -pyrazol-3-yl)cyclopentyl ester

N -Isopropylcarbamate (1 R ,3 S )-3-[1-tert-butyl-5-(pyrimidin-4-ylamino)pyrazole-3- in TFA (2.0 mL) A mixture of [cyclopentyl ester] (30.0 mg, 77.6 μmol) was warmed to 80°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 25% to 35% CH ₃ CN in 15 min) to give N -isopropylcarbamic acid [(1 R ,3 S )-3-[5 as a white solid -(pyrimidin-4-ylamino)-1 H -pyrazol-3-yl]cyclopentyl] ester (15.0 mg, 58% yield). LC-MS: m/z[M+H]+ 331.2.

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

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

Example 155

(3-Methyloxetan-3-yl)carbamic acid (1 R ,3 S )-3-(3-(pyrimidin-4-ylamine)-1 H -pyrazol-5-yl )cyclopentyl ester

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

To a stirred solution of 4-chloropyrimidine in 1,4-dioxane (20.0 mL) at 25°C, (1 R ,3 S )-3-(5-amino-1-(tertiary) was added sequentially Butyl) -1H -pyrazol-3-yl)cyclopent-1-ol (780 mg, 3.49 mmol), Pd ₂ (dba) ₃ (400 mg, 437 μmol), XantPhos (253 mg, 437 μmol) and Cs ₂ CO ₃ (2.85g, 8.73mmol). The residue was purified by flash column chromatography with PE/EtOAc (from 0% to 100% EtOAc in 25 min) to give (1 R ,3 S )-3-(1-) as a yellow solid (tert-Butyl)-5-(pyrimidin-4-ylamino)-1 H -pyrazol-3-yl)cyclopent-1-ol (270 mg, 21% yield). LC-MS: m/z[M+H] ⁺ 302.2.

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

(1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrimidin-4-ylamino)-1 H -pyridine in CH ₃ CN (5.0 mL) at 20 °C To a stirring solution of azole-3-yl)cyclopent-1-ol, 4-nitrophenyl carbonate (201 mg, 995 μmol), NMM (182 μL, 168 mg, 1.66 mmol) and DMAP (81.1 mg, 664μmol). The reaction mixture was stirred at this temperature for 1 hour and then filtered under reduced pressure to obtain (1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrimidin-4-ylamine)carbonate as a yellow oil). -1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (as is), which was used in the next step without further purification. LC-MS: m/z[M+H] ⁺ 467.0.

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

(1 R ,3 S )-3-(1-(tert-butyl)-5-(pyrimidin-4-ylamino)-1 H -pyrazol-3-yl carbonic acid in TFA (2.0 mL) ) a stirred solution of cyclopentyl ester (4-nitrophenyl ester) (100 mg, 214 μmol), heated to 70°C and stirred at this temperature for 16 hours. Subsequently, it was filtered under reduced pressure to obtain 4-nitrophenyl carbonate ((1 R ,3 S )-3-(3-(pyrimidin-4-ylamine)-1 H -pyrazol-5-yl) as a yellow solid Cyclopentyl ester) (original state). LC-MS: m/z[M+H] ⁺ 411.1.

Step 4: (3-methyloxetan-3-yl)carbamic acid (1 R ,3 S )-3-(3-(pyrimidin-4-ylamino)-1 H -pyrazole- 5-yl)cyclopentyl ester

4-nitrophenyl carbonate ((1 R ,3 S )-3-(3-(pyrimidin-4-ylamino)-1 H -pyridine) in CH ₃ CN (2.0 mL) at 20 °C. To a stirred solution of azole-5-yl)cyclopentyl ester (original state), Et3N (40.8 μL, 29.6 mg, 292 μmol) and 3-methyloxetane-3-amine (25.7 μL, 292 μmol) were added sequentially. 25.5mg, 292μmol). The resulting mixture was stirred at this temperature for 16 hours and then concentrated under reduced pressure. The reaction mixture was stirred at this temperature for 16 hours and then filtered under reduced pressure. The residue was purified by Prep-HOLC, eluating with CH ₃ CN (from 5% to 45% CH ₃ CN in 40 min) to give (3-methyloxetan-3-yl) as a white solid )carbamic acid (1 R ,3 S )-3-(3-(pyrimidin-4-ylamino)-1 H -pyrazol-5-yl)cyclopentyl ester (3.30 mg, 10% yield) . LC-MS: m/z[M+H] ⁺ 359.1.

Example 156

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

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

(1 R ,3 S )-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopenta in 1,4-dioxane (3.0 mL) at 25°C Alcohol (50.0 mg, 223 μmol) solution, add 4-chloro-2-methyl-pyrimidine (28.7 mg, 223 μmol), Pd2(dba)3 (41.0 mg, 44.7 μmol), XantPhos (51.8 mg, 89.5 μmol) and Cs ₂ CO ₃ (218 mg, 671 μmol) The mixture was degassed with N 5 times, heated to 100 °C and stirred at 100 ° _C under N ₂ environment 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 _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 100% EtOAc in 15 minutes) to give the product (1 R ,3 S )-3-(1-( tert-Butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-3-yl)cyclopent-1-ol (60.0 mg, 84% yield). LC-MS: (ESI)m/z[M+H] ⁺ 316.2.

Step 2: Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazole-3- Cyclopentyl ester (4-nitrophenyl ester)

(1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino)- in DCE (3.0 mL) at 25°C To a solution of 1H -pyrazol-3-yl)cyclopent-1-ol (60.0 mg, 190 μmol), add (4-nitrophenyl)carbophosphate chloride (38.3 mg, 190 μmol) and DIPEA (73.7 mg, 570 μmol). ) and DMAP (4.65 mg, 38.0 μmol). The mixture was degassed with _N2 5 times, then warmed to 70°C and stirred at 70°C under _N2 environment for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 90% EtOAc in 15 minutes) to give carbonic acid (1 R ,3 S )-3-(1-( tert-Butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (40.0 mg , 43% yield). LC-MS: m/z[M+H] ⁺ 481.2.

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

Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino) in NMP (1.5 mL) at 25°C -To a solution of 1H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (40.0 mg, 83.2 μmol), bicyclo[1.1.1]pentan-1-amine (13.8 mg, 166 μmol) and Et3N (25.2 mg, 249 μmol). The mixture was stirred at 25°C for 2 hours. 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 _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 96% EtOAc in 10 minutes) to give the product bicyclo[1.1.1]pentan-1-ylamine as a yellow solid Formic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-3-yl) ring Pentyl ester (20.0 mg, 56% yield). LC-MS: (ESI)m/z[M+H] ⁺ 425.2.

Step 4: Bicyclo[1.1.1]pentan-1-ylcarbamate ( 1R , 3S )-3-(3-((2-methylpyrimidin-4-yl)amino) -1H -pyridine Azol-5-yl)cyclopentyl ester

Bicyclo[1.1.1]pentan-1-ylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methyl)) in FA (2.0 mL) A solution of pyrimidin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (18.0 mg, 42.4 μmol) was heated to 80°C and stirred at 80°C for 2 hours. The mixture was brought to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC, eluating with _CH3CN (from 30% to 40% _CH3CN in 8 minutes) to give the product bicyclo[1.1 as a white solid .1]pentan-1-ylcarbamate (1 R ,3 S )-3-(3-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-5-yl) Cyclopentyl ester. . LC-MS: m/z[M+H] ⁺ 369.2.

Example 157

(3-Methyloxetan-3-yl)carbamic acid (1 R ,3 S )-3-(3-((2-methylpyrimidin-4-yl)amino)-1 H - Pyrazol-5-yl)cyclopentyl ester

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

At 0°C, to a solution of 4-chloro-2-methylpyrimidine 600 mg, 4.67 μmol) in DMF, 2-tert-butyl-5-[(1 S , 3 R )-3-[tert. Butyl(dimethyl)silyl]oxycyclopentyl]pyrazol-3-amine (1.58 g, 4.67 mmol) and KOt-Bu (1.57 g, 14.0 mmol). The mixture was stirred at 0°C for 1 hour, then quenched with cold water (20 mL) and extracted with EA (20 mL×2). The organic phase _was washed with brine (20 mL×2), dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 10% to 80% EtOAc in 25 minutes) to give N -(1-(tert-butyl)-3-( (1 S ,3 R )-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)-2-methylpyrimidin-4-amine (1.10 mg, 54% yield). LC-MS: m/z[M+H] ⁺ 430.3.

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

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

Step 3: Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazole-3- Cyclopentyl ester (4-nitrophenyl ester)

(1 R ,3 S )-3-(1-(tert-butyl)-5-((2-methylpyrimidin-4-yl)amino)- in DCM (20.0 mL) at 25 °C A solution of 1 H -pyrazol-3-yl) cyclopentan-1-ol (710 mg, 2.25 mmol) and (4-nitrophenyl) carbonyl chloride (1.81 g, 9.00 mmol) was added sequentially to NMM ( 1.24mL, 1.14g, 11.3mmol) and DMAP (136mg, 1.13mmol). The mixture was warmed to 50°C and stirred at this temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, dissolving with MeOH/CH ₂ Cl ₂ (from 0% to 80% MeOH in 25 min) to give carbonic acid (1 R ,3 S )-3-( as a yellow solid 1-(tert-Butyl)-5-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (620 mg, 57% yield). LC-MS: m/z[M+H] ⁺ 480.9.

Step 4: Carbonic acid (1 R ,3 S )-3-(3-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (4- Nitrophenyl ester)

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

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

Carbonic acid (1 R ,3 S )-3-(3-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazole- in CH ₃ CN (3.0 mL) at 25 °C To a stirring solution of 5-yl)cyclopentyl ester (4-nitrophenyl ester) (50.0 mg, 118 μmol), 3-methyloxetan-3-amine (20.7 μL, 20.5 mg, 235 μmol) and Et3N (82.1 μL, 59.6 mg, 589 μmol). The reaction mixture was stirred at this temperature for 16 hours, then the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC, eluating with CH ₃ CN (from 5% to 30% CH ₃ CN in 10 min) to give (3-methyloxetan-3-yl) as a white solid )carbamic acid (1 R ,3 S )-3-(3-((2-methylpyrimidin-4-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (8.4 mg , 19% yield). LC-MS: m/z[M+H] ⁺ 373.2.

Example 158

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

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

6-chloropyridine-3-carbonitrile (500 mg, 3.61 mmol) and (1 R ,3 S )-3-(5-amino-1-(th) in 1,4-dioxane (10.0 mL) To a stirring solution of tributyl) -1H -pyrazol-3-yl)cyclopent-1-ol (806 mg, 3.61 mmol), Pd ₂ (dba) ₃ (661 mg, 722 μmol), XantPhos (835 mg, 1.44mmol) and NaO t -Bu (867mg, 9.02mmol). The mixture was warmed to 90°C and stirred at this temperature under nitrogen for 2 hours. The mixture was filtered under reduced pressure, and the filtrate was concentrated. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 30% to 90% EtOAc/PE in 20 minutes) to give 6-((1-(tert-butyl)-) as a yellow solid 3-((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)nicotinecarbonitrile (500 mg, 42% yield). LC-MS: m/z[M+H] ⁺ 326.3.

Step 2: Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((5-cyanopyridin-2-yl)amino)-1 H -pyrazole-3- Cyclopentyl ester (4-nitrophenyl ester)

6-((1-(tert-Butyl)-3-((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazole-5 in CH ₂ Cl ₂ (20.0 mL) -To a stirred solution of nicotine carbonitrile (325 mg, 1.00 mmol), pyridine (158 mg, 2.00 mmol) and 4-nitrophenyl carbonate chloride (404 mg, 2.00 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 60% EtOAc/PE in 20 minutes) to give carbonic acid (1 R ,3 S )-3-( as a light yellow solid 1-(tert-Butyl)-5-((5-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (240 mg, 49% yield). LC-MS: m/z[M+H] ⁺ 491.2.

Step 3: Carbonic acid (1 R ,3 S )-3-(5-((5-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4- Nitrophenyl ester)

(1 R ,3 S )-3-(1-(tert-butyl)-5-((5-cyanopyridin-2-yl)amine) carbonate in TFA (3.0 mL, 4.47 g, 39.2 mmol) (150 mg, 305 μmol), stir at this temperature for 2 hours, and then cool to 25 ℃ and concentrated under reduced pressure. Original product carbonic acid (1 R ,3 S )-3-(5-((5-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4- Nitrophenyl carbonate was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 435.1.

Step 4: (1-Hydroxy-2-methylpropan-2-yl)carbamic acid (1 R ,3 S )-3-(3-((5-cyanopyridin-2-yl)amino)- 1H -pyrazol-5-yl)cyclopentyl ester

Carbonic acid (1 R ,3 S )-3-(5-((5-cyanopyridin-2-yl)amino)-1 H -pyrazole- in CH ₃ CN (10.0 mL) at 25 °C A mixture of 3-yl)cyclopentyl ester (4-nitrophenyl ester) (40.0 mg, 92.1 μmol) and 2-amino-2-methylpropan-1-ol (43.9 μL, 41.0 mg, 460 μmol) , add Et ₃ N (64.2 μL, 46.6 mg, 460 μmol). The mixture was warmed to 50°C and stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 10% to 40% _CH3CN in 30 min) to give (1-hydroxy-2-methylpropan- 2-yl)carbamic acid (1 R ,3 S )-3-(3-((5-cyanopyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester ( 21.5 mg, 60% yield). LC-MS: m/z[M+H] ⁺ 385.2.

Example 159

(3-Methyloxetan-3-yl)carbamic acid (1 R ,3 S )-3-(3-((5-cyanopyridin-2-yl)amino)-1 H - Pyrazol-5-yl)cyclopentyl ester

Carbonic acid (1 R ,3 S )-3-(3-((5-cyanopyridin-2-yl)amino)-1 H -pyrazole- in CH ₃ CN (3.0 mL) at 25 °C To a stirring solution of 5-yl)cyclopentyl ester (4-nitrophenyl ester) (70.0 mg, 161 μmol), 3-methyloxetan-3-amine (70.0 mg, 161 μmol) and Et ₃ N (112 μL, 81.5 mg, 805 μmol). The reaction mixture was stirred at this temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 20% to 40% _CH3CN (0.1% FA conditions) in 10 min) to give (3-methyl) as a white solid Oxetan-3-yl)carbamic acid (1 R ,3 S )-3-(3-((5-cyanopyridin-2-yl)amino)-1 H -pyrazole-5- cyclopentyl ester (1.8 mg, 3% yield). LC-MS: m/z[M+H] ⁺ 383.2.

Example 160

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

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

2-bromoisonicotinecarbonitrile (2.00 g, 10.9 mmol) and (1 R ,3 S )-3-(5-amino-1) in 1,4-dioxane (100 mL) at 25°C -(Tertiary butyl) -1H -pyrazol-3-yl)cyclopent-1-ol (2.43g, 10.9mmol) was stirred in a solution, and Pd ₂ (dba) ₃ (998mg, 1.09mmol) was added sequentially. , XantPhos (1.26g, 2.18mmol) and Cs ₂ CO ₃ (7.11g, 21.8mmol). The reaction mixture was warmed to 80°C, stirred at this temperature under nitrogen for 16 hours, then cooled to 25°C, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 60% EtOAc in 20 min) to give 2-((1-(tert-butyl)-3-) as a brown solid ((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)isonicotinecarbonitrile (2.81 g, 79% yield). LC-MS: m/z[M+H]+ 326.3.

Step 2: Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((4-cyanopyridin-2-yl)amino)-1 H -pyrazole-3- Cyclopentyl ester (4-nitrophenyl ester)

2-((1-(tert-Butyl)-3-((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyridine in CH ₂ Cl ₂ (100 mL) at 25 °C To a stirring solution of azol-5-yl)amino)isonicotinylcarbonitrile (2.81g, 8.65mmol), pyridine (1.37g, 17.3mmol) and 4-nitrobenzyl chloride (3.49g, 17.3mmol) were added sequentially. mmol). The reaction mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 25% EtOAc in 20 minutes) to give carbonic acid (1 R ,3 S )-3-(1-) as a pale yellow solid. (tert-Butyl)-5-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (2.85 g, 67% yield). LC-MS: m/z[M+H] ⁺ 491.2.

Step 3: Carbonic acid (1 R ,3 S )-3-(3-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (4- Nitrophenyl ester)

Carbonic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((4-cyanopyridin-2-yl)amino)-1 H - in TFA (6.0 mL) A solution of pyrazol-3-yl)cyclopentyl ester (4-nitrophenyl ester) (100 mg, 204 μmol) was heated to 70°C, stirred at this temperature for 2 hours, then cooled to 25°C and concentrated under reduced pressure. Original product carbonic acid (1 R ,3 S )-3-(3-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (4- Nitrophenyl ester), which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 435.1.

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

Carbonic acid (1 R ,3 S )-3-(3-((4-cyanopyridin-2-yl)amino)-1 H -pyrazole- in CH ₃ CN (10.0 mL) at 25 °C To a stirring solution of 5-yl)cyclopentyl ester (4-nitrophenyl ester), (trans)-3-aminocyclobutan-1-ol hydrochloride (50.6 mg, 408 μmol), and Et3N (113 μL, 82.4 mg, 816 μmol). The reaction mixture was stirred at this temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 20% to 30% _CH3CN in 15 min) to give ((1r, 3R )-3- as a pale yellow solid Hydroxycyclobutyl)carbamic acid (1 R ,3 S )-3-(3-((4-cyanopyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl Ester (41.8mg). LC-MS: m/z[M+H] ⁺ 383.2.

Example 23

(1 R ,3 S )-3-(3-(pyrazolo[1,5- a ]pyrimidin-5-ylamine)-1 H -pyrazol-5-yl)cyclopentylisopropylamine carbamate

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

Benzyl N -[2-tert-butyl-5-[(1 S ,3 R )-3-hydroxycyclopentyl]pyrazol-3-yl]amine in DCM (450 mL) at 25 °C To a solution of formate (15.0g, 41.9μmol), add (4-nitrophenyl)carbochloride (12.7g, 62.9mmol), pyridine (9.96g, 126mmol, 10.2mL) and DMAP (1.03g, 8.39 mmol). The reaction mixture was stirred at this temperature for 2 hours and then concentrated under reduced pressure to obtain white solid carbonic acid [(1 R ,3 S )-3-[5-(benzyloxycarbonylamino)-1-tert-butyl- Pyrazol-3-yl]cyclopentyl ester] (4-nitrophenyl ester) (21.0 g, 96% yield), which was used directly in step 1 without further purification. LC-MS: m/z[M+H] ⁺ 523.1.

Step 2: (1-(tert-Butyl)-3-((1 S ,3 R )-3-((isopropylaminoformyl)oxy)cyclopentyl)-1 H -pyrazole -5-yl)carbamate benzyl ester

Carbonic acid [(1 R ,3 S )-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl] ring in DCM (230 mL) at 25°C. To the solution of amyl ester] (4-nitrophenyl ester), add propyl-2-amine (3.73g, 63.1mmol, 4.90mL) and Et ₃ N (12.8g, 126mmol, 17.6mL). The reaction mixture was stirred at this temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 30 min) to give N- [2-tert-butyl-5-[( 1 S ,3 R )-3-(isopropylaminoformyloxy)cyclopentyl]pyrazol-3-yl]carbamic acid benzyl ester (15.0 g, 81% yield). LC-MS: m/z[M+H] ⁺ 443.3.

Step 3: Isopropylcarbamic acid ( 1R , 3S )-3-(5-amino-1-(tert-butyl) -1H -pyrazol-3-yl)cyclopentyl ester (middle Body 3)

N -[2-tert-butyl-5-[(1 S ,3 R )-3-(isopropylaminoformyloxy)cyclopentyl]pyridine in MeOH (160 mL) at 25°C To a solution of benzyl azol-3-yl]carbamate (15.0 g, 33.9 mmol), Pd/C (1.20 g, 1.13 mmol, 10% wt.%) was added. The reaction mixture was stirred at this temperature under hydrogen atmosphere (balloon) for 3 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 30% EtOAc in 30 min) to give N -isopropylcarbamic acid [(1 R ,3 S )-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl ester] (9.30 g, 89% yield). LC-MS: m/z[M+H] ⁺ 309.2.

