WO2023098699A1

WO2023098699A1 - Compounds and their uses as cd38 inhibitors

Info

Publication number: WO2023098699A1
Application number: PCT/CN2022/135278
Authority: WO
Inventors: Jianbei XI; Guohuang FAN; Jianfei Wang
Original assignee: Nanjing Immunophage Biotech Co., Ltd
Priority date: 2021-12-01
Filing date: 2022-11-30
Publication date: 2023-06-08

Abstract

The present invention provides compounds of Formula (I) which can be used as CD38 inhibitors; methods for the production of the compounds of the invention; pharmaceutical compositions comprising the compounds of the invention; as well as uses and methods for treating a disease mediated by CD38 by administering the compounds of the invention.

Description

COMPOUNDS AND THEIR USES AS CD38 INHIBITORS

FILED OF THE INVENTION

The present invention relates to novel compounds; methods for the production of the compounds of the invention; pharmaceutical compositions comprising the compounds of the invention; as well as uses and methods for treating a disease mediated by CD38 by administering the compounds of the invention. In particular, the compounds of the invention may be used as CD38 inhibitors.

BACKGROUND OF THE INVENTION

CD38 is a protein of 300 amino acids encoded by homologous genes located on chromosomes 4 and 5 in humans and mice, respectively. Within the cell, CD38 is often found localized on the cell surface, but it can also be detected in intracellular compartments such as the endoplasmic reticulum, nuclear membrane and mitochondria. Structurally, CD38 is a single chain glycoprotein with a single transmembrane segment and can topologically behave as a type II or type III membrane protein depending on its membrane orientation. In the most common type II orientation, CD38’s short amino tail faces into the cytosol while CD38’s catalytic domain faces the extracellular environment. A type III orientation, with the catalytic domain facing the cytosol, has been also reported. These two orientations have functional implications, given that CD38’s enzymatic substrates and products would be consumed and produced in the extracellular or the intracellular compartments.

CD38 catalyzes the synthesis of nicotinamide (NAM) and ADPR using nicotinamide adenine dinucleotide (NAD ⁺) as a substrate. NAD ⁺, an essential cofactor that regulates energy metabolism, can be converted to cADPR with the release of NAM. Interestingly, cADPR can also be hydrolyzed to ADP-ribose by CD38. Thus, CD38 has both ADP-ribosyl cyclase and cADPR hydrolase enzymatic activities. Both ADPR and cADPR act as second messengers controlling several cell functions through calcium (Ca ²⁺) mobilization. In addition to its enzymatic function, CD38 can also act as a receptor to CD31. Through the latter interaction, CD38 could act as an adhesion molecule mediating selectin-like binding of hematopoietic cells to endothelial cells and facilitating their transmigration to tissue.

CD38 is a ubiquitous protein expressed in multiple tissues. Nonhematopoietic tissue expression include prostatic epithelial cells, pancreatic islet astrocytes, smooth muscle cells, retinal tubes, kidney, gut, and brain in both mice and humans. However, CD38 is most highly expressed in hematopoietic tissues such as the bone marrow and lymph nodes. Within immune cells, CD38 is highly expressed in B cells, macrophages, dendritic cells (DCs) , innate lymphoid cells (ILC) , natural killer (NK) cells, T cells, neutrophils, and monocytes. Nevertheless, the level of CD38 expression among these populations may differ between human and mouse, as observed in a transcriptional comparison between species.

The surface marker and multifunctional enzyme CD38 appear to provide a link between inflammation and age-and disease-related decline in tissue homeostasis and, therefore, represents a critical target for therapeutic intervention. CD38 is expressed predominately on immune cells in response to stimulation by cytokines, endotoxins, and interferon. Expression of the enzyme is regulated by a promoter region containing binding sites for NF-kB, RXR, LXR, and STAT suggesting that it plays a key role in the inflammatory response. CD38 expression causes a substantial decline in cellular NAD ⁺ levels, thus altering the availability of substrates for enzymes regulating cellular homeostasis. Thus, infiltration of CD38-expressing immune cells during infection, aging, or tumorigenesis has the potential to alter NAD ⁺ homeostasis in parenchymal tissues or the tumor microenvironment; disrupt normal metabolic processes, and undermine tissue integrity.

The important role of CD38 in multiple diseases including neurodegeneration, neuroinflammation, cancer development and autoimmune diseases suggests that targeted inhibition of CD38 is a potential therapeutic approach for the treatment of neurodegenerative diseases, cancer, autoimmune diseases, metabolic disease and other inflammatory diseases. One of the most important strategies targeting CD38 is to develop small molecule inhibitors against CD38, which have demonstrated promising preclinical efficacy.

SUMMARY OF THE INVENTION

In one aspect, provided herein is a compound of formula (I) that functions as CD38 inhibitors.

In one aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient.

In one aspect, provided herein is a method of treating a disease mediated by CD38 comprising a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

In one aspect, provided herein is the use of the compound disclosed herein in the manufacture of a medicament for the treatment of a disease mediated by CD38.

In one aspect, provided herein is a method of inhibiting CD38 function, comprising contacting a compound of formula I described above, or a pharmaceutically acceptable salt thereof, with the CD38.

In an embodiment, the CD38 is in a cell. In another embodiment, the contacting occurs in vitro. In yet another embodiment, the contacting occurs in vivo.