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

To a solution of 5-chloropyrazolo[1,5- a ]pyrimidine (50.0 mg, 326 μmol) in 1,4-dioxane (10.0 mL) at 25°C, isopropylcarbamic acid was added sequentially (1 R ,3 S )-3-(5-amino-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopentyl ester (84.0 mg, 271 μmol), K ₂ CO ₃ (112 mg, 814 μmol) and Pd(dtbpf)Cl ₂ (35.0 mg, 54.0 μmol). The reaction mixture was heated to 90°C, stirred at this temperature for 6 hours, then cooled to 25°C, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 100% EtOAc in 20 minutes) to obtain N -isopropylcarbamic acid [(1 R ,3 S )-3-[1-tert-butyl-5-(pyrazolo[1,5- a ]pyrimidin-5-ylamino)pyrazol-3-yl]cyclopentyl ester] (70.0g, 61% yield). LC-MS: m/z[M+H] ⁺ 426.2.

Step 5: Isopropylcarbamic acid (1 R ,3 S )-3-(3-(pyrazolo[1,5- a ]pyrimidin-5-ylamino)-1 H -pyrazole-5- cyclopentyl ester

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

Example 20

Example 28

Isopropylcarbamic acid (1 R ,3 S )-3-(3-([3,4'-bipyridin]-2'-ylamine)-1 H -pyrazol-5-yl)cyclopentan base ester

Step 1: Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((4-chloropyridin-2-yl)amino)-1 H -pyridine Azol-3-yl)cyclopentyl ester

To a solution of 2-bromo-4-chloropyridine (100 mg, 519 μmol) in 1,4-dioxane (3.0 mL) at 25°C, isopropylcarbamate (1 R ,3 S ) was added sequentially. -3-(5-Amino-1-(tert-butyl) -1H -pyrazol-3-yl)cyclopentyl ester (192 mg, 623 μmol), Pd ₂ (dba) ₃ (95.2 mg, 103 μmol) , XantPhos (120 mg, 207 μmol) and Cs ₂ CO ₃ (507 mg, 1.56 mmol). The mixture was warmed to 80°C and stirred at this temperature for 6 hours. 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 _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 43% EtOAc in 120 min) to give isopropylcarbamic acid (1 R ,3 S )-3 as a brown solid. -(1-(tert-Butyl)-5-((4-chloropyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (100 mg, 45% yield) . LC-MS: (ESI)m/z[M+H] ⁺ 420.1.

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

(1 R ,3 S )-3-(1-(tert _- butyl)-5-(((1 R ,3 S )-3-(1-(tert-butyl)-5-(( To a solution of 4-chloropyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentylisopropylcarbamate (30.0 mg, 71.4 μmol), pyridine-3 was added sequentially -boronic acid (17.6 mg, 142 μmol), Pd(OAc) ₂ (3.21 mg, 14.3 μmol), X-Phos (6.42 mg, 13.4 μmol), K ₂ CO ₃ (29.6 mg, 214 μmol). The mixture was heated to 110°C and stirred at this temperature for 5 hours. The mixture was cooled and concentrated under reduced pressure. Dilute with water (10 mL) and extract with DCM (10 mL×3). _The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with DCM/MeOH (from 0% to 5% MeOH in 10 min) to give isopropylcarbamic acid (1 R ,3 S )-3 as a brown oil. -(5-([3,4'-bipyridin]-2'-ylamine)-1-(tert-butyl) -1H -pyrazol-3-yl)cyclopentyl ester (25.0 mg, 76% yield). LC-MS: m/z[M+H] ⁺ 463.2.

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

Isopropylcarbamate (1 R ,3 S )-3-(5-([3,4'-bipyridin]-2'-ylamine)-1-(th) in TFA (2.0 mL) A solution of tributyl) -1H -pyrazol-3-yl)cyclopentyl ester (20.0 mg, 43.2 μmol) was heated to 80°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 10% to 100% CH ₃ CN in minutes) to give isopropylcarbamic acid (1 R ,3 S )-3-(3-([3 ,4'-bipyridyl]-2'-ylamine)-1 H -pyrazol-5-yl)cyclopentyl ester (9.40 mg, 53% yield). LC-MS: m/z[M+H] ⁺ 407.2.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 28.

Example 30

(1 R ,3 S )-3-(3-((4-(1-methyl-1 H -pyrazol-3-yl)pyridin-2-yl)amino)-1 H -pyrazole-5 -Cyclopentyl isopropyl carbamate

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 ₂ O (1.0 mL) at 25°C, 3 - Iodo-1-methyl-pyrazole (100 mg, 480 μmol, 51.0 μL), Pd(dppf)Cl ₂ (70.3 mg, 96.1 μmol) and K ₂ CO ₃ (199 mg, 1.44 mmol, 87.0 μL). The reaction mixture was warmed to 100°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluating with MeOH/DCM (from 0% to 5% MeOH in 10 min) to give 2-chloro-4-(1-methyl- 1 H -pyrazol-3-yl)pyridine (60.0 g, 64% yield). LC-MS: m/z[M+H] ⁺ 194.1.

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

Suspension of 2-chloro-4-(1-methyl-1 H -pyrazol-3-yl)pyridine (37.6 mg, 194 μmol) in 1,4-dioxane (4.0 mL) at 25°C , add N -isopropylcarbamic acid [(1 R ,3 S )-3-(5-amino-1-tert-butylpyrazol-3-yl)cyclopentyl] ester (50.0mg) in sequence , 162 μmol), Pd ₂ (dba) ₃ (29.6 mg, 32.4 μmol), XantPhos (37.5 mg, 64.8 μmol), and Cs ₂ CO ₃ (158 mg, 486 μmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography, dissolving with MeOH/DCM (from 0% to 5% MeOH in 10 min) to give isopropylcarbamic acid ( 1R , 3S) as a yellow oil )-3-(1-(tert-butyl)-5-((4-(1-methyl-1 H -pyrazol-3-yl)pyridin-2-yl)amino)-1 H -pyra Azol-3-yl)cyclopentyl ester (30.0 g, 39% yield). LC-MS: m/z[M+H] ⁺ 466.2.

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

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((4-(1-methyl-1 H -pyra)) in TFA (5.0 mL) A suspension of azol-3-yl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (20.0 mg, 42.9 μmol) was heated to 80°C and stirred at this temperature 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 23% to 33% _CH3CN in 5 min) to give isopropylcarbamic acid ( 1R , 3S )-3-(3-( (4-(1-Methyl-1 H -pyrazol-3-yl)pyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (3.20 g, 18% yield Rate). LC-MS: m/z[M+H] ⁺ 410.2.

Example 31

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

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

Isopropylcarbamic acid (1 R ,3 S )-3-(5-amino-1-(tert-butyl)-1 in DCE (4.0 mL) and AcOH (1.0 mL) at 25°C To a solution of H -pyrazol-3-yl)cyclopentyl ester (50.0 mg, 162 μmol), 1-methylsulfonylpiperidin-4-one (72.0 mg, 406 μmol) and triacetyloxyboron were added sequentially. Sodium hydride (100 mg, 471 μmol). The mixture was stirred at this temperature for 4 hours, treated with saturated NaHCO _solution and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography, dissolving with MeOH in DCM (from 0% to 5% MeOH) over 15 min to give isopropylcarbamic acid ( 1R , 3S) as a white solid )-3-(1-(tert-butyl)-5-((1-(methylsulfonyl)piperidin-4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (40.0 mg, 52% yield). LC-MS: m/z[M+H] ⁺ 470.3.

Step 2: Isopropylcarbamate (1 R ,3 S )-3-(3-((1-(methylsulfonyl)piperidin-4-yl)amino)-1 H -pyrazole- 5-yl)cyclopentyl ester

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((1-(methylsulfonyl)piperdine) in HCO ₂ H (5.0 mL) A mixture of (din-4-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (40.0 mg, 85.1 μmol) was heated to 110°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 15% to 45% _CH3CN in 7 min) to give isopropylcarbamic acid ( 1R , 3S )-3-(3-( (1-(methylsulfonyl)piperidin-4-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (3.10 mg, 9% yield). LC-MS: m/z[M+H] ⁺ 414.3.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 31 .

Example 33

Isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentan base ester

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

To a stirred suspension of (6-bromo-2-pyridyl)methanol (100 mg, 519 μmol) in CH ₂ Cl ₂ (20 mL) at 25 °C, TBSCl (1.60 g, 10.6 mmol) and imidazole (724 mg) were added sequentially. ,10.6mmol). The mixture was stirred at this temperature for 15 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 5% EtOAc in 15 min) to give 2-bromo-6-((tert-butyldimethyl) as a colorless oil Silyl)oxy)methyl)pyridine (1.07 mg, 66% yield). LC-MS: m/z[M+H] ⁺ 302.1.

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

Stirred solution of (6-bromo-2-pyridyl)methoxy-tert-butyl-dimethyl-silane (300 mg, 992 μmol) in 1,4-dioxane (5.0 mL) at 25 °C , add (1 R ,3 S )-3-(5-amino-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopent-1-ol (221 mg, 992 μmol) in sequence. , Pd ₂ (dba) ₃ (90.9 mg, 99.2 μmol), XantPhos (115 mg, 199 μmol), and Cs ₂ CO ₃ (647 mg, 1.98 mmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 5 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 5% to 70% EtOAc in 15 min) to give (1 R ,3 S )-3-(1-( tert-Butyl)-5-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl ) cyclopent-1-ol (390 mg, 88% yield). LC-MS: m/z[M+H] ⁺ 445.3.

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

(1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethyl)) in CH ₂ Cl ₂ (5.0 mL) at 25°C A stirred suspension of silyl)oxy)methyl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopent-1-ol (390 mg, 877 μmol) was added sequentially. (427 mg, 2.63 mmol) and Et ₃ N (367 μL, 266 mg, 2.63 mmol). The reaction mixture was warmed to 40°C and stirred at this temperature for 2 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with _CH2Cl2 (20 _mL ×3). The combined organic phases were dried over _{anhydrous Na2SO4} and filtered. The filtrate was concentrated under reduced pressure to obtain 1H -imidazole-1-carboxylic acid ( 1R , 3S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldimethyl) Silyl)oxy)methyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 539.3.

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

1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-() in CH ₃ CN (5.0 mL) at 25°C To a stirred solution of ((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester, add prop-2 -Amine (74.6 μL, 51.6 mg, 872 μmol). The reaction mixture was warmed to 70°C and stirred at this temperature for 4 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 5% to 70% EtOAc in 15 minutes) to give isopropylcarbamic acid (1 R ,3 S )- as a yellow solid 3-(1-(tert-butyl)-5-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1 H - Pyrazol-3-yl)cyclopentyl ester (290 mg, 62% yield). LC-MS: m/z[M+H] ⁺ 530.0.

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

Isopropylcarbamic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(((tert-butyldi-butyl)) in HCO ₂ H (2.0 mL) A solution of methylsilyl)oxy)methyl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (290 mg, 547 μmol) was heated to 50°C and allowed to cool at temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, dissolving with MeOH/CH ₂ Cl ₂ (from 0% to 15% MeOH in 15 min) to give isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-(hydroxymethyl)pyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (86.1 mg, 43% yield) . LC-MS: m/z[M+H] ⁺ 359.9.

Example 34

Isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-(methoxymethyl)pyridin-2-yl)amino)-1 H -pyrazol-5-yl) Cyclopentyl ester

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

To a stirred suspension of (6-bromo-2-pyridyl)methanol (500 mg, 2.66 μmol) in THF (5.0 mL) at 0 °C was added NaH (128 mg, 60 wt.%, 3.19 mmol). The reaction mixture was stirred at this temperature for 10 minutes, then Mel (248 μL, 566 mg, 3.99 mmol) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 5 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with brine (50 mL) and dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 15 minutes) to give 2-bromo-6-(methoxymethyl)pyridine (2-bromo-6-(methoxymethyl)pyridine) as a colorless liquid. 450mg, 83% yield). LC-MS: m/z[M+H] ⁺ 202.0.

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

To a stirred solution of 2-bromo-6-(methoxymethyl)pyridine (200 mg, 989 μmol) in 1,4-dioxane (5.0 mL) at 25°C, (1 R , 3 S )-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 ₂ CO ₃ (645 mg, 1.98 mmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 5 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 5% to 70% EtOAc in 15 minutes) to obtain the desired product (1 R ,3 S )-3-[1 as a yellow solid - tert-Butyl-5-[[6-(methoxymethyl)-2-pyridyl]amino]pyrazol-3-yl]cyclopentanol (300 mg, 87% yield). LC-MS: m/z[M+H] ⁺ 345.3.

Step 3: 1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(methoxymethyl)pyridin-2-yl) )Amino)-1 H -pyrazol-3-yl)cyclopentyl ester

(1 R ,3 S )-3-[1-tert-butyl-5-[[6-(methoxymethyl)pyridine-2- in CH ₂ Cl ₂ (5.0 mL) at 25 °C To a stirred suspension of methyl]amino]pyrazol-3-yl]cyclopentanol (300 mg, 871 μmol), CDI (424 mg, 2.61 mmol) and Et ₃ N (364 μL, 264 mg, 2.61 mmol) were added sequentially. The reaction mixture was warmed to 40°C and stirred at this temperature for 2 hours, quenched with ice water (20 mL) and extracted with _CH2Cl2 (20 _mL ×3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5 -((6-(methoxymethyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester, which was used in the next step without further purification. LC-MS: m/z[M+H] ⁺ 439.2.

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

1 _{H -imidazole} -1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5 - ((6- To a stirred solution of (methoxymethyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester, add propyl-2-amine (74.1 μL, 51.2 mg, 866 μmol) . The reaction mixture was warmed to 80°C and stirred at this temperature for 4 hours, then it was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 5% to 70% EtOAc in 15 minutes) to give isopropylcarbamic acid (1 R ,3 S )-3 as a yellow solid. -(1-(tert-Butyl)-5-((6-(methoxymethyl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (300 mg , 80% yield). LC-MS: m/z[M+H] ⁺ 430.3.

Step 5: Isopropylcarbamate (1 R ,3 S )-3-(3-((6-(methoxymethyl)pyridin-2-yl)amino)-1 H -pyrazole-5 -yl) cyclopentyl ester

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

The following compounds were prepared using similar procedures disclosed in Synthesis Example 34 .

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

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

To a stirred solution of 3-bromo-5-methyl-1 H -pyrazole (1.00 g, 6.21 μmol) in HCl (10 mL, 0.1 M, 1.0 mmol) at 25 °C was added H ₂ O (5.0 mL ) in KMnO ₄ (2.94g, 18.6mmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 12 hours. The reaction mixture was acidified with HCl (2.0M aqueous solution) to pH=4 and extracted with EtOAc (50 mL×3). The combined organic phases were dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo- 1H -pyrazole-5-carboxylic acid _as a white solid, which was used directly in step one 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-1 H -pyrazole-5-carboxylic acid (800 mg, 4.19 mmol) in 1,4-dioxane (10.0 mL) at 50 °C was added CDI (663 mg, 4.61 mmol) . The reaction was stirred at this temperature for 30 minutes, then 2,2-dimethylethylamine (502 μL, 484 mg, 4.61 mmol) was added. The reaction mixture was stirred at this temperature for an additional 30 minutes, then HCl (9.0 mL, 12.0 M aqueous solution) was added. The reaction mixture was warmed to 100° C. and stirred at this temperature for 12 hours, then concentrated under reduced pressure. The raw product was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 30 minutes) to obtain 2-bromopyrazolo[1,5- a ]pyridine as a white solid. Azin-4-ol (450 mg, 50% yield). 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) at 110 °C was added POBr ₃ (696 mg, 2.43 mmol, 247) and the resulting mixture was stirred at this temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and basified with aqueous _Na2CO3 to _pH =8, and extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 30 min) to give 2,4-dibromopyrazolo[1,5- a as a yellow oil ]pyrazine (300 mg, 89% yield). LC-MS: m/z[M+H] ⁺ 275.8.

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

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

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

2-Bromo- N -[2-tert-butyl-5-[(1 S ,3 R )-3 in tetrabutylammonium fluoride (3.0 mL, 1.0 M in THF, 3.0 mmol) - A solution of [tert-butyl(dimethyl)silyl]oxycyclopentyl]pyrazol-3-yl]pyrazolo[1,5- a ]pyrazin-4-amine (280 mg, 524 μmol), It was heated to 60° C. and stirred at this temperature for 2 hours, then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 100% EtOAc in 30 min) to give (1 R ,3 S )-3-[5-[( 2-Bromopyrazolo[1,5- a ]pyrazin-4-yl)amino]-1-tert-butyl-pyrazol-3-yl]cyclopentanol (220 mg, 99% yield). LC-MS: m/z[M+H] ⁺ 419.0.

Step 6: 1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(5-((2-bromopyrazolo[1,5- a ]pyrazin-4-yl)amine) -1-(tert-Butyl)-1 H -pyrazol-3-yl)cyclopentyl ester

(1 R ,3 S )-3-[5-[(2-bromopyrazolo[1,5- a ]pyrazin-4-yl) in CH ₂ Cl ₂ (10.0 mL) at 35 °C To a stirred suspension of amino]-1-tert-butyl-pyrazol-3-yl]cyclopentanol (200 mg, 476 μmol), CDI (205 mg, 1.43 mmol)) and DIPEA (0.41 mL, 307 mg, were added sequentially, 2.38mmol). The reaction mixture was stirred at this temperature for 2 hours, then quenched with water (20 mL) and extracted with _CH2Cl2 (20 _mL ×3). The combined organic phases were dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated _under reduced pressure. Original product imidazole-1-carboxylic acid [(1 R ,3 S )-3-[5-[(2-bromopyrazolo[1,5- a ]pyrazin-4-yl)amine]-1 - tert-Butyl-pyrazol-3-yl]cyclopentyl ester], which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 512.9.

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

Imidazole-1-carboxylic acid [(1 R ,3 S )-3-[5-[(2-bromopyrazolo[1,5- a ]pyra]) in CH ₃ CN (10.0 mL) at 25°C. To a stirring solution of oxazin-4-yl)amino]-1-tert-butyl-pyrazol-3-yl]cyclopentyl ester], add propyl-2-amine (119 μL, 82.9 mg, 1.40 mmol) in sequence. and Et ₃ N (195 μL, 141 mg, 1.40 mmol). The resulting reaction mixture was stirred at this temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 30 minutes) to give N -isopropylcarbamic acid [(1 R ,3 S )-3-[5-[(2-bromopyrazolo[1,5- a ]pyrazin-4-yl)amino]-1-tert-butyl-pyrazol-3-yl]cyclopentyl ester] (140mg). LC-MS: m/z[M+H] ⁺ 504.0.

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

N -Isopropylcarbamate [(1 R ,3 S )-3-[5-[(2-bromopyrazolo[1,5- a ]pyridin) in toluene (3.0 mL) at 25°C To a stirring solution of oxazin-4-yl)amino]-1-tert-butyl-pyrazol-3-yl]cyclopentyl] ester, add tributyl(methoxymethyl)stannane (79.0 mg, 237 μmol) and Pd(PPh ₃ ) ₄ (13.7 mg, 11.8 μmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 12 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE 1:1) to obtain N -isopropylcarbamic acid [(1 R ,3 S )-3-[1-tert-butyl-5- as yellow oil [[2-(Methoxymethyl)pyrazolo[1,5- a ]pyrazin-4-yl]amino]pyrazol-3-yl]cyclopentyl ester] (6 mg, 10% yield ) and N -isopropylcarbamate [(1 R ,3 S )-3-[1-tert-butyl-5-(pyrazolo[1,5- a ]pyrazin-4-ylamine )pyrazol-3-yl]cyclopentyl ester] (17.0 mg, 34% yield). LC-MS: m/z[M+H] ⁺ 470.1.

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

N -Isopropylcarbamic acid [(1 R ,3 S )-3-[1-tert-butyl-5-[[2-(methoxymethyl)pyrazole) in TFA (2.0 mL) [1,5- a ]pyrazin-4-yl]amino]pyrazol-3-yl]cyclopentyl ester] (9.0 mg, 19.1 μmol) solution, heated to 50°C, and stirred at this temperature 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC with _CH3CN in water (from 20% to 40% _CH3CN in 10 min) to give N -isopropylcarbamic acid as a white solid [(1 R ,3 S )-3-[3-[[2-(methoxymethyl)pyrazolo[1,5- a ]pyrazin-4-yl]amine]-1 H -pyrazole-5 -yl]cyclopentyl ester] (4.0 mg, 50% yield). LC-MS: m/z[M+H] ⁺ 414.0.

Step 10: Isopropylcarbamic acid (1 R ,3 S )-3-(3-(pyrazolo[1,5- a ]pyrazin-4-ylamino)-1 H -pyrazole-5 -yl) cyclopentyl ester

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

Example 49

Isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-(methylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazole-5- cyclopentyl ester

Step 1: 6-Bromo- N -methylpicolamide

To a solution of 6-bromopyridinecarboxylic acid (200 mg, 990 μmol) in DCM (8.0 mL) at 25°C, methylamine hydrochloride (133 mg, 1.98 mmol), EDCI (379 mg, 1.98 mmol), and HOBt were added sequentially. (267 mg, 1.98 mmol) and DIPEA (383 mg, 2.97 mmol, 516 μL). The reaction mixture was stirred at this temperature for 3 hours, then it was diluted with water (50 mL) and extracted with DCM (50 mL x 3). _The combined organic phases were washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 32% EtOAc in 20 minutes) to give 6-bromo- N -methylpyridinecarboxamide (200 mg, 94% yield). LC-MS: m/z[M+H] ⁺ 215.0.

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

To a solution of 6-bromo- N -methyl-pyridine-2-carboxamide (100 mg, 465 μmol) in 1,4-dioxane (5.0 mL) at 25°C, (1 R , 3 S )-3-(5-amino-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopent-1-ol (124 mg, 558 μmol), Pd ₂ (dba) ₃ (85.1 mg, 93.0 μmol), XantPhos (107 mg, 186 μmol), and Cs ₂ CO ₃ (454 mg, 1.40 mmol). The mixture was warmed to 100°C and stirred at this temperature for 12 hours. 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 (10 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography, dissolving with MeOH/DCM (from 0% to 6% DCM in 15 min) to give 6-((1-(tert-butyl)-3- ((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino) -N -picolinamide (140 mg, 84% yield). LC-MS: m/z[M+H] ⁺ 358.2.

Step 3: 1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(methylaminoformyl)pyridine-2) -yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester

6-[[2-tert-Butyl-5-[(1 S ,3 R )-3-hydroxycyclopentyl]pyrazol-3-yl]amine in DCM (4.0 mL) at 25 °C ] -N -methyl-pyridine-2-carboxamide) solution, add CDI (136 mg, 839 μmol) and DIPEA (180 mg, 1.40 mmol, 243 μL) in sequence. The mixture was warmed to 35°C and stirred at this temperature for 2 hours. The mixture was cooled, diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (30 mL _× 2), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 85% EtOAc in 15 minutes) to give 1H -imidazole-1-carboxylic acid ( 1R , 3S) as a yellow oil )-3-(1-(tert-butyl)-5-((6-(methylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl) ring Pentyl ester (50.0 mg, 39% yield). LC-MS: m/z[M+H] ⁺ 452.2.

Step 4: Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(methylaminoformyl)pyridin-2-yl) Amino)-1 H -pyrazol-3-yl)cyclopentyl ester

1 H -imidazole-1-carboxylic acid (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-() in CH ₃ CN (2.0 mL) at 25 °C To a solution of methylaminoformyl)pyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (50.0 mg, 110 μmol), add propyl-2-amine ( 65.4 mg, 1.11 mmol, 95.0 μL) and DIPEA (143 mg, 1.11 mmol, 193 μL). The reaction mixture was warmed to 80°C and stirred at this temperature for 20 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 68% EtOAc in 15 minutes) to give isopropylcarbamic acid (1 R ,3 S )-3 as a yellow solid. -(1-(tert-Butyl)-5-((6-(methylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (40.0 mg, 81% yield). LC-MS: m/z[M+H] ⁺ 443.3.

Step 5: Isopropylcarbamate (1 R ,3 S )-3-(3-((6-(methylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazole -5-yl)cyclopentyl ester

Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(methylaminoformyl)pyridine) in TFA (2.0 mL) A solution of -2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (40.0 mg, 90.3 μmol) was heated to 70°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 30% to 100% CH ₃ CN in 8 min) to give isopropylcarbamic acid ((1 R ,3 S )-3-(3-( (6-(methylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (11.4 mg, 32% yield). LC-MS: m/z[M+H] ⁺ 387.2.

Example 50 Isopropylcarbamate (1 R ,3 S )-3-(3-((6-aminoformylpyridin-2-yl)amino)-1 H -pyrazol-5-yl ) cyclopentyl ester, Example 51 isopropylcarbamate (1 R ,3 S )-3-(5-((6- (isopropylaminoformyl)pyridin-2-yl)amino )-1 H -pyrazol-3-yl)cyclopentylisopropylcarbamate, and Example 52 6-((5-((1 S ,3 R )-3-((isopropyl Aminoformyl)oxy)cyclopentyl)-1 H -pyridin-3-yl)amino)pyridinecarboxylic acid

Step 1: Methyl 6-bromopyridinecarboxylate isopropylcarbamate

To a solution of 6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol) in DCM (10.0 mL) at 0°C, DMF (10.0 mg, 136 μmol, 10.5 μL) and oxalic acid chloride (943 mg, 7.43mmol, 648μL). The resulting reaction mixture was warmed to 25°C, stirred at this temperature for 1 hour, and then methanol (5.0 mL) was added. The mixture was stirred at this temperature for 5 minutes and then concentrated under reduced pressure. The residue was diluted with _H2O (30 mL) and extracted with DCM (10 mL×3). _The combined organic phases were washed with brine (50 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to afford 6-bromopyridine-2-carboxylic acid methyl ester (514 mg, 96% yield). LC-MS: m/z[M+H] ⁺ 216.0/218.0.

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

(1 R ,3 S )-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentan in 1,4-dioxane (10.0 mL) at 25°C To a solution of alcohol (250 mg, 1.12 mmol), 6-bromopyridine-2-carboxylic acid methyl ester (375 mg, 1.73 mmol), Pd ₂ (dba) ₃ (82.0 mg, 89.4 μmol), and XantPhos (52.0 mg) were added in sequence. , 89.8 μmol) and Cs ₂ CO ₃ (750 mg, 2.30 mmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was diluted with _H2O (30 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (50 mL), dried over _Na2SO4 , filtered, and concentrated _under reduced pressure. The residue was purified by silica gel chromatography, dissolving with MeOH/DCM over 15 min (from 0% to 5% MeOH) to give 6-((1-(tert-butyl)-3-) as a white solid ((1 S ,3 R )-3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)pyridinecarboxylic acid methyl ester (188 mg, 46% yield). LC-MS: m/z[M+H] ⁺ 359.2.

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

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

Step 4: Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(isopropylaminoformyl)pyridin-2-yl) )Amino)-1 H -pyrazol-3-yl)cyclopentyl ester

6-((3-((1 S ,3 R )-3-((1 H -imidazole-1-carbonyl)oxy)cyclopentyl)- in CH ₃ CN (5.0 mL) at 25 °C To a solution of 1-(tert-butyl) -1H -pyrazol-5-yl)amino)pyridinecarboxylic acid methyl ester (140 mg, 309 μmol), propyl-2-amine (100 mg, 1.69 mmol, 0.15mL) and DIPEA (120mg, 928μmol, 0.16mL). The reaction mixture was warmed to 80°C and stirred at this temperature for 6 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography, dissolving with MeOH/DCM over 15 min (from 0% to 5% MeOH) to give 6-((1-(tert-butyl)-3-) as a white solid ((1 S ,3 R )-3-((isopropylaminoformyl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)amino)pyridinecarboxylic acid methyl ester ( 100 mg, 73% yield) and white solid isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(isopropylaminomethyl) Cyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (30.0 mg, 20% yield). LC-MS: (ESI)m/z[M+H] ⁺ 444.2 and 471.3.

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

6-((1-(tert-butyl)-3-((1 S ,3 R )-3-((isopropyl)) in MeOH (6.0 mL) and H ₂ O (1.0 mL) at 25 °C To a solution of methylaminoformyl)oxy)cyclopentyl) -1H -pyrazol-5-yl)amino)pyridinecarboxylate (80.0 mg, 180 μmol), NaOH (40.0 mg, 1.00 mmol). The mixture was stirred at this temperature for 2 hours, then it was concentrated under reduced pressure. The residue was diluted with H ₂ O (2.0 mL) and acidified with aqueous HCl (2.0 M) to pH=5, then filtered and dried to give 6-((1-(tert-butyl)-3-() as a colorless solid (1 S ,3 R )-3-((isopropylaminoformyl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)amino)pyridinecarboxylic acid (70.0 mg, 91 % yield). LC-MS: m/z[M+H] ⁺ 430.2.

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

6-((1-(tert-butyl)-3-((1 S ,3 R )-3-((isopropylaminoformyl)oxy) in THF (5.0 mL) at 25°C Base) cyclopentyl)-1 H -pyrazol-5-yl) amino) pyridine carboxylic acid (40.0 mg, 93.1 μmol) solution, add HATU (70.0 mg, 184 μmol), DIPEA (36.0 mg, 278 μmol, 48.5 μL) and NH ₄ Cl (15.0 mg, 280 μmol). The mixture was stirred at this temperature for 12 hours, then it was concentrated under reduced pressure. The residue was diluted with _H2O (30 mL) and extracted with DCM (30 mL×2). The combined organics were washed with brine (50 mL). The residue was purified by silica gel chromatography and eluted with MeOH/DCM over 12 minutes (from 0% to 10% MeOH) to give isopropylcarbamic acid (1 R ,3 S )-3 as a white solid. -(1-(tert-Butyl)-5-((6-aminoformylpyridin-2-yl)amino) -1H -pyrazol-3-yl)cyclopentyl ester (35.0 mg, 87% yield). LC-MS: m/z[M+H] ⁺ 429.2.

Step 7: Isopropylcarbamic acid (1 R ,3 S )-3-(3-((6-aminoformylpyridin-2-yl)amino)-1 H -pyrazol-5-yl )cyclopentyl ester

Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-aminoformylpyridin-2-yl) in TFA (4.0 mL) )Amino) -1H -pyrazol-3-yl)cyclopentyl ester (35.0 mg, 81.6 μmol) was heated to 70°C and stirred at this temperature for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 21% to 31% CH ₃ CN in 8 min) to give isopropylcarbamic acid (1 R ,3 S )-3-(3-((( 6-Aminoformylpyridin-2-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl ester (6.00 mg, 19% yield). LC-MS: m/z[M+H] ⁺ 373.1.

Step 8: 6-((5-((1 S ,3 R )-3-((isopropylaminoformyl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)amine pyridinecarboxylic acid

6-((1-(tert-butyl)-3-((1 S ,3 R )-3-((isopropylaminoformyl)oxy)oxy)cyclopentyl in TFA (4.0 mL) (20.0 mg, 46.5 μmol) was heated to 70° C. and stirred at this temperature for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 18% to 28% CH ₃ CN in 8 min) to give 6-((5-((1 S ,3 R )-3-(iso Propylaminoformyl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)amino)pyridinecarboxylic acid (6.00 mg, 34% yield). LC-MS: (ESI)m/z[M+H] ⁺ 374.2.

Step 9: Isopropylcarbamate (1 R ,3 S )-3-(5-((6-(isopropylaminoformyl)pyridin-2-yl)amino)-1 H -pyridine Azol-3-yl)cyclopentyl ester

Isopropylcarbamate (1 R ,3 S )-3-(1-(tert-butyl)-5-((6-(isopropylaminoformyl)) in TFA (4.0 mL) A solution of pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (25.0 mg, 53.1 μmol) was heated to 70° C. and stirred at this temperature for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 20% to 50% CH ₃ CN in 7 min) to give isopropylcarbamic acid (1 R ,3 S )-3-(5-((( 6-(isopropylaminoformyl)pyridin-2-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl ester (15.0 mg, 68% yield). LC-MS: m/z[M+H] ⁺ 415.3.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 49 .

Example 60

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

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

Benzyl N- [2-tert-butyl-5-(3-oxocyclopentyl)pyrazol-3-yl]carbamate (1.00 mg) in THF (20.0 mL) at 0°C. To a stirred solution of 2.81 mmol), NaH (203 mg, 60 wt.% in mineral oil, 8.44 mmol) was added. The reaction mixture was stirred at 0°C for 30 minutes, then a solution of ethyl 2-diethoxyphosphoacetate (1.68 mL, 1.89 g, 8.44 mmol) in THF (5.0 mL) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 5 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 25% EtOAc in 25 minutes) to give ( E )-2-(3-(5-(((((E)) as a yellow oil Benzyloxy)carbonyl)amino)-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopentylene)acetic acid ethyl ester (1.1 g, 91% yield). LC-MS: m/z[M+H] ⁺ 426.1.

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

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

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

Ethyl 2-(3-(5-amino-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopentyl)acetate in DMF (5.0 mL) at 0 °C To the stirring solution, 4-bromo-2-methyl-pyrazolo[1,5- a ]pyrazine (281.8 mg, 1.33 mmol) and KOt-Bu (343.5 mg, 3.07 mmol) were added sequentially. The resulting mixture was stirred at this temperature for 0.5 h, then quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over _{anhydrous Na2SO4} then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 25% EtOAc in 25 min) to give 2-[3-[1-tert-butyl-5- as a yellow oil [(2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino]pyrazol-3-yl]cyclopentyl]acetate ethyl ester (100 mg, 9% yield for two steps). 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)-1 H - Pyrazol-3-yl)cyclopentyl)acetic acid

2-[3-[1-tert-butyl-5-[(2-methylpyrazolo[1,5- a ]pyridin) in THF (2.0 mL) and water (2.0 mL) at 25°C. To a stirred solution of oxazin-4-yl)amino]pyrazol-3-yl]cyclopentyl]ethyl acetate, add LiOH. _H2O (13.8 mg, 0.329 mmol) and the reaction mixture was stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove most of the THF. The mixture was acidified with aqueous HCl (2.0 M) to pH=3, and then it was extracted with EtOAc (10 mL×2). The combined organic phases were dried over _{anhydrous Na2SO4} and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(3-(1-(tert-butyl)-5-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amine) as a yellow oil) )-1 H -pyrazol-3-yl)cyclopentyl)acetic acid, which was used 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)-1 H - Pyrazol-3-yl)cyclopentyl) -N -isopropylacetamide

2-(3-(1-(tert-butyl)-5-(2-methylpyrazolo[1,5- a ]pyrazine) in CH ₂ Cl ₂ (3.0 mL) at 25 °C -4-yl)amino) -1H -pyrazol-3-yl)cyclopentyl)acetic acid (60.0mg, 0.151mmol) solution, add DIPEA (52.5μL, 39.0mg, 0.302mmol) and HATU in sequence (115 mg, 0.302 mmol) and propyl-2-amine (12.9 μL, 8.90 mg, 0.151 μmol). The reaction mixture was stirred at this temperature for 2 hours, then quenched with water (5.0 mL) and extracted with _CH2Cl2 (15 _mL ×2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, dissolving with CH ₃ OH/CH ₂ Cl ₂ (from 0% to 8% CH ₃ OH in 25 min) to give 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). LC-MS: m/z[M+H] ⁺ 438.1.

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

2-(3-(1-(tert-butyl)-5-(2-methylpyrazolo[1,5- a ]pyrazin-4-yl) in HCO ₂ H (2.0 mL) A solution of amino) -1H -pyrazol-3-yl)cyclopentyl) -N -isopropylacetamide (60.0 mg, 65.0 μmol) was heated to 50°C and stirred at this temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was chromatographed by SFC (Daicel CHIRALCEL AD-H, CO ₂ /EtOH=60/40,, EtOH containing 0.2% NH ₄ OH, 2.5 mL/min, 40°C) to obtain ( cis , rac ) -N -Isopropyl-2-((1 R ,3 S )-3-(3-((2-methylpyrazolo[1,5- a ]pyrazin-4-yl)amino)-1 H -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-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrazole -3-yl) -1H -pyrazole-5-methamide

Step 1: 3-(Bromomethyl)-1-methyl- 1H -pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of 2,5-dimethylpyrazole-3-carboxylic acid ethyl ester (2.00 g, 11.8 mmol) in CCl ₄ (20 mL) at 25 °C, followed by the addition of BPO (147 mg, 2.38 mmol) and NBS (2.00g, 11.8mmol). The mixture was warmed to 80°C and stirred at this temperature for 16 hours. The mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc/PE over 30 minutes (from 0% to 2% EtOAc) to obtain the as-received product (1.8 g as-is), which was further treated with PE (5.0 mL). Slurrying gave 3-(bromomethyl)-1-methyl- 1H -pyrazole-5-carboxylic acid ethyl ester as a white solid (880 mg, 30% yield). LC-MS: m/z[M+H]+ 247.0.

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

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

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

N -[2-tert-Butyl-5-[(1 S ,3 R )-3-hydroxycyclopentyl]pyrazol-3-yl]amine in dioxane (4.0 mL) at 0 °C To a suspension of benzyl formate (250 mg, 0.70 mmol), 2-chloropyrimidine (160 mg, 1.40 mmol) and NaH (279 mg, 6.99 mmol, 60% wt.%) were added sequentially. The mixture was warmed to 80°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C, quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL×2) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE over 20 minutes (from 0% to 50% EtOAc) to give (1-(tert-butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrazol-5-yl)carbamate benzyl ester (200 mg, 66% yield). LC-MS: m/z[M+H] ⁺ 436.2.

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

(1-(tert-Butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H in MeOH (6.0 mL) at 25°C To a stirred solution of benzyl-pyrazol-5-yl)carbamate (150 mg, 0.34 mmol), Pd/C (42.0 mg, 39.6 μmol, 10% wt.%) was added. The reaction mixture was stirred at this temperature under hydrogen atmosphere (balloon) for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain 1-(tert-butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy) as a yellow oil (100 mg , 96% yield), 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-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrazole-5- methyl)-3-(methoxymethyl)-1-methyl- 1H -pyrazole-5-carboxamide

1-(tert-Butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 in pyridine (5.0 mL) at -5°C To a stirred solution of H -pyrazole-5-amine (80.0 mg, 0.27 mmol), 5-(methoxymethyl)-2-methyl-pyrazole-3-carboxylic acid (90.0 mg, 0.53 mmol) was added sequentially. ) and POCl ₃ (122 mg, 0.80 mmol, 74.2 μL). The reaction mixture was stirred at this temperature for 3 hours, then quenched with _H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE in 20 minutes (from 0% to 50% EtOAc) to give N -(1-(tert-butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1 H - Pyrazole-5-methamide (52.0 mg, 43% yield). LC-MS: m/z[M+H] ⁺ 454.2.

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

N -(1-(tert-butyl)-3-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 in HCO ₂ H (3.0 mL) A mixture of H -pyrazole-5-yl)-3-(methoxymethyl)-1-methyl-1 H -pyrazole-5-carboxamide (45.0 mg, 0.10 mmol), heated to 80°C And stir at this temperature for 4 hours. The mixture was cooled to 25°C and filtered under reduced pressure. The residue was purified by prep-HPLC, dissolving with CH ₃ CN in water over 8 minutes (from 25% to 55% CH ₃ CN) to give 3-(methoxymethyl)-1 as a white solid -Methyl- N -(5-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrazol-3-yl)-1 H -pyrazole -5-Formamide (9.70 mg, 25% yield). 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 )-1 H -pyrazole-3-yl)-1 H -pyrazole-5-methamide

Step 1: Methanesulfonic acid ( trans , rac )-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl) -1H -pyrazol-3-yl) ring Amyl ester

( trans , rac )-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amine in DCM (10 mL) at 0 °C To a stirred solution of benzyl formate (600 mg, 1.68 mmol), Et ₃ N (700 μL, 510 mg, 5.04 mmol) and methanesulfonyl chloride (288 mg, 2.52 mmol, 195 μL) were added sequentially. The mixture was stirred at this temperature for 2 hours, then quenched with _H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE over 25 minutes (from 0% to 10% EtOAc) to give methanesulfonic acid ( trans , rac )-3-(5-() as a colorless oil ((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1 H -pyrazol-3-yl)cyclopentyl ester (700 mg, 95% yield). LC-MS: m/z[M+H] ⁺ 436.2.

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

To a stirred solution of 1-methylpyrazol-3-ol (315 mg, 3.21 mmol) in THF (10 mL) at 0 °C was added NaH (257 mg, 6.43 mmol, 60% wt.%). The mixture was stirred at 0°C for 0.5 hours, then methanesulfonic acid ( trans , rac )-3-(5-((benzyloxy)carbonyl)amino)-1-(tert-butyl) -1H -pyridine was added Azol-3-yl)cyclopentyl ester (700 mg, 1.61 mmol). The mixture was warmed to 80°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C, diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were _washed with brine (40 mL), dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography, dissolving with MeOH/DCM in 20 minutes (from 0% to 5% MeOH) to give ( cis , rac )-(1-(tert-butyl)) as a white solid -3-(3-((1-Methyl-1 H -pyrazol-3-yl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)carbamic acid benzyl ester (80.0 mg , 11% yield). 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

( cis , rac )-(1-(tributyl)-3-(3-((1-methyl-1 H -pyrazol-3-yl)) in MeOH (5.0 mL) at 25°C To a solution of benzyl oxy)cyclopentyl)-1 H -pyrazol-5-yl)carbamate (80.0 mg, 0.18 mmol), Pd/C (11.1 mg, 10.4 μmol, 10% wt.%) was added ). The reaction mixture was stirred at this temperature under hydrogen atmosphere (balloon) for 3 hours. 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, dissolving with MeOH/DCM in 20 minutes (from 0% to 5% MeOH) to give ( cis , rac )-1-(tert-butyl)- as a white solid 3-(3-((1-Methyl-1 H -pyrazol-3-yl)oxy)cyclopentyl)-1 H -pyrazol-5-amine (45.0 mg, 81% yield). 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-methamide

( cis , rac )-1-(tert-butyl)-3-(3-((1-methyl-1 H -pyrazol-3-yl)oxy) in pyridine (6.0 mL) at 0°C (methyl)cyclopentyl) -1H -pyrazole-5-amine (40.0mg, 0.13mmol) solution, 5-(methoxymethyl)-2-methyl-pyrazole-3-carboxylic acid was added sequentially Acid (44.8 mg, 0.26 mmol) and POCl ₃ (60.6 mg, 0.40 mmol, 40.9 μL). The mixture was stirred at this temperature for 6 hours, then quenched with saturated _NaHCO3 solution (50 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography, dissolving with MeOH/DCM in 20 minutes (from 0% to 5% MeOH) to give ( cis , rac )-1-(tert-butyl)- as a white solid 3-(3-((1-methyl-1 H -pyrazol-3-yl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)-3-(methoxymethyl) -1-Methyl- 1H -pyrazole-5-methamide. 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 (yl)cyclopentyl) -1H -pyrazol-3-yl) -1H -pyrazole-5-carboxamide

( cis , rac )- N -[2-tert-butyl-5-[3-(1-methylpyrazole-3-yl)oxycyclopentyl]pyrazole-3 in TFA (5.0 mL) -A mixture of -5-methoxymethyl)-2-methyl-pyrazole-3-carboxamide (25.0 mg, 0.05 mmol) was heated to 80°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by prep-HPLC with _CH3CN in water (from 50% to 80% _CH3CN in 12 min) to give ( cis , rac )-3-(methoxy) as a white solid methyl)-1-methyl- N- (5-(3-((1-methyl-1 H -pyrazol-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3 -yl) -1H -pyrazole-5-methamide (1.00 mg, 4% yield). LC-MS: m/z[M+H] ⁺ 400.2.

Example 63 intentionally left blank

Examples 64 and 65

Isopropylcarbamic acid (1 R ,3 S )-3-(2-(1-methyl-1 H -pyrazole-5-amine)-1 H -pyrrolo[2,3- b ]pyridine- 5-yl)cyclopentyl ester (optional) and isopropylcarbamic acid (1S, 3R )-3-(2-(1-methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (optional)

Step 1: 5-Bromo-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridine

To a stirred suspension of NaH (1.10 g, 27.4 mmol, 60% wt.%) in DMF (30 mL) at 0 °C was added 5-bromo-1 H -pyrrolo[2, 3- b ] A solution of pyridine (3.00 g, 15.2 mmol). The mixture was stirred at this temperature for 1 hour, then a solution of 4-toluenesulfonyl chloride (2.90 g, 15.2 mmol) in DMF (15 mL) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 3 hours. The mixture was quenched with saturated NaHCO _solution (100 ml) and DCM (100 mL x 2). The combined organic layers were washed with saturated NaCl solution (50 mL×2) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 15 min) to give 5-bromo-1-toluenesulfonyl- 1H- as a yellow solid Pyrro[2,3- b ]pyridine (4.50 g, 84% yield). LC-MS: m/z[M+H] ⁺ 353.2.

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

Solution of 5-bromo-1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridine (6.00 g, 17.08 mmol) in THF (60 mL) at -50°C over 10 min LDA (6.40 mL, 25.6 mmol, 2.0 M in THF) was added. The mixture was stirred at this temperature for 1 hour, then a solution of _I2 (7.37g, 29.0mmol) in THF (20ml) was added over 20 minutes at -65°C. The reaction mixture was warmed to 10°C and stirred at this temperature for 1 hour. The mixture was quenched with water (100 ml) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL×2) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 7% EtOAc in 15 minutes) to obtain 5-bromo-2-iodo-1-toluenesulfonate as a yellow solid Cyl- 1H -pyrrolo[2,3- b ]pyridine (2.33 g, 22% yield). LC-MS: m/z[M+H] ⁺ 476.2.

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

5-bromo-2-iodo-1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridine (1.76 g, 2.58) in DME (15 mL) and water (2.0 mL) at 25°C mmol) suspension, add Pd(PPh ₃ ) ₄ (298 mg, 258 μmol) and Na ₂ CO ₃ (820 mg, 7.73 mmol) in sequence. The mixture was warmed to 60°C and stirred at this temperature for 3 hours. The mixture was cooled to 25°C, diluted with water (50 mL) and quenched with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 31% EtOAc in 20 min) to give 5-bromo-2-(1-methyl- 1H) as a yellow solid -pyrazol-5-yl)-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridine (501 mg, 45% yield). LC-MS: m/z[M+H] ⁺ 431.0.

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

5-Bromo-2-(2-methylpyrazol-3-yl)-1-(p-toluenesulfonyl)pyrrole in dioxane (5.0 mL) and water (1.0 mL) at 25°C To a stirring solution of [2,3- b ]pyridine (300 mg, 695 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added sequentially -2-ylcyclopent-2-en-1-one (434 mg, 2.09 mmol), K ₂ CO ₃ (288 mg, 2.09 mmol) and Pd(dppf)Cl ₂ (50.8 mg, 69.5 μmol). The mixture was heated to 100 °C and stirred at this temperature for 2 hours. The reaction was diluted with water (20 mL) and quenched with DCM (20 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂ SO _4. The mixture was filtered and Concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 15 min) to give 3-[2-(2-methyl) as a yellow solid Pyrazol-3-yl)-1-(p-toluenesulfonyl)pyrrolo[2,3-bpyridin-5-yl]cyclopent-2-en-1-one (170 mg, 56% yield) .LC-MS: m/z[M+H] ⁺ 433.1.

Step 5: ( cis , rac )-3-(2-(1-methyl- 1H -pyridin-5-yl)-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridine -5-yl)cyclopent-1-ol (intermediate 5)

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

Step 6: 1H -imidazole-1-carboxylic acid ( cis , rac )-3-(2-(1-methyl- 1H -pyridin-5-yl)-1-toluenesulfonyl- 1H -pyrrole And[2,3- b ]pyridin-5-yl)cyclopentyl ester

( cis , rac )-3-[2-(2-methylpyrazol-3-yl)-1-(p-toluenesulfonyl)pyrrolo[2] in DCM (2.0 mL) at 25 °C , 3- b ]pyridin-5-yl] cyclopentanol (30.0 mg, 68.7 μmol) was added to a stirring solution of Et ₃ N (34.7 mg, 343 μmol, 47.8 μL) and CDI (29.6 mg, 206 μmol). The reaction was warmed to 35°C and stirred at this temperature for 2 hours. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 55% EtOAc in 10 minutes) to give imidazole-1-carboxylic acid ( cis , rac )-[3 -[2-(2-methylpyrazol-3-yl)-1-( p -toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (30.0 mg , 82% yield). LC-MS: m/z[M+H] ⁺ 531.1.

Step 7: Isopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -pyridin-5-yl)-1-toluenesulfonyl- 1H -pyrrolo[2 ,3- b ]pyridin-5-yl)cyclopentyl ester

Imidazole-1-carboxylic acid ( cis , rac )-[3-[2-(2-methylpyrazol-3-yl)-1-(p-toluenesulfonate) in DCM (3.0 mL) at 25°C To a stirring solution of acyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl] ester (30.0 mg, 56.5 μmol), Et ₃ N (28.6 mg, 282 μmol, 39.4 μL) and Propan-2-amine (10.0 mg, 169 μmol, 14.5 μL). The reaction was warmed to 35°C and stirred at this temperature for 16 hours. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over _{anhydrous Na2SO4} . The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 10 minutes) to give N -isopropylcarbamic acid ( cis , rac )- as a yellow solid [3-[2-(2-methylpyrazol-3-yl)-1-( p-toluenesulfonyl )pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester]( 28.0 mg, 94% yield). LC-MS: m/z[M+H] ⁺ 522.2.

Step 8: Isopropylcarbamic acid (1 R ,3 S )-3-(2-(1-methyl-1 H -pyridin-5-yl)-1 H -pyrrolo[2,3- b ] Pyridin-5-yl)cyclopentyl ester and isopropylcarbamic acid (1 S ,3 R )-3-(2-(1-methyl-1 H -pyridin-5-yl)-1 H -pyrrole And[2,3- b ]pyridin-5-yl)cyclopentyl ester

N -isopropylcarbamate ( cis , rac )-[3-[2-(2-methylpyrazol-3-yl) in THF (2.0 mL) and water (2.0 mL) at 25°C -To a stirred solution of 1-( p-toluenesulfonyl )pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl] ester (30.0 mg, 57.5 μmol), KOH (32.7 mg, 575 μmol) was added . The reaction was warmed to 100°C and stirred at this temperature for 24 hours. The reaction was cooled, diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by SFC (REGIS CHIRAL ( S , S )-Whelk O1, CO ₂ /MeOH=50/50,, MeOH containing 0.1% DEA, 1.5ml/min, 37°C) to obtain isopropyl as a white solid Carbamic acid (1 R , 3S )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) Cyclopentyl ester (lag time = 3.1 min, random distribution absolute configuration, 1.00 mg, 10% yield), LC-MS: m/z [M+H]+ 368.2, and isopropylcarbamic acid as white solid (1 S , 3R )-3-(2-(1-methyl-1H pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) cyclopentyl ester ( Lag time = 3.4 minutes, arbitrary dispensing absolute configuration, 1.00 mg, 10% yield). LC-MS: m/z[M+H] ⁺ 368.2.

Example 66

( cis , rac )-3-(2-(1-methyl-1 H -pyrazole-5-yl)-1 H -pyrrolo[2,3- b ]pyridine-5-yl) cyclopentyl ester

Step 1: Carbonic acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazol-5-yl)-1-toluenesulfonyl- 1H -pyrrolo[2,3-b ]Pyridin-5-yl)cyclopentyl (4-nitrophenyl) ester

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

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

Carbonic acid ( cis , rac )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-1-toluenesulfonyl-1 in CH ₃ CN (10 mL) at 25 °C To a solution of H -pyrrolo[2,3- b ]pyridin-5-yl) cyclopentyl (4-nitrophenyl) ester (50.0 mg, 83.1 μmol), cyclopropylamine (14.0 mg, 249 μmol, 17.2 μL) and Et ₃ N (25.0 mg, 249 μmol, 34.7 μL). The reaction mixture was warmed to 80°C and stirred at this temperature for 2 hours. The mixture was cooled to 25°C and concentrated under reduced pressure to obtain cyclopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazol-5-yl)-1-toluenesulfonate yl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg) which was used in one step without further purification. LC-MS: m/z[M+H] ⁺ 520.2.

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

Cyclopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl-1 H -pyrazole-5) in THF (5.0 mL) and H ₂ O (5.0 mL) at 25°C -To a mixture of -1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg, 76.9 μmol), add KOH (43.0 mg, 769 μmol) ). The reaction mixture was warmed to 110°C and stirred at this temperature for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 34% to 44% _CH3CN in 8 min) to give cyclopropylcarbamate ( cis , rac )-3-(2-(1- Methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (5.0 mg, 17% yield). LC-MS: m/z[M+H] ⁺ 366.2.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 66 .

Example 75

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

( cis , rac )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-1-toluenesulfonyl-1 H - in DMF (5.0 mL) at 0°C To a solution of pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (50.0 mg, 114 μmol), NaH (27.0 mg, 687 μmol, 60% wt.%) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 12 hours. The mixture was diluted with _H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by prep-HPLC (elution with _CH3CN in water, from 45% to 100% _CH3CN in 8 min) to afford ( cis , rac )-2-(1 as a white solid -Methyl-1 H -pyrazol-5-yl)-5-((1 S ,3 R )-3-(pyrimidin-2-yloxy)cyclopentyl)-1 H -pyrrolo[2, 3- b ]pyridine (3.00 mg, 7% yield). LC-MS: m/z[M+H] ⁺ 361.1.

Example 76

Isopropylcarbamic acid ( cis , rac )-3-(3-chloro-2-(1-methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ] Pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazol-5-yl) -1H- in _CHCl3 (8.0 mL) at 25°C To a suspension of pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg, 109 μmol), NCS (17.4 mg, 130 μmol, 10.6 μL) was added. The reaction mixture was warmed to 60°C and stirred at this temperature for 10 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 45% to 75% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(3-chloro-2) as a white solid -(1-Methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (11.3 mg, 26% yield). LC-MS: m/z[M+H] ⁺ 402.1.

Example 77

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

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

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

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

Isopropylcarbamic acid ( cis , rac )-3-(3-bromo-2-(1-methyl) in 1,4-dioxane (2.0 mL) and water (0.4 mL) at 25°C -To a stirred solution of -1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) cyclopentyl ester (35.0 mg, 78.4 μmol), methyl groups were added sequentially Boric acid (14.1 mg, 235 μmol), Pd(dppf)Cl ₂ ˙CH2Cl2 (5.1 mg, 7.8 μmol), and K ₂ CO ₃ (21.7 mg, 157 μmol). The mixture was warmed to 120°C in the microwave and stirred at this temperature for 1 hour. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (elution with _CH3CN in water, from 31% to 41% _CH3CN in 9 min) to give isopropylcarbamic acid ( cis , rac ) as a white solid )-3-(3-methyl-2-(1-methyl-1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl Ester (1.2 mg, 4% yield). LC-MS: m/z[M+H] ⁺ 382.2.

Example 78

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

Step 1: 5-Bromo-2-methyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridine

To a solution of 5-bromo-2-methyl-1 H -pyrrolo[2,3- b ]pyridine (1.00 g, 4.74 mmol) in DMF (20 mL) at 0 °C was added NaH (125 mg, 5.21 mmol , 60% wt.%). The mixture was stirred at this temperature for 30 minutes, then 4-toluenesulfonyl chloride (993 mg, 5.21 mmol) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 1 hour. The mixture was quenched with saturated NaHCO solution (20 _ml ) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated NaCl solution (50 mL×2) and dried over anhydrous Na ₂ SO ₄ . The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with EtOAc/PE over 15 min (from 0% to 10% EtOAc) to give 5-bromo-2-methyl-1-( p-Toluenesulfonyl)pyrrolo[2,3- b ]pyridine (1.54 g, 80% yield). LC-MS: m/z[M+H] ⁺ 365.0.

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

5-Bromo-2-methyl-1-(p-toluenesulfonyl)pyrrolo[2,3- b in 1,4-dioxane (12 mL) and water (2.0 mL) at 25°C ] Pyridine (1.20g, 3.29mmol) solution, add K ₂ CO ₃ (1.36g, 9.86mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxy Bororol-2-yl)cyclopent-2-en-1-one (2.05 g, 9.86 mmol) and Pd(dppf)Cl ₂ (268 mg, 328 μmol). The mixture was warmed to 100°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography with EtOAc/PE over 15 min (from 0% to 70% EtOAc) to give 3-[2-methyl-1-(p) as a yellow solid -Tosyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopent-2-en-1-one (700 mg, 55% yield). LC-MS: m/z[M+H] ⁺ 367.0.

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

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

Step 4: 1H -imidazole-1-carboxylic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl )cyclopentyl ester

( cis , rac )-3-(2-methyl-1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl in DCM (2.0 mL) at 25 °C ) to a solution of cyclopent-1-ol (60.0 mg, 161 μmol), CDI (78.7 mg, 485 μmol) and Et ₃ N (81.9 mg, 809 μmol, 112 μL) were added sequentially. The mixture was warmed to 35°C and stirred at this temperature for 18 hours. The mixture was concentrated under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (65.0 mg, 73% yield), which was used in the next step without further purification. LC-MS: m/z[M+H] ⁺ 465.1.

Step 5: Isopropylcarbamic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentan base ester

1 H _-imidazole -1-carboxylic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl-1 H -pyrrolo[ To a solution of 2,3- b ]pyridin-5-yl)cyclopentyl ester (65.0 mg, 111 μmol), propyl-2-amine (132 mg, 2.24 mmol, 192 μL) and Et ₃ N (33.9 mg, 335 μmol) were added sequentially. , 46.6 μL). The mixture was warmed to 80°C and stirred at this temperature for 5 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=3:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl-) as a light yellow solid 1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg, 70% yield). LC-MS: m/z[M+H] ⁺ 456.1.

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

Isopropylcarbamic acid ( cis , rac )-3-(2-methyl-1-toluenesulfonyl) in 1,4-dioxane (1.0 mL) and water (1.0 mL) at 25°C -To a solution of 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (150 mg, 329 μmol), KOH (554 mg, 9.88 mmol) was added. The mixture was warmed to 110°C and stirred at this temperature for 6 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=3:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(2-methyl- 1H -pyrrolo[2, 3- b ]pyridin-5-yl)cyclopentyl ester (32.0 mg, 30% yield). LC-MS: m/z[M+H] ⁺ 302.1.

Example 79

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

Isopropylcarbamic acid ( cis , rac )-3-(2-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl) in DCE (1.0 mL) at 25°C To a solution of cyclopentyl ester (25.0 mg, 82.9 μmol), NCS (12.1 mg, 91.2 μmol) was added. The mixture was stirred at this temperature for 0.5 hours, then it was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=3:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(3-chloro-2-methyl- 1H- ) as a light yellow solid. Pyrro[2,3- b ]pyridin-5-yl)cyclopentyl ester (2.10 mg, 7% yield). LC-MS: m/z[M+H] ⁺ 336.1.

Example 80

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

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

To a solution of 5-bromo-1 H -pyrrolo[2,3- b ]pyridine (5.00 g, 25.4 mmol) in DMF (30 mL) at 0 °C, NaH (1.22 g, 30.5 mmol, 60 % wt.%). The mixture was stirred at this temperature for 10 minutes, then 2-(chloromethoxy)ethyl-trimethyl-silane (6.35 g, 38.0 mmol, 6.74 mL) was added. The mixture was warmed to 25°C and stirred at this temperature for 17 hours. The reaction was quenched with aqueous _NH4Cl (120 mL) and extracted with EtOAc (25 mL×2). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 10% EtOAc in 20 min) to give 5-bromo-1-((2-(trimethyl) as a brown oil Silyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine (6.60 g, 79% yield). 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

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborate in 1,4-dioxane/H ₂ O = 5:1 (60 mL) at 25°C To a solution of heterocyclopentan-2-yl)cyclopent-2-en-1-one (5.72g, 27.5mmol), 5-bromo-1-((2-(trimethylsilyl)ethyl) was added sequentially Oxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine (3.00g, 9.17mmol), K ₂ CO ₃ (2.53g, 18.3mmol) and Pd(dppf)Cl ₂ ˙CH ₂ Cl ₂ (374mg, 458μmol). The mixture was warmed to 100°C and stirred at this temperature for 3 hours. The mixture was cooled to 25°C, diluted with brine (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 10% EtOAc in 20 min) to give 3-(1-((2-(trimethylsilica) as a yellow oil (yl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-2-en-1-one (2.50 g, 83% yield). 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) ring Pen-2-en-1-one

3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ] To a stirred solution of pyridin-5-yl)cyclopent-2-en-1-one (2.50 g, 7.61 mmol)), NaBH ₄ (432 mg, 11.4 mmol) was added in portions. The mixture was stirred at this temperature for 30 minutes, then another portion of NaBH4 (288 mg, 7.61 mmol) was added portionwise. The mixture was stirred at 0°C for 30 min, quenched with aqueous NaCl (50 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give ( rac )-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 as a brown oil H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-2-en-1-one (2.50 g, 99% yield), which was used in step one 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 )Cyclopent-1-ol (Intermediate 6)

( rac )-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ] Pyridin-5-yl) cyclopent-2-en-1-one (2.50 g, 7.56 mmol) was stirred to a stirred solution, and PtO ₂ (300 mg, 1.32 mmol) was added. The reaction mixture was stirred under hydrogen atmosphere (balloon) at 25°C for 17 hours. The reaction polymer was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 25% EtOAc in 15 min) to give ( cis , rac )-3-(1-((2 -(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (523 mg, 21% yield). 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 ]pyridine -5-yl)cyclopent-1-ol

( cis , rac )-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2, To a stirred solution of 3- b ]pyridin-5-yl)cyclopent-1-ol (550 mg, 1.65 mmol) was added n -BuLi (1.98 mL, 2.5 M in hexane, 4.95 mmol). The mixture was stirred at this temperature for 2 hours, then a solution of _I2 (756 mg, 2.98 mmol) in THF (15 mL) was added. The mixture was warmed to 25°C and stirred at this temperature for 1 hour. The mixture was quenched with saturated aqueous _NH4Cl (50 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 25% EtOAc in 15 min) to give ( cis , rac )-3-(2-iodo-1) as a yellow oil -((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (361 mg, 48% yield Rate). LC-MS: m/z[M+H] ⁺ 459.0.

Step 6: 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrole And[2,3- b ]pyridin-5-yl)cyclopentyl ester

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

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

1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(2-iodo-1-((2-(trimethylsilyl))ethyl) in _CH3CN (1.0 mL) at 25°C To a stirred solution of oxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (340mg, 615μmol), propyl-2-amine (529μL, 364mg , 6.15 mmol) and Et ₃ N (427 μL, 311 mg, 3.08 mmol). The mixture was heated to 70° C. and stirred at this temperature in a Schlenk pressure tube for 16 hours. The reaction was cooled, diluted with _H2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 10% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow solid (2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (300mg , 90% yield). LC-MS: m/z[M+H] ⁺ 544.1.

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

Isopropylcarbamic acid ( cis , rac )-3-(2-iodo _- 1-((( A stirred solution of 2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (50.0 mg, 91.9 μmol), Phenylboronic acid (33.7 mg, 276 μmol), K ₂ CO ₃ (38.1 mg, 276 μmol) and Pd(dppf)Cl ₂ ˙CH ₂ Cl ₂ (15.1 mg, 18.4 μmol) were added in sequence. The mixture was warmed to 100°C in a microwave oven and stirred at this temperature for 0.5 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EtOAc=3:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(2-phenyl-1-((2-(tri Methylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (30.0 mg, 66% yield). LC-MS: m/z[M+H] ⁺⁴ 494.2.

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

Isopropylcarbamic acid ( cis , rac )-3-(2-phenyl-1-((2-(trimethylsilyl))ethoxy in HCO ₂ H (2.0 mL) and methanol (1.0 mL) methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (30.0 mg, 60.8 μmol), the temperature was raised to 100°C and the Schlenk Stir in a pressure tube for 4 hours. The mixture is cooled and concentrated under reduced pressure. The residue is purified by pre-TLC (PE/EtOAc=3:1), dissolving out as _CH3CN in water (from 10% in 8 minutes to 20% CH ₃ CN) to obtain isopropylcarbamic acid ( cis , rac )-3-(2-phenyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl as a white solid ) Cyclopentyl ester (7.60 mg, 34% yield). LC-MS: m/z [M+H] ⁺ 364.2.

Example 81

Isopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -indazol-5-yl) -1H -pyrrolo[2,3- b ]pyridine-5- cyclopentyl ester

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

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

Step 2: Isopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -indazol-5-yl) -1H -pyrrolo[2,3- b ]pyridine -5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-(1-methyl- 1H -indazole-5-) in EtOH (2.0 mL) and HCl (2.0 mL, 2.0 M aq.) yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (25.0 mg, 45.6 μmol) solution was heated to 80°C and stirred at this temperature for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 45% to 75% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-(1- Methyl- 1H -indazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (2.50 mg, 13% yield). LC-MS: m/z[M+H] ⁺ 418.2.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 80 .

Example 95

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

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) at 25°C, Pd was added sequentially (dppf)Cl _{2 (} 71.3mg, 97.5μmol), AcOK (287mg, 2.93mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1,3,2-dioxaborane (371 mg, 1.46 mmol). The reaction mixture was warmed to 100°C and stirred at this temperature for 12 hours. The reaction mixture was cooled to 25°C, filtered and concentrated under reduced pressure to obtain (3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl)boronic acid (150 mg, 90%) as a brown oil yield), which was used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 171.2.

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

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

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

Isopropylcarbamic acid ( cis , rac )-3-(2-(3-(methoxymethyl)-1-methyl-1 H -pyrazole) in EtOH (2.0 mL) at 25°C -5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester ( 30.0 mg, 55.3 μmol) solution, add HCl (2.0 mL, 4.0 M aq.). The mixture was warmed to 80°C and stirred at this temperature for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 30% to 60% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-(3-) as a white solid (Methoxymethyl)-1-methyl-1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl isoester (5.20 mg , 23% yield). LC-MS: m/z[M+H] ⁺ 412.2.

Example 96 Isopropylcarbamate ( cis , rac )-3-(2-(1,1-dioxo-3,6-dihydro- 2H -thiopyran-4-yl) -1H -pyrrole [2,3- b ]pyridin-5-yl)cyclopentyl ester and Example 97 isopropylcarbamate ( cis , rac )-3-(2-(1,1-tetrahydrodioxide-2 H -Thiopyran-4-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

Step 1: Isopropylcarbamate ( cis , rac )-3-(2-(1,1-dioxy-3,6-dihydro- 2H -thiopyran-4-yl)-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-iodo-1-((2) in 1,4-dioxane (2.0 mL) and H ₂ O (0.50 mL) at 25°C -(Trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (157mg, 290μmol), add 4 in sequence -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H -thiopyran 1,1- Sulfur dioxide (50.0 mg, 193 μmol), Pd(dtbpf)Cl ₂ (25.0 mg, 38.7 μmol) and K ₂ CO ₃ (26.7 mg, 193 μmol). The reaction mixture was warmed to 100°C in a microwave oven and stirred at this temperature for 3 hours. The reaction mixture was cooled and 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 _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 52% EtOAc in 20 minutes) to obtain orange gum isopropylcarbamic acid ( cis , rac )-3 -(2-(1,1-dioxo-3,6-dihydro-2 H -thiopyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (100 mg, 94% yield). LC-MS: m/z[M+H] ⁺ 548.2.

Step 2: Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-dioxy-3,6-dihydro- 2H -thiopyran-4-yl) -1H -pyrrole And[2,3- b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-dioxo-3,6-dihydro- 2H ) in HCO ₂ H (1.0 mL) and MeOH (0.5 mL) -Thiopyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentan A solution of the ester (25.0 mg, 45.6 μmol) was heated to 100° C. and stirred at this temperature for 6 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution with CH ₃ CN from 0% to 52% in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-( 1,1-dioxo-3,6-dihydro-2 H -thiopyran-4-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (3.10 mg , 16% yield). LC-MS: m/z[M+H] ⁺ 418.2.

Step 3: Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-tetrahydrodioxide- 2H -thiopyran-4-yl)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-dioxo-3,6-dihydro- 2H -thiopyran-) in MeOH (5.0 mL) at 25°C 4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (50.0 mg, 91.2 μmol) solution, add Pd/C (9.71 mg, 9.12 μmol, 10% wt.%). The reaction mixture was stirred at this temperature for 2 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-dioxotetrahydro- 2H -thiopyran-4-yl)-1-( as a yellow oil) (2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (45.0 mg, 89% yield). LC-MS: m/z[M+H] ⁺ 550.2.

Step 4: Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-tetrahydrodioxide- 2H -thiopyran-4-yl) -1H -pyrrolo[2,3 - b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(2-(1,1-dioxotetrahydro- 2H -thiopyran-4) in HCO2H ( _1.0mL ) and MeOH (0.50mL) -yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg , 72.7 μmol) solution, heated to 100°C and stirred at this temperature for 6 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 26% to 100% CH ₃ CN in 8 min) to afford isopropylcarbamate ( cis , rac )-3-(2-(1, 1-Tetrahydrodioxide- 2H -thiopyran-4-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (10.6 mg, 34% yield). LC-MS: m/z[M+H] ⁺ 420.2.

The following compounds were prepared using similar procedures as disclosed in Synthetic Examples 96 or 97 .

Example 104

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

N -isopropylcarbamate [( cis , rac )-3-[2-iodo-1-(2-trimethylsilylethoxymethyl)pyrrole in EtOH (1.0 mL) at 25°C To a solution of [2,3- b ]pyridin-5-yl]cyclopentyl ester] (40.0 mg, 73.6 μmol), HCl (1.0 mL, 3.0 M aq.) was added. The mixture was warmed to 100°C and stirred at this temperature for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 37% to 95% _CH3CN in 10 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-chloro-1) as a white solid H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (7.00 mg, 29% yield). LC-MS: m/z[M+H] ⁺ 322.1.

Example 105

Isopropylcarbamic acid ( cis , rac )-3-(2-iodo- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester .

N-isopropylcarbamate [( cis , rac )-3-[2-iodo-1-(2-trimethylsilylethoxy) in HCO ₂ H (1.0 mL) and MeOH (1.0 mL) A mixture of methyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl] ester (40.0 mg, 73.0 μmol) was warmed to 100° C. and stirred at this temperature for 2 hours. The reaction was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 37% to 95% _CH3CN in 10 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-iodo-1) as a white solid H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (2.00 mg, 7% yield). LC-MS: m/z[M+H] ⁺ 414.0.

Example 106

Isopropylcarbamic acid ( cis , rac )-3-(2-(1-isopropyl-1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridine-5 -yl)cyclopentylisopropylcarbamatepyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

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

Isopropylcarbamic acid ( cis , rac )-3-(2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) in THF (10 mL) at 25°C -1H -pyrrolo[2,3- b ]pyridin-5-yl) cyclopentyl ester (75.0 mg, 138 μmol) suspension, add Et ₃ N (69.8 mg, 690 μmol, 96.2 μL) and acetylene in sequence Trimethylsilane (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). The mixture was warmed to 70°C and stirred at this temperature for 12 hours. 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 _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow oil (1-((2-(trimethylsilyl)ethoxy)methyl)-2-((trimethylsilyl)ethynyl)-1 H -pyrrolo[2,3- b ]pyridine- 5-yl)cyclopentyl ester (62.0 mg, 87% yield). LC-MS: m/z[M+H] ⁺ 514.3.

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

Isopropylcarbamic acid ( cis , rac )-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-2- in MeOH (2.0 mL) at 25°C To a solution of ((trimethylsilyl)ethynyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (60.0 mg, 117 μmol), K ₂ CO ₃ (48.4 mg, 350 μmol). The reaction mixture was stirred at this temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x 2). The mixture was washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 15% EtOAc in 20 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow oil (2-ethynyl-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester ( 45.0 mg, 87% yield). LC-MS: m/z[M+H] ⁺ 442.2.

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

Isopropylcarbamic acid ( cis , rac )-3-(2-ethynyl-1-((2-(trimethyl)) in DMF (0.40 mL) and Et ₃ N (2.0 mL) at 25°C To a suspension of silyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (45.0 mg, 101 μmol), 5-iodo- 1-Methyl- 1H -pyrazole e (15.0 mg, 72.1 μmol), Pd(PPh ₃ ) ₂ Cl ₂ (7.59 mg, 10.8 μmol) and CuI (2.06 mg, 10.8 μmol). The suspension was warmed to 70° C. and stirred at this temperature for 2 hours. The mixture was cooled, diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 12% EtOAc in 20 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow oil (2-((1-Methyl-1 H -pyrazol-5-yl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo [2,3- b ]pyridin-5-yl)cyclopentyl ester (42.0 mg, 70% yield). LC-MS: m/z[M+H] ⁺ 552.2.

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

Isopropylcarbamic acid ( cis , rac )-3-(2-((1-methyl-1 H -pyrazol-5-yl)ethynyl)- in methanol (1.00 mL) at 25°C 1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (40.0 mg, 76.7 μmol) solution, add formic acid (2.0 mL). The mixture was warmed to 100°C and stirred at this temperature for 16 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 50% to 100% CH ₃ CN in 15 min) to give isopropylcarbamic acid ( cis , rac )-3-(2-((1 -Methyl- 1H -pyrazol-5-yl)ethynyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (1.50 mg, 5% yield). LC-MS: m/z[M+H] ⁺ 392.2.

Example 107

Isopropylcarbamic acid ( cis , rac )-3-(2-(N-morpholinylmethyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

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

Isopropylcarbamate ( cis , rac )-3-(2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) in MeOH (4.0 mL) at 25°C )-1 H -pyrrolo[2,3- b ]pyridin-5-yl) cyclopentyl ester (200 mg, 353 μmol) solution, add Pd(dppf)Cl ₂ (103 mg, 141 μmol) and Et ₃ N in sequence (4.0mL). The reaction mixture was warmed to 70°C and stirred at this temperature for 5 hours under a CO atmosphere (balloon). The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc/PE over 15 minutes (from 0% to 30% EtOAc) to give ( cis , rac )-5-(3-(iso Propylaminemethyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine- 2-Carboxylic acid methyl ester (200 mg, 95% yield). LC-MS: m/z[M+H] ⁺ 476.2.

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

( cis , rac )-5-[3-(isopropylaminemethyloxy)cyclopentyl]-1-(2-trimethylsilylethoxy) in THF (5.0 mL) at 0°C To a solution of methyl)pyrrolo[2,3- b ]pyridine-2-carboxylate (88.0 mg, 185 μmol), LiAlH ₄ (370 μL, 370 μmol, 1.0 M in THF) was added. The reaction mixture was stirred at this temperature for 1 hour, then it was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure to obtain N -isopropylcarbamic acid ( cis , rac )-[3-[2-(hydroxymethyl)-1-(2-trimethylsilylethoxymethyl) as a colorless oil )pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (80.0 mg, 96% yield). LC-MS: m/z[M+H] ⁺ 448.3.

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

N -isopropylcarbamate ( _cis , rac )-3-[2-(hydroxymethyl)-1-(2-trimethylsilyl ) in _CH2Cl2 (3.0 mL) at 25°C To a solution of ethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (80.0 mg, 179 μmol), add Et ₃ N (54.3 mg, 536 μmol, 74.7 μL) and methanesulfonate Chloride (30.7 mg, 268 μmol, 20.8 μL). The reaction mixture was stirred at this temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain N -isopropylcarbamic acid ( cis , rac )-[3-[2-(chloromethyl)-1-(2-trimethylsilylethoxymethyl)) as a yellow oil Pyrro[2,3- b ]pyridin-5-yl]cyclopentyl ester] (80.0 mg, 96% yield), which was used in step one without further purification. LC-MS: m/z[M+H] ⁺ 466.1.

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

N -isopropylcarbamate ( cis , rac )-[3-[2-(chloromethyl)-1-(2-trimethylsilylethoxy) in DCM (4.0 mL) at 25°C To a solution of methyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (80.0 mg, 172 μmol), add Et ₃ N (52.1 mg, 515 μmol, 71.8 μL) and morpholine (22.4 mg, 257 μmol, 22.5 μL). The reaction mixture was stirred at this temperature for 1 hour, then it was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc/PE over 10 minutes (from 0% to 20% EtOAc) to give N -isopropylcarbamic acid ( cis , rac )- as a colorless oil [3-[2-(N-morpholinylmethyl)-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester ] (75.0 mg, 84% yield). LC-MS: m/z[M+H] ⁺ 517.2.

Step 5: Isopropylcarbamic acid ( cis , rac )-(1 R ,3 S )-3-(2-(N-morpholinomethyl)-1 H -pyrrolo[2,3- b ] Pyridin-5-yl)cyclopentyl ester

N -isopropylcarbamic acid ( cis , rac )-[3-[2-(N-morpholinomethyl)-1-(2-trimethyl) in MeOH (1.5 mL) at 25°C To a solution of silylethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (70.0 mg, 135 μmol), formic acid (3.0 mL) was added. The reaction mixture was warmed to 100°C and stirred at this temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (from 15% to 100% _CH3CN in 8 min) to give N -isopropylcarbamic acid ( cis , rac )-[3-[2- (N-morpholinylmethyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl ester] (14.5 mg, 28% yield). LC-MS: m/z[M+H] ⁺ 387.2.

Example 108

Isopropylcarbamic acid ( cis , rac )-3-(2-(dimethylaminomethyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

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

( cis , rac )-Methyl 5-(3-((isopropylaminemethyl)oxy)cyclopentyl)-1 in MeOH (1.0 mL) and THF (1.0 mL) at 25°C To a solution of -((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine-2-carboxylate (80.0 mg, 168 μmol), add NaOH (757 μL, 2.0 M in H ₂ O). The reaction mixture was stirred at this temperature for 2 hours and then diluted with water (20 mL). The mixture was acidified with HCl (2.0M) aqueous solution to pH=4, and then extracted with CH ₂ Cl ₂ (50 mL×2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure to obtain ( cis , rac )-5-[3-(isopropylaminemethanoyloxy)cyclopentyl]-1-(2-trimethylsilylethoxymethyl) as a white solid Pyrro[2,3- b ]pyridine-2-carboxylic acid (75.0 mg, 96% yield). LC-MS: m/z[M+H] ⁺ 462.2.

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

( cis , rac )-5-(3-((isopropylaminemethyl)oxy)cyclopentyl)-1-((2-(trimethyl)) in THF (4.0 mL) at 25°C To a solution of silyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridine-2-carboxylic acid (60.0 mg, 130 μmol), HATU (74.1 mg, 195 μmol), and Dimethylamine (29.3 mg, 650 μmol, 37.8 μL) and DIPEA (84.0 mg, 650 μmol, 113 μL). The reaction mixture was stirred at this temperature for 2 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE over 15 minutes (from 0% to 50% EtOAc) to give isopropylcarbamate ( cis , rac )-3- as a white solid (2-(Dimethylaminoformyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine-5- cyclopentyl ester (60.0 mg, 94% yield). LC-MS: m/z[M+H] ⁺ 397.1.

Step 3: Isopropylcarbamic acid ( cis , rac )-3-(2-(dimethylaminomethanoyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentan base ester

N -Isopropylcarbamate ( cis , rac )-[3-[2-(dimethylaminoformyl)-1-(2-trimethyl) in MeOH (1.0 mL) at 25°C To a solution of silylethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl] ester (30.0 mg, 61.4 μmol), HCO ₂ H (2.0 mL) was added. The reaction mixture was warmed to 100°C and stirred at this temperature for 5 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 0% to 100% _CH3CN in 8 min) to give N -isopropylcarbamic acid ( cis , rac )-[3-[2- (Dimethylaminoformyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl]cyclopentyl] ester (12.0 mg, 54% yield). LC-MS: m/z[M+H] ⁺ 359.2.

The following compounds were prepared using similar procedures disclosed in Synthetic Example 108 .

Example 113

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

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

5-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridine (6.00 g, 17.0 mmol) in dioxane (100 mL) and water (20 mL) at 25°C. solution, add 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one ( 10.6g, 51.2mmol), K ₂ CO ₃ (7.08g, 51.2mmol) and Pd(dppf)Cl ₂ (1.25g, 1.71mmol). The mixture was warmed to 100°C in a microwave oven and stirred at this temperature for 2 hours. The reaction mixture was cooled to 25°C, diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 15 min) to give 3-[1-(p-toluenesulfonyl)pyrrole as a yellow solid And[2,3- b ]pyridin-5-yl]cyclopent-2-en-1-one (5.00 g, 83% yield). LC-MS: m/z[M+H] ⁺ 353.0.

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

3-[1-( p -toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopent-2-en-1-one in THF (50 mL) at -60°C (3.00g, 8.51mmol) was stirred to a stirred solution, and LiBHEt ₃ (1.80g, 17.0mmol) was added. The resulting mixture was warmed to 25°C and stirred at this temperature for 2 hours. The reaction was diluted with water (100 mL) and extracted with EtOAc (120 mL x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to obtain ( rac )-3-[1-( p -toluenesulfonyl)pyrrolo[2,3- b ]pyridine-5 _as a yellow solid -yl]cyclopent-2-en-1-one (2.50 g, 82% yield). LC-MS: m/z[M+H] ⁺ 355.1.

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

( rac )-3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopent-2-en- in MeOH (50 mL) at 25°C. To a stirred solution of 1-one (2.50 g, 7.05 mmol), PtO ₂ (320 mg, 1.41 mmol) was added. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (balloon) at this temperature for 16 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 45% to 75% _CH3CN in 8 min) to give ( cis , rac )-3-(1 as a yellow solid -Tosyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (600 mg, 25% yield). LC-MS: m/z[M+H] ⁺ 357.1.

Step 4: 1H -imidazole-1-carboxylic acid ( cis , rac )-3-(1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

( cis , rac )-3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentanol (200 mg) in DCM (10 mL) at 25°C , 561 μmol) to a stirred solution, add Et ₃ N (283 mg, 2.81 mmol, 391 μL) and CDI (272 mg, 1.68 mmol) in sequence. The mixture was stirred at this temperature for 2 hours, and then it was concentrated under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(1-toluenesulfonyl-1 H -pyrrolo[ 2,3- b ]pyridin-5-yl)cyclopentyl ester (250 mg, 95% yield). LC-MS: m/z[M+H] ⁺ 451.0.

Step 5: Isopropylcarbamate ( rac )-( 1R , 3S )-3-(1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl) ring Amyl ester

Imidazole-1-carboxylic acid ( cis , rac )-[3-[1-( p -toluenesulfonyl )pyrrolo[2,3- b ]pyridine in CH ₃ CN (5.0 mL) at 25 °C To a stirred solution of -5-yl]cyclopentyl ester] (200 mg, 443 μmol), add propyl-2-amine (262 mg, 4.44 mmol, 379 μL). The mixture was warmed to 80°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 80% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow solid (1-Toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (180 mg, 92% yield). LC-MS: m/z[M+H] ⁺ 442.2.

Step 6: Isopropylcarbamic acid ( cis , rac )-3-(3-bromo-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl in DCE (10 mL) at 25°C ) to a solution of cyclopentyl ester (600 mg, 1.36 mmol), NBS (242 mg, 1.36 mmol) was added. The reaction mixture was warmed to 60°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 37% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a white solid (3-Bromo-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (620 mg, 88% yield). LC-MS: m/z[M+H] ⁺ 520.0.

Step 7: Isopropylcarbamic acid ( cis , rac )-3-(3-phenyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentan base ester

Isopropylcarbamic acid ( cis , rac )-3-(3-bromo-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridine- in dioxane (2.0 mL) To a solution of 5-yl)cyclopentyl ester (50.0 mg, 96.1 μmol), phenylboronic acid (23.2 mg, 192 μmol), Pd(dppf)Cl ₂ (14.1 mg, 19.2 μmol), and K ₂ CO ₃ ( 40.4 mg, 288 μmol) and H ₂ O (0.40 mL). The reaction mixture was warmed to 100°C and extracted with DCM (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by flash column chromatography with EtOAc/PE (from 0% to 27% EtOAc in 10 min) to give isopropylcarbamic acid ( cis , rac )- as a yellow solid 3-(3-phenyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (41.0 mg, 82% yield). LC-MS: m/z[M+H] ⁺ 518.2.

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

Isopropylcarbamic acid ( cis , rac )-3-(3-phenyl-1-toluenesulfonyl- 1H -pyrrolo[2,3- b] in MeOH (1.5 mL) at 25°C To a solution of pyridin-5-yl)cyclopentyl ester (35.0 mg, 67.6 μmol), NaOH (22.0 mg, 541 μmol) in H ₂ O (0.10 mL) was added. The reaction mixture was warmed to 75°C and stirred at this temperature for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 55% to 100% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(3-phenyl- 1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (8.2 mg, 33% yield). LC-MS: m/z[M+H] ⁺ 364.2.

The following compounds were prepared using similar procedures disclosed in Synthesis Example 113 .

Example 130

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

Step 1: 1H -imidazole-1-carboxylic acid ( cis , rac )-3-(1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

( cis , rac )-3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentanol (700 mg) in DCM (10 mL) at 25°C , 1.96mmol) solution, add Et ₃ N (993mg, 9.82mmol, 1.37mL) and CDI (955mg, 5.89mmol) in sequence. The reaction mixture was warmed to 35°C and stirred at this temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a brown oil of imidazole-1-carboxylic acid ( cis , rac )-[3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl] Cyclopentyl ester] (880 mg, 99% yield), which was used in one step without further purification. LC-MS: m/z[M+H] ⁺ 451.1

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

Imidazole-1-carboxylic acid ( cis , rac )-[3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridine- in _CH3CN (10 mL) at 25°C To a solution of 5-yl]cyclopentyl ester] (880 mg, 1.95 mmol), propyl-2-amine (1.73 g, 29.3 mmol, 2.51 mL) and Et ₃ N (988 mg, 9.77 mmol, 1.36 mL) were added sequentially. The reaction mixture was warmed to 70°C and stirred at this temperature for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-(1) as a white solid R ,3 S )-3-(1-toluenesulfonyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (700 mg, 81% yield). LC-MS: m/z[M+H] ⁺ 442.1.

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

_{Isopropylcarbamic} acid ( cis , rac )-3-(1-toluenesulfonyl- 1H -pyrrolo[2, To a solution of 3- b ]pyridin-5-yl)cyclopentyl ester (100 mg, 226 μmol), KOH (127 mg, 2.26 mmol) was added. The reaction mixture was warmed to 110°C and stirred at this temperature for 16 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 10% to 100% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-( 1H -pyrrolo) as a white solid [2,3- b ]pyridin-5-yl)cyclopentyl ester (35.0 mg, 53% yield). LC-MS: m/z[M+H] ⁺ 288.1.

Example 131

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

N -isopropylcarbamic acid ( cis , rac )-[3-( 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopenta in DCM (2.0 mL) at 25°C ester] (10.0 mg, 34.8 μmol), NBS (6.81 mg, 38.2 μmol) was added. The reaction mixture was stirred at this temperature for 2 hours, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 55% to 100% _CH3CN in 8 min) to give N -isopropylcarbamic acid ( cis , rac )-[3-(3- Bromo- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester] (4.00 mg, 31% yield). LC-MS: m/z[M+H] ⁺ 366.0.

Example 132

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

N -isopropylcarbamic acid ( cis , rac )-( 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester in _CHCl3 (2.0 mL) at 25°C ] (30.0 mg, 104 μmol) solution, add NCS (13.9 mg, 104 μmol). The reaction mixture was warmed to 60°C and stirred at this temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 55% to 100% _CH3CN in 8 min) to give N -isopropylcarbamic acid ( cis , rac )-[3-(3- Chloro- 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester] (18.3 mg, 54% yield). LC-MS: m/z[M+H] ⁺ 322.2.

Example 133

Isopropylcarbamic acid ( cis , rac )-3-(4-fluoro-2-(1-methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ] Pyridin-5-yl)cyclopentyl ester

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-1 H -pyrrolo[2,3- b ]pyridine (900 mg, 4.19 mmol) in THF (30 mL) at 0 °C was added KHMDS (5.44 mL, 1.0 M , 5.44mmol) The mixture was stirred at this temperature for 10 minutes, and SEMCl (1.05g, 6.28mmol, 1.11mL) was added. The mixture was warmed to 25°C and stirred at this temperature for 2 hours. The mixture was diluted with aqueous _NH4Cl (50 mL) and quenched with EtOAc (30 ml x 3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 10% EtOAc in 20 min) to give 5-bromo-4-fluoro-1-((2- (Trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine (1.20 g, 83% yield). 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) ring Pen-2-en-1-one

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborate in 1,4-dioxane/H ₂ O = 5:1 (60 mL) at 25°C To a stirring solution of heterocyclopentan-2-yl)cyclopent-2-en-1-one (1.99g, 9.56mmol), 5-bromo-4-fluoro-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine (1.10g, 3.19mmol), Pd(dppf)Cl ₂ (260mg, 0.32mmol) and Na ₂ CO ₃ (675mg, 6.37mmol). The mixture was warmed to 80°C and stirred at this temperature for 3 hours. The mixture was cooled to 25°C, diluted with brine (200 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were dried over _Na2SO4 and concentrated under _reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 30% EtOAc 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) . 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)cyclopent-1-ol

3-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ] Pyridin-5-yl) cyclopent-2-en-1-one (760 mg, 2.19 mmol) was stirred to a stirred solution, to which NaBH ₄ (498 mg, 13.2 mmol) and NiCl ₂ (28.4 mg, 0.220 mmol) were added sequentially. The mixture was stirred at this temperature for 30 minutes and then quenched with aqueous NaCl (50 mL). The mixture was extracted with EtOAc (25 mL×3). The combined organic layers were dried _, filtered over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 40% EtOAc in 20 min) to give ( cis + trans , rac )-3-(4-fluoro) as a yellow oil -1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (600 mg, 78 % yield). 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)cyclopent-1-ol

( cis + trans , rac )-3-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H in THF (40 mL) at -65°C To a solution of -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (400 mg, 1.14 mmol), n -BuLi (1.42 mL, 2.4 M in hexane, 3.42 mmol) was added. The mixture was stirred at -65°C for 6 minutes, then a solution of iodine (579 mg, 2.28 mmol) in THF was added. The mixture was warmed to 25°C and stirred at this temperature for 2 hours. The mixture was quenched with aqueous Na ₂ S ₂ O ₃ (500 mL), and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 minutes) to give ( cis + trans , rac )-3-(4-fluoro) as a brown oil -2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (310 mg, 57% yield) ( cis + trans , rac )-3-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[ 2,3- b ]pyridin-5-yl)cyclopent-1-ol (600 mg, 78% yield). 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)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol

( cis + trans , rac )-3-(4-fluoro-2-iodo-1-((2-(trimethyl)) in dioxane/H ₂ O = 5:1 (10 mL) at 25°C To a solution of silyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (300mg, 629μmol), K ₂ CO ₃ was added sequentially (261mg, 1.89mmol), Pd(dppf)Cl ₂ (103mg, 126μmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Cyclopentan-2-yl) -1H -pyrazole (393 mg, 1.89 mmol). The mixture was warmed to 100°C in a microwave oven and stirred at this temperature for 0.5 hours. The mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 min) to give ( cis + trans , rac )-3-(4-fluoro) as a yellow oil -2-(1-Methyl-1 H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3 - b ]pyridin-5-yl)cyclopent-1-ol (152 mg, 56% yield). LC-MS: m/z[M+H] ⁺ 431.2.

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

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

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

Carbonic acid ( cis + trans , rac )-3-(4-fluoro-2-(1-methyl-1 H -pyrazol-5-yl)-1- in CH ₃ CN (10 mL) at 25 °C ((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (4-nitrophenyl ester) (230 mg, 309 μmol) solution, add propyl-2-amine (183 mg, 3.09 mmol, 264 μL) and DIPEA (120 mg, 927 μmol, 161 μL) in sequence. The mixture was warmed to 80°C and stirred at this temperature for 16 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 30% EtOAc in 20 minutes) to give isopropylcarbamic acid ( cis + trans , rac )- as a yellow oil 3-(4-fluoro-2-(1-methyl-1 H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H - Pyrro[2,3- b ]pyridin-5-yl)cyclopentyl ester (120 mg, 75% yield). LC-MS: m/z[M+H] ⁺ 516.2.

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

Isopropylcarbamate ( cis + trans , rac )-3-(4-fluoro-2-(1-methyl-1 H -) in 1,4-dioxane (5.0 mL) at 25°C Pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl To a solution of the ester (110 mg, 213 μmol), HCl (5.0 mL, 4.0 M in 1,4-dioxane) and H ₂ O (5.0 ml) were added sequentially. The mixture was stirred at this temperature for 48 hours, then it was concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 30% to 60% _CH3CN in 8 min) and further by SFC (Daicel CHIRALCEL OZ column, CO2/MeOH=85/15, MeOH containing 0.2% NH3, 2.0ml/min, 35℃) to obtain yellow solid isopropylcarbamic acid ( cis , rac )-3-(4-fluoro-2-(1-methyl- 1H -pyrazole-5- (21.8 mg, 27% yield ) . LC-MS: m/z[M+H] ⁺ 386.2.

Example 134

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

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

( cis , rac )-3-[1-(p-toluenesulfonyl)pyrrolo[2,3- b ]pyridin-5-yl]cyclopentanol (700 mg) in DMF (15 mL) at 0°C , 1.96mmol) solution, add NaH (202mg, 5.05mmol, 60% wt.%). The mixture was stirred at this temperature for 1 hour, then 2-(chloromethoxy)ethyl-trimethyl-silane (972 mg, 5.83 mmol, 1.03 mL) was added. The mixture was stirred at 0°C for 10 min, then quenched with water (50 mL) and extracted with EtOAc (20 mL×2). The combined layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE over 15 min (from 0% to 70% EtOAc) to give 5-bromo-4-chloro-1-((2- (Trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine (1.26 g, 89% yield). 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) ring Pen-2-en-1-one

5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H in dioxane (15 mL) and water (2.5 mL) at 25°C -To a solution of pyrrolo[2,3- b ]pyridine (1.33g, 3.68mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane was added sequentially Cyclopent-2-yl)cyclopent-2-en-1-one (1.53 g, 7.35 mmol), K ₂ CO ₃ (1.52 g, 11 mmol) and Pd(dppf)Cl ₂ (300 mg, 367 μmol). The mixture was warmed to 80°C and stirred at this temperature for 4 hours. The mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE over 20 min (from 0% to 7% EtOAc) to give 3-(4-chloro-1-((2-() as a yellow solid Trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-2-en-1-one (680 mg, 50% yield) . 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)cyclopent-1-ol

3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ] Pyridin-5-yl) cyclopent-2-en-1-one (680 mg, 1.87 mmol) was added to a solution of NiCl ₂ (24.2 mg, 187 μmol) and NaBH ₄ (425 mg, 11.2 mmol) in sequence. The mixture was stirred at this temperature for 30 minutes, then quenched with water (4.0 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)- as a yellow oil 1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (301 mg, 43% yield). 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)cyclopent-1-ol

3-(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3] in THF (4.0 mL) at -65°C - To a solution of b ]pyridin-5-yl)cyclopent-1-ol (250 mg, 681 μmol), was added n -BuLi (0.85 mL, 2.4 M in hexane, 2.04 mmol). The mixture was stirred at -65°C for 1 hour, then _I2 (345 mg, 1.36 mmol) was added. The mixture was warmed to 25°C and stirred at this temperature for 1 hour. The mixture was quenched with aqueous _NH4Cl (4.0 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (from 85% to 90% _CH3CN in 7 min) to give ( cis , rac )-3-(4-chloro-2-iodo-1-( (2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (80.0 mg, 23% yield ). LC-MS: m/z[M+H] ⁺ 493.0.

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

( cis , rac )-3-(4-chloro-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- in THF (4.0 mL) at 25°C To a stirred solution of 1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (25.0 mg, 50.7 μmol), DIPEA (32.7 mg, 253 μmol, 44.1 μL) and CDI were added in sequence. (24.6 mg, 152 μmol). The mixture was warmed to 40°C and stirred at this temperature for 16 hours. The mixture was cooled down and dissolved under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(4-chloro-2-iodo-1-((2-(trimethylsilica)) as a yellow oil (yl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (28.0 mg, 56% yield), which was used directly without further purification Next step. LC-MS: m/z[M+H] ⁺ 587.0.

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

1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(4-chloro-2-iodo-1-((2-(trimethylsilyl)) in acetonitrile (1.0 mL) at 25°C )ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (25.0mg, 42.6μmol) solution, isopropylamine (50.3mg, 851 μmol, 73.1 μL) and DIPEA (16.5 mg, 127 μmol, 17.5 μL). The mixture was warmed to 80°C and stirred at this temperature for 5 hours. The mixture was cooled and dissolved under reduced pressure to obtain a light yellow solid of isopropylcarbamic acid ( cis , rac )-3-(4-chloro-2-iodo-1-((2-(trimethylsilyl)ethyl)ethyl). Oxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (15.0 mg, 61% yield), which was used in step one without further purification. LC-MS: m/z[M+H] ⁺ 579.0.

Step 7: Isopropylcarbamic acid ( cis , rac )-3-(4-chloro-2-(1-methyl- 1H -pyrazol-5-yl)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(4-chloro-2-iodo-1-() in 1,4-dioxane (4.0 mL) and water (2.0 mL) at 25°C A solution of (2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (60.0 mg, 103 μmol), (2-methylpyrazol-3-yl)boronic acid (26.1 mg, 207 μmol), Pd(dppf)Cl ₂ (8.48 mg, 10.3 μmol) and K ₂ CO ₃ (43.0 mg, 311 μmol) were added sequentially. The mixture was warmed to 80°C and stirred at this temperature for 3 hours. The mixture was cooled to 25°C, diluted with brine (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over _Na2SO4 and concentrated under _reduced pressure. The residue was purified by prep-TLC (PE:EtOAc=3:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(4-chloro-2-(1-methyl-1) as a yellow solid H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) ring Pentyl ester (28.0 mg, 50% yield). LC-MS: m/z[M+H] ⁺ 532.2.

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

Isopropylcarbamate ( cis , rac )-3-(4-chloro-2-(1-methyl-1H-) in methanol (1.0 mL) and formic acid (51.8 mg, 1.13 mmol, 42.5 μL ) Pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl A solution of the ester (30.0 mg, 56.3 μmol) was warmed to 100°C and stirred at this temperature for 6 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (from 30% to 100% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac )-3-(4-chloro-2) as a yellow solid -(1-Methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (11.4 mg, 50% yield). LC-MS: m/z[M+H] ⁺ 402.1.

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

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

To a stirred solution of 2-bromo-5 H -pyrrolo[2,3- b ]pyrazine (2.00 g, 10.1 mmol) in THE (25 mL) at 0 °C was added NaH (1.62 g, 40.4 mmol, 60 % wt.%). The mixture was stirred at this temperature for 30 minutes, then 2-(chloromethoxy)ethyl-trimethyl-silane (5.05 g, 30.3 mmol, 5.36 mL) was added. The reaction mixture was warmed to 25°C and stirred at this temperature for 12 hours. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 50% EtOAc in 15 min) to give 2-bromo-5-((2-(trimethyl) as a yellow oil Silyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazine (3.30 g, 99% yield). 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

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

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

3-[5-(2-Trimethylsilylethoxymethyl)pyrrolo[2,3- b ]pyrazin-2-yl] in methanol (20 mL) and DCM (20 mL) at 0°C. To a stirred solution of cyclopent-2-en-1-one (2.70 g, 8.20 mmol), NaBH ₄ (930 mg, 24.6 mmol) was added. The mixture was warmed to 25°C and stirred at this temperature for 5 hours. The mixture was quenched with saturated aqueous _NaHCO3 (100 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 min) to give ( cis,rac )-3-(5-((2 -(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopent-1-ol (1.50 g, 55% yield) . 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 ]pyra Azin-2-yl)cyclopent-1-ol and ( cis , rac )-3-(7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H - Pyrro[2,3- b ]pyrazin-2-yl)cyclopent-1-ol

( cis , rac )-3-(5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2, To a solution of 3- b ]pyrazin-2-yl)cyclopent-1-ol (1.50 g, 4.50 mmol) was added n-BuLi (3.75 mL, 2.4 M in THF, 9.00 mmol). The reaction mixture was stirred at this temperature for 1 hour, then _I2 (1.48g, 5.85mmol) was added. The reaction mixture was warmed to 0°C and stirred at this temperature for 1 hour. The mixture was quenched with saturated aqueous _NaHCO3 (80 mL) and extracted with EtOAc (80 mL×2). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 20 min) to give ( cis , rac )-3-(6-iodo-5) as a yellow oil -((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopent-1-ol and ( cis , rac )-3-(7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl) ring Pentan-1-ol (mixture, 200 mg, 10% yield). LC-MS: m/z[M+H] ⁺ 460.1.

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

( cis , rac )-3-(6-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo in DCM (10 mL) at 20 °C [2,3- b ]pyrazin-2-yl) cyclopent-1-ol and ( cis , rac )-3-(7-iodo-5-((2-(trimethylsilyl))ethoxy )Methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopent-1-ol (200mg, 435 μmol) solution, add DIPEA (281mg, 2.18mmol, 379μL) in sequence ) and CDI (212mg, 1.31mmol). The mixture was warmed to 35°C and stirred at this temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(6-iodo-5-((2-(trimethylsilyl)ethoxy)methyl) as a yellow gum base)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl) cyclopentyl ester and 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(7-iodo-5 -((2-(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester (mixture, 230 mg), which Used directly in the next step without further purification. LC-MS: m/z[M+H] ⁺ 544.0.

Step 6: Isopropylcarbamic acid ( cis , rac )-3-(6-iodo-5-((2-(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2 ,3- b ]pyrazin-2-yl)cyclopentyl ester and isopropylcarbamic acid ( cis , rac )-3-(7-iodo-5-((2-(trimethylsilyl)ethyl)ethyl Oxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester

1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(6-iodo-5-((2-(trimethylsilyl))ethyl) in _CH3CN (8.0 mL) at 25°C Oxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl) cyclopentyl ester and 1 H -imidazole-1-carboxylic acid ( cis , rac )-3-(7 -Iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester (230 mg) To the solution, add propyl-2-amine (1.34g, 22.6mmol, 2.00mL) and DIPEA (1.48g, 11.5mmol, 2.00mL) in sequence. The reaction mixture was warmed to 80°C and stirred at this temperature for 15 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=1:1) to obtain isopropylcarbamic acid ( cis , rac )-3-(6-iodo-5-((2-(trimethyl)) as a yellow oil Silyl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester and isopropylcarbamate ( cis,rac )-3- (7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester ( mixture, 160 mg, 71% yield). LC-MS: m/z[M+H] ⁺ 545.1.

Step 7: Isopropylcarbamic acid ( cis , rac )-3-(6-(1-methyl- 1H -pyrazol-5-yl)-5-((2-(trimethylsilyl)) Ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester and isopropylamine Formic acid ( cis , rac )-3-(7-(1-methyl- 1H -pyrazol-5-yl)-5-((2-(trimethylsilyl)ethoxy)methyl) -5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentylisopropylcarbamate

Isopropylcarbamate ( cis , rac )-3-(6-iodo-5-((2-(trimethylsilica)) in 1,4-dioxane (5.0 mL) and water (0.20 mL) (yl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester and isopropylcarbamic acid ( cis , rac )-3-(7 -Iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester (60.0 mg , 110 μmol) solution, sequentially add 1-methyl-5-(4,4,5,5-ttetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Azole (45.9 mg, 220 μmol), Pd(dppf)Cl ₂ (16.1 mg, 22.0 μmol) and K ₂ CO ₃ (45.7 mg, 331 μmol). The mixture was warmed to 100°C and stirred at this temperature for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 15 minutes) to give isopropylcarbamic acid ( cis , rac )-3- as a yellow oil (6-(1-Methyl-1 H -pyrazol-5-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5 H -pyrrolo[2,3 - b ]pyrazin-2-yl) cyclopentyl ester and isopropylcarbamic acid ( cis , ra-c ) 3-(7-(1-methyl-1 H -pyrazol-5-yl)- 5-((2-(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester (mixture, 50.0 mg, 91% yield). LC-MS: m/z[M+H] ⁺ 499.2.

Step 8: Isopropylcarbamic acid ( cis , rac )-3-(6-(1-methyl- 1H -pyrazol-5-yl) -5H -pyrrolo[2,3- b ]pyra Azin-2-yl) cyclopentyl ester and isopropylcarbamic acid ( cis , rac )-3-(7-(1-methyl-1 H -pyrazol-5-yl)-5 H -pyrrolo [2,3- b ]pyrazin-2-yl)cyclopentyl ester

Isopropylcarbamic acid ( cis , rac )-3-(6-(1-methyl-1 H -pyrazol-5-yl)- in methanol (2.0 mL) and HCO ₂ H (3.0 mL) 5-((2-(trimethylsilyl)ethoxy)methyl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester and isopropylamino Formic acid ( cis , rac )-3-(7-(1-methyl- 1H -pyrazol-5-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)- A solution of 5 H -pyrrolo[2,3- b ]pyrazin-2-yl) cyclopentyl ester (50.0 mg, 100 μmol) was heated to 100° C. and stirred at this temperature for 8 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by Prep-HPLC with _CH3CN in water (from 28% to 58% _CH3CN in 8 min) to give isopropylcarbamic acid ( cis , rac ) as a white solid )-3-(6-(1-methyl-1 H -pyrazol-5-yl)-5 H -pyrrolo[2,3- b ]pyrazin-2-yl) cyclopentyl ester (5.00 mg , 14% yield). LC-MS: m/z[M+H] ⁺ 369.2. And obtain white solid isopropylcarbamic acid ( cis , rac )-3-(7-(1-methyl- 1H -pyrazol-5-yl) -5H -pyrrolo[2,3- b ]pyrazin-2-yl)cyclopentyl ester (4.00 mg, 11% yield). LC-MS: m/z[M+H] ⁺ 369.2.

Example 137

Isopropylcarbamic acid (1 R ,3 S )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-3 H -imidazo[4,5- b ]pyridine- 6-yl) cyclopentyl ester (optional) and Example 138 isopropylcarbamate (1 S , 3 R )-3-(2-(1-methyl-1 H -pyrazol-5-yl) ) -3H -imidazo[4,5- b ]pyridin-6-yl)cyclopentylisopropylcarbamate (optional)

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

To a stirred solution of 1-methyl-1 H -pyrazole-5-carbaldehyde (2.00 g, 18.5 mmol) in AcOH (40.0 mL) at 25°C was added 5-bromopyridine-2,3-diamine ( 3.42g, 18.2mmol). The reaction mixture was warmed to 120°C and stirred at this temperature for 16 hours. The mixture was cooled to 25°C and the precipitate was collected by filtration and dried to obtain 6-bromo-2-(1-methyl- 1H -pyrazol-5-yl) -3H -imidazo[4,5- b ] Pyridine (1.10 g, 22% yield). 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 -imidazole And[4,5- b ]pyridine

To a solution of NaH (174 mg, 60 wt.% in mineral oil, 4.35 mmol) in THF (10.0 mL) at 0 °C, 6-bromo-2-(1-) in THF (20.0 mL) was added dropwise A solution of methyl-1 H -pyrazol-5-yl)-3 H -imidazo[4,5- b ]pyridine (1.10 g, 3.96 mmol) was added followed by SEMCl (700 μL) in THF (20.0 mL) , 659mg, 3.96mmol) solution. The resulting mixture was heated to 25°C and stirred at this temperature for 5 hours. 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 _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 50% EtOAc in 25 min) to give 6-bromo-2-(1-methyl- 1H) as a yellow solid -pyrazol-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl) -3H -imidazo[4,5- b ]pyridine (900 mg, 56% yield ). LC-MS: m/z[M+H] ⁺ 408.0.

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

6-bromo-2-(1-methyl-1 H -pyrazol-5-yl)-3-((2-(trimethyl)) in 1,4-dioxane (30.0 mL) at 25°C To a stirring solution of silyl)ethoxy)methyl) -3H -imidazo[4,5- b ]pyridine (900mg, 2.20mmol), 3-(4,4,5,5-tetrakis) was added sequentially. Methyl-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 ₂ CO ₃ (912 mg, 6.61 mmol). The reaction mixture was warmed to 80°C and stirred at this temperature for 2 hours. The reaction mixture was cooled to 25°C, diluted with water (25 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were dried _{over Na2SO4} and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 80% EtOAc 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). LC-MS: m/z[M+H] ⁺ 410.1.

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

3-(2-(1-Methyl-1 H -pyrazol-5-yl)-3-((2-(trimethylsilyl))ethoxy in MeOH (10.0 mL) at 25 °C ) Methyl) -3H -imidazo[4,5- b ]pyridin-6-yl) cyclopent-2-en-1-one (400 mg, 977 μmol) was stirred and NiCl ₂₍ was added in batches. 12.7 mg, 97.7 μmol) and NaBH ₄ (148 mg, 3.91 mmol). The reaction mixture was stirred at this temperature for 2 hours. The mixture was quenched with saturated aqueous _NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (30 mL) and dried over _{anhydrous Na2SO4} , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 80% EtOAc in 25 min) to give 3-(2-(1-methyl- 1H ) as a pale yellow solid -pyrazol-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3 H -imidazo[4,5- b ]pyridin-6-yl)cyclopentan -1-ol (220 mg, 55% yield). LC-MS: m/z[M+H] ⁺ 414.3.

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

3-(2-(1-Methyl-1 H -pyrazol-5-yl)-3-(2-(trimethylsilyl)ethyl) in CH ₃ CN (10.0 mL) at 25 °C To a stirred solution of oxy)methyl) -3H -imidazo[4,5- b ]pyridin-6-yl)cyclopent-1-ol (200 mg, 484 μmol), 4-nitrophenyl carbon was added sequentially Chloride (292 mg, 1.45 mmol), DMAP (118 mg, 967 μmol) and NMM (266 μL, 245 mg, 2.42 mmol). The reaction mixture was stirred at this temperature for 3 hours, then it was concentrated under reduced pressure. The residue was purified by silica gel chromatography. , dissolved with EtOAc/PE (from 0% to 70% EtOAc in 25 minutes) to obtain 3-(2-(1-methyl- 1H -pyrazol-5-yl)carbonate as a light yellow solid -3-((2-(Trimethylsilyl)ethoxy)methyl)-3 H -imidazo[4,5- b ]pyridin-6-yl)cyclopentyl ester (4-nitrobenzene ester) (100 mg, 36% yield). LC-MS: m/z [M+H] ⁺ 579.2.

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

Carbonic acid 3-(2-(1-methyl-1 H -pyrazol-5-yl)-3-((2-(trimethylsilyl)) in CH ₃ CN (10.0 mL) at 25 °C A stirred solution of ethoxy)methyl) -3H -imidazo[4,5- b ]pyridin-6-yl)cyclopentyl ester (4-nitrophenyl ester) (100 mg, 173 μmol), sequence Propan-2-amine (44.4 μL, 30.6 mg, 518 μmol,) and Et ₃ N (72.3 μL, 52.5 mg, 518 μmol) were added. The reaction mixture was stirred at this temperature for 16 hours. 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 Na2SO4} , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 80% EtOAc in 25 minutes) to give isopropylcarbamate 3-(2-(1) as a pale yellow solid -Methyl-1 H -pyrazol-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3 H -imidazo[4,5- b ]pyridine- 6-yl)cyclopentyl ester (80.0 mg, 93% yield). LC-MS: m/z[M+H] ⁺ 499.1.

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

Isopropylcarbamate 3-(2-(1-methyl-1 H -pyrazol-5-yl)-3-((( A stirred solution of 2-(trimethylsilyl)ethoxy)methyl) -3H -imidazo[4,5- b ]pyridin-6-yl)cyclopentyl ester (80.0 mg, 160 μmol) was added HCl (5.0 mL, 4.0 M in 1,4-dioxane, 20.0 mmol). The reaction mixture was stirred at this temperature for 16 hours, then it was concentrated under reduced pressure. The residue was purified by Prep-HPLC, eluating with CH ₃ CN in water (from 5% to 70% CH ₃ CN in 30 min) to give isopropylcarbamate 3-(2-( 1-Methyl- 1H -pyrazol-5-yl) -3H -imidazo[4,5- b ]pyridin-6-yl)cyclopentyl ester (20.0 mg, 34% yield, trans + cis ), which was further separated by SFC (Daicel CHIRALCEL AD-H, CO ₂ /MeOH = 60/40, MeOH containing 0.2% NH ₄ OH, 2.5 mL/min, 40°C) to obtain the isopropylamine group as a white solid Formic acid (1 R ,3 S )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-3 H -imidazo[4,5- b ]pyridin-6-yl) ring Amyl ester (lag time = 8.8 min, dispensed ad libitum, 2.1 mg, 1.2% yield), LC-MS: m/z [M+H] ⁺ 369.2, and isopropylcarbamic acid as white solid (1 S ,3 R )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-3 H -imidazo[4,5- b ]pyridin-6-yl) cyclopentyl ester ( Delay time = 11.1 min, dispensed arbitrarily, 2.1 mg, 1.2% yield), LC-MS: m/z [M+H] ⁺ 369.2.

Example 139 ( cis , rac )-5-(3-((3-isopropylpyridin-2-yl)oxy)cyclopentyl)-2-(1-methyl-1 H -pyrazole-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)-1 H -pyrrolo[2,3- b ]pyridine

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

( cis , rac )-3-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl in THF (150 mL) at -65°C ] To a stirred solution of cyclopentanol (6.00g, 18.0mmol), add n -BuLi (21.6mL, 2.50M, 54.0mmol). The mixture was stirred at this temperature for 2 hours, then a solution of _I2 (4.58 g, 18.0 mmol) in THF (50 mL) was added. The mixture was warmed to 25°C and stirred at this temperature for 1 hour. The mixture was quenched with saturated aqueous _NH4Cl (120 mL). The aqueous layer was extracted with EtOAc (40 mL x 3). The combined organic layers _were washed with _Na2SO4 (30 mL), dried over _Na2SO4 and filtered _. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 20% EtOAc in 20 min) to give ( cis , rac )-3-(2-iodo-1) as a brown solid -(2-Trimethylsilylethoxymethyl)pyrrolo[2,3- b ]pyridin-5-yl)cyclopentanol (3.50 g, 42% yield). 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 )-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol

( cis , rac )-3-(2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) in DME (30 mL) and H ₂ O (6.0 mL) at 25°C base) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (1.50g, 3.27mmol) suspension, and add (1-methyl- 1H- Pyrazol-5-yl)boronic acid (824 mg, 6.54 mmol), Pd(PPh ₃ ) ₄ (378 mg, 327 μmol) and Na ₂ CO ₃ (1.04 g, 9.82 mmol). The mixture was warmed to 60°C and stirred at this temperature for 5 hours. 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 _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 46% EtOAc in 40 min) to give ( cis , rac )-3-(2-(1-) as a yellow oil Methyl- 1H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridine-5 -yl)cyclopent-1-ol (1.30 g, 96% yield). 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)-1 H -pyrrolo[2,3- b ]pyridine

To a suspension of NaH (29.1 mg, 727 μmol, 60% wt.%) in DMF (5.0 mL) at 0 °C, ( cis , rac )-3-(2-(1-methyl-1 H - Pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent- 1-alcohol (100 mg, 242 μmol). The reaction was warmed to 80°C and stirred at this temperature for 3 hours. The mixture cools down. Quenched with NH ₄ Cl solution (20 mL) and extracted with DCM (20 mL×3). _The combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with EtOAc/PE (from 0% to 23% EtOAc in 20 min) to give ( cis , rac )-5-(3-((3 -Bromopyridin-2-yl)oxy)cyclopentyl)-2-(1-methyl- 1H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy (100 mg , 72% yield ). 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)pyridine- 2-yl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridine

( cis , rac )-5-(3-((3-bromopyridin-2-yl)oxy) in 1,4-dioxane (5.0) and H ₂ O (1.0 mL) at 25°C Cyclopentyl)-2-(1-methyl- 1H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo [2,3- b ]pyridine (100mg, 175μmol) solution, add 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2 in sequence - Dioxaborane (59.1 mg, 351 μmol), Pd(dppf)Cl ₂ (25.7 mg, 35.1 μmol) and Na ₂ CO ₃ (55.9 mg, 527 μmol). The mixture was warmed to 100°C and stirred at this temperature for 2 hours. 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 (20 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/PE (from 0% to 28% EtOAc in 20 min) to give ( cis , rac )-2-(1-methyl-) as a colorless oil 1 H -pyrazol-5-yl)-5-((1 S ,3 R )-3-((3-(prop-1-en-2-yl)pyridin-2-yl)oxy)cyclopentyl (80.0 mg , 85 % yield). LC-MS: m/z[M+H] ⁺ 530.2.

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

( cis , rac )-2-(1-methyl-1 H -pyrazol-5-yl)-5-(3-((3-(propan-1)) in MeOH (2.0 mL) at 25 °C -en-2-yl)pyridin-2-yl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2, 3- b ] To a solution of pyridine pyridine (40.0 mg, 75.5 μmol), Pd/C (8.0 mg, 7.5 μmol, 10% wt.) was added sequentially. The reaction mixture was stirred at this temperature under hydrogen atmosphere for 6 hours, then it was filtered through a pad of celite and concentrated under reduced pressure to obtain ( cis , rac )-5-(-((3-isopropylpyridine-2) as a yellow oil -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), 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 -pyrazole-5 -yl) -1H -pyrrolo[2,3- b ]pyridine

( cis , rac )-5-(3-((3-isopropylpyridin-2-yl)oxy)cyclopentyl)-2- in HCO ₂ H (2.0 mL) and MeOH (1.0 mL) (1-Methyl- 1H -pyrazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ] A solution of pyridine (30.0 mg, 56.4 μmol) was heated to 100° C. and stirred at this temperature for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (from 45% to 100% _CH3CN in 13 min) to give ( cis , rac )-5-(3-((3-isopropylpyridine- 2-yl)oxy)cyclopentyl)-2-(1-methyl-1 H -pyrazol-5-yl)-1 H -pyrrolo[2,3- b ]pyridine (3.40 mg, 15% yield). 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)pyridine- 2-yl)oxy)cyclopentyl)-1 H -pyrrolo[2,3- b ]pyridine

( cis , rac )-2-(1-methyl-1 H -pyrazol-5-yl)-5-(3-((3-) in HCO ₂ H (2.0 mL) and MeOH (1.0 mL) (prop-1-en-2-yl)pyridin-2-yl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrole A solution of [2,3- b ]pyridine (30.0 mg, 56.6 μmol) was heated to 100° C. and stirred at this temperature for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC and resolved (from 45% to 100% _CH3CN in 13 min) to give ( cis , rac )-2-(1-methyl- 1H-) as a white solid Pyrazol-5-yl)-5-(3-((3-(prop-1-en-2-yl)pyridin-2-yl)oxy)cyclopentyl)-1 H -pyrrolo[2, 3- b ]pyridine (3.50 mg, 15% yield). LC-MS: m/z[M+H] ⁺ 400.2.

Example 142

Step 1: 3-methylbutyric acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazol-5-yl)-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester

( cis , rac )-3-(2-(1-methyl-1 H -pyrazol-5-yl)-1-((2-(trimethyl)) in DCM (2.0 mL) at 0 °C Silyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopent-1-ol (77.0mg, 186μmol) and pyridine (148mg, 1.87mmol, 151μL ) solution, add 3-methylbutyryl chloride (113 mg, 933 μmol, 114 μL). The mixture was warmed to 25°C and stirred at this temperature for 1 hour. 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 _Na2SO4 , filtered and concentrated under reduced pressure _. The residue was purified by prep-TLC (PE/EtOAc=2:1) to obtain 3-methylbutyric acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazole) as yellow oil -5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester ( 32.0 mg, 35% yield). LC-MS: m/z[M+H] ⁺ 497.3.

Step 2: 3-Methylbutanoic acid ( cis , rac )-(2-(1-methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridine-5 -yl) cyclopentyl ester

3-Methylbutyric acid ( cis , rac )-3-(2-(1-methyl- 1H -pyrazol-5 _- yl)-1-((2- A solution of (trimethylsilyl)ethoxy)methyl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (27.0 mg, 54.4 μmol) was heated to 90 °C and stirred at this temperature for 3 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-TLC (from 35% to 100% _CH3CN in 13 min) to give 3-methylbutyric acid ( cis , rac )-3-(2-(1- Methyl- 1H -pyrazol-5-yl) -1H -pyrrolo[2,3- b ]pyridin-5-yl)cyclopentyl ester (6.10 mg, 31% yield). LC-MS: m/z[M+H] ⁺ 367.2.

Biological Example 1. Assay of CDK2/Cyclin E1 Inhibition

In the detection buffer containing 50mM HEPES, pH=7.5, 10mM MgCl ₂ , 1mM EGTA, 2mM DTT, 0.01% Tween and 0.1% BSA, perform homogeneous time-resolved fluorescence (HTRF) detection. Phosphorylation of peptide receptors catalyzed by CDK2/cyclin E1. In a 10 μL volume containing 0.4 nM CDK2/cyclin E1 enzyme (SignalChem, C22-18G), 80 μM ATP, 20 nM LANCE Ultra ULight ^™ -eIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer) in assay buffer , TRF0128-M)) and 1% DMSO (or test compound appropriately diluted in DMSO) to perform enzymatic reactions. All components were added to a 384-well plate (PerkinElmer, 6008280) and incubated at room temperature for 4 hours. The reaction was stopped by adding 10 μL of detection buffer (PerkinElmer, CR97-100) containing 20mM EDTA and 4nM LANCE® Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) (PerkinElmer, TRF0216-M) antibody. . The plates were then incubated at room temperature for 1 hour. Use Envision Reader (PerkinElmer, EnVision Multilabel Reader) to read the well plate. The _IC50 value of the test compound was determined by fitting an inhibition curve with a 4-parameter sigmoidal dose-response model using GraphPad Prism 8 software.

Biological Example 2. Assay of CDK1/Cyclin A2 Inhibition

In the detection buffer containing 50mM HEPES, pH=7.5, 10mM MgCl ₂ , 1mM EGTA, 2mM DTT, 0.01% Tween and 0.1% BSA, perform homogeneous time-resolved fluorescence (HTRF) detection. CDK1/cyclin A2 catalyzed phosphorylation of peptide receptors. In a 10 μL volume containing 0.4 nM CDK2/cyclin E1 enzyme (SignalChem, C22-18G), 10 μM ATP, 20 nM LANCE Ultra ULight ^™ -eIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer) in assay buffer , TRF0128-M)) and 1% DMSO (or test compound appropriately diluted in DMSO) to perform enzymatic reactions. All components were added to a 384-well plate (PerkinElmer, 6008280) and incubated at room temperature for 2 hours. The reaction was stopped by adding 10 μL of detection buffer (PerkinElmer, CR97-100) containing 20mM EDTA and 4nM LANCE® Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) (PerkinElmer, TRF0216-M) antibody. . The plates were then incubated at room temperature for 1 hour. Use Envision Reader (PerkinElmer, EnVision Multilabel Reader) to read the well plate. The _IC50 value of the test compound was determined by fitting an inhibition curve with a 4-parameter sigmoidal dose-response model using GraphPad Prism 8 software.

50nM且<200nM；「+++」表示

200nM且<1000nM；「++++」表示

1000nM。CDK1/CDK2的比率如下列所示，「+」表示<5倍；「++」表示

5倍且<20倍；「+++」表示

20倍且<50倍；「++++」表示

50倍。 The _IC50 values for CDK2 and the CDK1/CDK2 ratio for each exemplary compound are provided in Table 2. The IC ₅₀ values are as follows: "+" means <50nM;"++" means

50nM and <200nM;"+++" means

200nM and <1000nM;"++++" means

1000nM. The ratio of CDK1/CDK2 is as follows, "+" means <5 times; "++" means

5 times and <20 times; "+++" means

20 times and <50 times; "++++" means

50 times.

Biological Example 3. Assay of anti-proliferation in OVCAR3 cells

OVCAR3 cells (ATCC, HTB-161) were seeded in 96-well plates at 5000 cells/well and cultured in RPMI 1640 medium (Gibco, 31800105) at 37°C, 5% _CO2 and 10% FBS. After overnight incubation, baseline values were measured for samples from one well plate using CyQUANT reagent (Invitrogen, C35011) according to the manufacturer's recommendations. Cells were incubated with detection reagents for 1 hour at 37°C, and fluorescence was measured using an Envision Multilabel Plate Reader (PerkinElmer) with excitation at 485 nm and emission at 535 nm. Add test compounds in a 3-fold dilution scheme to other well plates. On day 6 after compound addition, CyQUANT reagent was added and fluorescence was measured using Envision. _IC50 values for the antiproliferative activity of the test compounds were determined by subtracting the viability readout curve from the baseline using GraphPad Prism 5 software.

50nM且<200nM；「+++」表示

200nM且<1000nM；「++++」表示

1000nM。 Cellular data obtained from Biological Example 3 are presented in Table A below. IC ₅₀ values are shown below respectively, "+" means <50nM;"++" means

50nM and <200nM;"+++" means

200nM and <1000nM;"++++" means

1000nM.

Claims (38)

A compound represented by formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

in, Ring A is a heteroaryl group represented by:

W is

,

, 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein the 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl represented by W is optionally replaced by one or more halogens, C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl substitution; R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl represented by R ¹ is optionally substituted by one or more halogens, CN, side oxy groups or -NH ₂ ; R ^1' is H, C _1-6 alkyl, 3 to 12 membered carbocyclyl, 3 to 12 membered heterocyclyl, or 5 to 10 membered heteroaryl; wherein the C _1-6 represented by R ^1' Alkyl, 3 to 12-membered carbocyclyl, 3 to 12-membered heterocyclyl or 5 to 10-membered heteroaryl is optionally substituted by one or more halogens, CN, side oxy groups or C _1-6 alkyl groups; R ² is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 alkylene group, -(CH ₂ ) ₀ or ₁ -3 to 12-membered carbocyclyl group, -(CH ₂ ) _{0 or 1} -3 to 12-membered heterocyclyl group, -(CH ₂ ) ₀ or ₁ - 6 to 10-membered aryl or -(CH ₂ ) _{0 or 1} -5 to 10-membered heteroaryl; wherein the C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) represented by R ² _{0 or 1} -3 to 12-membered carbocyclyl, -(CH ₂ ) _{0 or 1} -3 to 12-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -6-10-membered aryl or -(CH ₂ ) _{0 or 1-5-10} membered heteroaryl optionally substituted by one or more halogen, hydroxyl, CN or C _1-6 alkyl; or R ¹ and R ² together with the attached N atom form a 3 to 8 membered heterocyclyl group; wherein the 3 to 8 membered heterocyclyl group is optionally substituted with one or more R ^# ; wherein each R ^# is independently F , hydroxyl, C _1-4 alkyl, C _1-4 alkoxy or CN; R ³ is H or halogen; R ⁴ is

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

; R ⁶ is H, halogen or C _1-6 alkyl; in, Each ring B is independently a 3- to 12-membered carbocyclyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; U is a bond, -CH ₂ -, -C≡C- or -C(O)NH-; R ^5a and R ^5b are independently H or C _1-6 alkyl; Each R ^4a or R ^5c is independently halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 extension Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C(O)R ^* , -C(O)OR ^* , -C(O)NR ^* R ^* , OR ^* , SO ₂ R ^* , NR ^* R ^* , NR ^* C(O)R ^* , -NR ^* C(O)OR ^* , -NR ^* SO ₂ R ^* , -NR ^* SO ₂ NR ^* R ^* , -P(O)R ^* R ^* , 3 to 12 membered carbocyclyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; wherein, The 3 to 12-membered carbocyclic group, 3 to 12-membered heterocyclyl group, 6 to 10-membered aryl group or 5 to 10-membered heteroaryl group represented by R ^4a or R ^5c is optionally replaced by one or more halogens or C _1-6 alkyl substitution; and Each R ^* is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-6 carbon Cyclic groups and 4 to 6-membered heterocyclyl groups; n 0, 1, 2, 3, 4 or 5, as needed; m is 0, 1, 2, 3, 4 or 5, depending on needs; R ⁷ is H or halogen; and Wherein the heterocyclic group contains 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; the heteroaryl group contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. The compound of claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein the compound is represented by formula IIA

The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein the compound is represented by formula IIB

The compound as described in any one of claims 1 to 3, its pharmaceutically acceptable salt or its stereoisomer, wherein ring A is selected from the group consisting of:

The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt or its stereoisomer, wherein Ring A is

. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt or its stereoisomer, wherein ring A is

. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt or its stereoisomer, wherein Ring A is

. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt or its stereoisomer, wherein W is

. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt or its stereoisomer, wherein W is optionally substituted by 1 to 3 C _1-4 alkyl, C _1-4 halogen 5-10 membered heteroaryl substituted by alkyl, C _2-4 alkenyl or C _2-4 alkynyl. The compound of claim 9, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein W is optionally substituted by C _1-4 alkyl (for example, isopropyl) or C _2-4 alkenyl (for example , isopropenyl) substituted 5- to 6-membered heteroaryl (such as pyridyl, pyrimidinyl). The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or its stereoisomer, wherein R ¹ is H. The compound as described in any one of claims 1 to 8 and 11, its pharmaceutically acceptable salt or its stereoisomer, wherein R ² is H, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 hydroxyalkyl, C _{1-6 alkoxy, C 1-6 alkylene} , C _2-4 alkenyl, C _2-4 alkynyl, -(CH ₂ ) _{0 or 1} -3 to 6 -(CH ₂ ) _{0 or 1} -3 to 6-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -phenyl or -(CH ₂ ) _{0 or 1} -5 to 6-membered heteroaryl ; wherein the C _2-4 alkenyl group, C _2-4 alkynyl group, -(CH ₂ ) _{0 or 1} -3 to 6-membered carbocyclyl group represented by R ² , -(CH ₂ ) _{0 or 1} -3 to 6-membered heterocyclyl, -(CH ₂ ) _{0 or 1} -phenyl or -(CH ₂ ) _{0 or 1} - 5 to 6 membered heteroaryl optionally substituted by 1 to 3 selected from halogen, hydroxyl, CN and Substitution with C _1-4 alkyl group. The compound as described in any one of claims 1 to 8, 11 and 12, its pharmaceutically acceptable salt or its stereoisomer, wherein R ² is H, C _1-5 alkyl, C _1-5 halogen Alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy C _1-4 alkylene, 3 to 6 membered cycloalkyl, 4 to 6 membered heterocyclyl or -(CH ₂ )-phenyl ; wherein the 3- to 6-membered cycloalkyl group, 4- to 6-membered heterocyclyl group or -(CH ₂ )-phenyl group represented by R ² is optionally replaced by one or two selected from the group consisting of halogen, hydroxyl, CN, and C Substituted with _1-4 alkyl groups. The compound as described in any one of claims 1 to 8 and 11 to 13, its pharmaceutically acceptable salt or its stereoisomer, wherein R ² is C _1-4 alkyl, C _1-4 hydroxyalkyl Or cyclopropyl; wherein the cyclopropyl represented by R ² is optionally substituted by C _1-2 alkyl. The compound as described in any one of claims 1 to 8 and 11 to 13, its pharmaceutically acceptable salt or its stereoisomer, wherein R ² is selected from the group consisting of: H,

,

,

,

,

,

The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or its stereoisomer, wherein R ¹ and R ² together with the connected N atom form a 4 to 6 membered heterocyclyl group; wherein the 4- to 6-membered heterocyclyl is optionally substituted with one to three halogens (eg, F) or C _1-4 alkyl. The compound of any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ¹ and R ² together with the attached N atom form a pyrrolidine group. The compound as described in any one of claims 1 to 5 and 8 to 17, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ³ is H or F. The compound as described in any one of claims 1 to 5 and 8 to 18, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ³ is H. The compound as described in any one of claims 1 to 4 and 6 to 17, its pharmaceutically acceptable salt or its stereoisomer, wherein R ⁵ is H, halogen, CH ₃ , isopropyl, C(O) OH, C(O)N(CH ₃ ) ₂

The compound as described in any one of claims 1 to 4, 6 to 17 and 20, its pharmaceutically acceptable salt or its stereoisomer, wherein R ⁵ is

. The compound as described in any one of claims 1 to 4, 6 to 17, 20 and 21, its pharmaceutically acceptable salt or its stereoisomer, wherein U is a bond. The compound according to any one of claims 1 to 22, its pharmaceutically acceptable salt or its stereoisomer, wherein, Each ring B is independently a 3- to 8-membered carbocyclyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, or a 5- to 10-membered heteroaryl group; Each R ^4a or R ^5c is independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy C _1-4 extension Alkyl, C _2-4 alkenyl, C _2-6 alkynyl, OR ^* , SO ₂ R ^* , -C(O)NR ^* R ^* , -NR ^* SO2NR ^* R ^* , C(O)R ^* , C(O)OR ^* , -P(O)R ^* R ^* , phenyl or 5 to 6-membered heteroaryl; wherein, The phenyl or 5- to 6-membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by 1 to 3 halogens or C _1-4 alkyl; and Each R ^* is independently selected from the group consisting of: hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, 4 to 6 membered carbons Cyclic groups and 5 to 6-membered heterocyclyl groups; m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3. The compound according to any one of claims 1 to 23, its pharmaceutically acceptable salt or its stereoisomer, wherein, Each ring B is independently a 4- to 6-membered monocyclic carbocyclyl group, a 4- to 6-membered monocyclic heterocyclyl group, a phenyl group, or a 5- to 10-membered heteroaryl group; Each R ^4a or R ^5c is independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkyne group, C _1-4 alkylene group, C _1-2 alkoxy group, OR ^* , SO ₂ R ^* , C(O)NR ^* R ^* , C(O)OR ^* , -P(O)R ^* R ^* , phenyl or 5-6 membered heteroaryl; where, The phenyl or 5- to 6-membered heteroaryl represented by R ^4a or R ^5c is optionally substituted by 1 to 2 halogens or C _1-2 alkyl; and Each R ^* is independently selected from the group consisting of: hydrogen, C _1-4 alkyl, and C _1-4 haloalkyl; m is 0, 1 or 2; and n is 0, 1 or 2. The compound of claim 24, its pharmaceutically acceptable salt or its stereoisomer, wherein, The B ring represented in the R ⁴ group is a 5- to 6-membered monocyclic heterocyclyl group, a phenyl group or a 5- to 9-membered heteroaryl group; Each R ^4a is F, -CN, -OH, C _1-3 alkyl, C _1-2 hydroxyalkyl, C _1-2 alkylene, C _1-2 alkoxy, -OC _1-2 alkyl , SO ₂ C _1-2 alkyl, C(O)NR ^* R ^* , C(O)OR ^* , -P(O)R ^* R ^* , phenyl or 5 to 6-membered heteroaryl; wherein, The phenyl or 5- to 6-membered heteroaryl represented by R ^4a is optionally substituted by halogen or C _1-2 alkyl; Each R ^* is independently selected from hydrogen or C _1-3 alkyl; and m is 0, 1 or 2. The compound as described in claim 24 or 25, its pharmaceutically acceptable salt or its stereoisomer, wherein, The B ring represented in the R ⁴ group is a 6-membered heteroaryl group; Each R ^4a is C _1-2 hydroxyalkyl; and m is 0 or 1. The compound as described in any one of claims 1 to 25, its pharmaceutically acceptable salt or its stereoisomer, wherein the B ring represented in the R ⁴ group is selected from the group consisting of:

The compound as described in any one of claims 1 to 5, 8 to 25 and 27, its pharmaceutically acceptable salt or its stereoisomer, wherein R ^4a is selected from the group consisting of: F,

,

,

,

,

,

The compound of claim 24, its pharmaceutically acceptable salt or its stereoisomer, wherein, The B ring represented in the R ⁵ group is a 5- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclyl group, a phenyl group or a 5- to 9-membered heteroaryl group; Each R ^5c is halogen, -CN, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-2 alkoxy C _1-2 alkylene group, SO ₂ C _1-3 alkyl group or SO ₂ C _1-3 haloalkyl group; and n is 0, 1 or 2. The compound as described in any one of claims 1 to 29, its pharmaceutically acceptable salt or its stereoisomer, wherein the B ring represented in the R ⁵ group is selected from the group consisting of:

The compound as described in any one of claims 1 to 30, its pharmaceutically acceptable salt or its stereoisomer, wherein R ^5C is selected from the group consisting of: F, Cl,

,

,

,

,

The compound as described in any one of claims 1 to 7 and 18 to 31, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ^1' is H or C _1-4 alkyl (for example, isopropyl ). A compound as described in Table 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 33, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. A method of treating a disease or condition that is at least partially modulated by CDK2 in an individual, comprising administering to an individual in need thereof a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described in any one of claims 1 to 33, Or the pharmaceutical composition as described in claim 34. A method for inhibiting CDK2 in a patient, comprising administering to the patient a compound as described in any one of claims 1 to 33, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as described in claim 34 . A method of treating a CDK2-related disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or The pharmaceutical composition as described in claim 34; wherein the disease or disorder is related to the amplification of the cyclin E1 (CCNE1) gene and/or the overexpression of CCNE1. The method of any one of claims 35 to 37, wherein the disease and disorder is cancer.