DETAILED DESCRIPTION OF THE INVENTION

Provided is a compound of formula (I)

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

wherein

A ₁ is C _1-6alkyl, phenyl or 5-to 9-membered heteroaryl;

A ₂ is

each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C _1- ₆alkyl, -C _2-6alkenyl, -C _2-6alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR _aR _b, -C (O) R _a, -C (O) OR _a, -NO ₂, -OR _a, -SO ₂R _a, -CONR _aR _b, -NR _aCOR _b, -NR _aCO ₂R _b, or -NR _aSO ₂R _b, wherein R _a and R _b are each independently hydrogen or C _1-4alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH ₂, -C (O) CH ₃, or CH ₃, wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁;

L ₁ and L ₂ are each independently a direct bond, -C (O) -, or - (CR _cR _d) _n-, wherein R _c and R _d are each independently hydrogen, C _1-4alkyl, hydroxyC _1-4alkyl, or -C (O) OR _e, wherein R _e is hydroxy or C _1-4alkyl, and n is a number of 1, 2, 3 or 4;

R is H or C _1-6alkyl; and

A ₃ is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C _5- ₈cycloalkyl ring, a C _5-8cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, or a bridged bicyclic cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl.

The definition of A ₁

In some embodiments, A ₁ is C _1-6alkyl, phenyl or 5-to 9-membered heteroaryl. In some other embodiments, A ₁ is a monocyclic 5-to 9-membered heteroaryl comprising from 1 to 3 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , preferably monocyclic 5-to 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen as the ring member (s) . In some even further embodiments, A ₁ is pyridyl, thiazolyl, imidazolyl, pyrazinyl, or pyrazolyl. In some even further embodiments, A ₁ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl. In some embodiments, A ₁ is pyridin-4-yl, thiazol-5-yl, pyridin-3-yl, 1H-imidazol-1-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, methyl or phenyl.

The definition of A ₂

In some embodiments, A ₂ is

each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C _1-6alkyl, -C _2-6alkenyl, -C _2-6alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR _aR _b, -C (O) R _a, -C (O) OR _a, -NO ₂, -OR _a, -SO ₂R _a, -CONR _aR _b, -NR _aCOR _b, -NR _aCO ₂R _b, or -NR _aSO ₂R _b, wherein R _a and R _b are each independently hydrogen or C _1-4alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH ₂, -C (O) CH ₃, or CH ₃, wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁.

In other embodiments, A ₂ is

In some embodiments, A ₂ is

The definition of L ₁, L ₂ and R

In some embodiments, L ₁ and L ₂ are each independently a direct bond, -C (O) -, or - (CR _cR _d) _n-, wherein R _c and R _d are each independently hydrogen, C _1-4alkyl, hydroxyC _1-4alkyl, or -C (O) OR _e, wherein R _e is hydroxy or C _1-4alkyl, and n is a number of 1, 2, 3 or 4. In further embodiments, L ₁ is a direct bond or -C (O) -. In further embodiments, L ₂ is a direct bond, -C (O) -, or - (CR _cR _d) _n-, wherein R _c and R _d are each independently hydrogen, C _1-4alkyl, hydroxyC _1-4alkyl, or -C (O) OR _e, wherein R _e is hydroxy or C _1-4alkyl, and n is a number of 1, 2, 3 or 4.

In some embodiments, L ₁ is -C (O) -or a direct bond. In some embodiments, L ₂ is a direct bond, -C (O) -, -CH ₂-, -CH ₂CH ₂-, -CH (CH ₃) -, -CH (CH ₂OH) -, or -CH (COOMe) -. In some embodiments, L ₁ is -C (O) -, and L ₂ is a direct bond, -CH ₂-, -CH ₂CH ₂-, -CH (CH ₃) -, -CH (CH ₂OH) -, or -CH (COOMe) -. In some further embodiments, L ₁ is -C (O) -, and L ₂ is a direct bond. In some embodiments, L ₁ and L ₂ are both a direct bond.

In some embodiments, R is H or C _1-6alkyl. In some further embodiments, R is H.

The definition of A ₃

In some embodiments, A ₃ is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C _5-8cycloalkyl ring, a C _5-8cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, or a bridged bicyclic cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl.

In some embodiments, A ₃ is a monocyclic 5-to 9-membered heteroaryl. In some embodiments, A ₃ is a monocyclic 5-to 9-membered heterocyclyl ring comprising from 1 to 3 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , preferably a monocyclic 5-or 6-membered heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , more preferably a pyridinyl ring, e.g., pyridin-2-yl or pyridin-3-yl.

In some embodiments, A ₃ is a C ₅ or C ₆cycloalkyl ring, preferably a cyclohexyl ring.

In some embodiments, A ₃ is a C ₅ or C ₆cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C _1- ₆alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with one or two substituents selected from halogen, C _1- ₆alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at the phenyl ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at position 5 of the fused ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group, e.g., a 2, 3-dihydro-1H-inden-2-yl group.

In some embodiments, A ₃ is Cyclohexyl, (1r, 4r) -4-hydroxycyclohexyl, (1r, 4r) -4-methoxycyclohexyl,

( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) ,

(2, 3-dihydro-1H-inden-2-yl) ,

(5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) ,

(5-ethoxy-2, 3-dihydro-1H-inden-2-yl) ,

(bicyclo [2.2.2] octan-1-yl) , tetrahydro-2H-pyran-4-yl, phenyl or pyridin-3-yl.

In some embodiments, In some embodiments, A ₃ is Cyclohexyl, (1r, 4r) -4-hydroxycyclohexyl, (1r, 4r) -4-methoxycyclohexyl,

( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) ,

(2, 3-dihydro-1H-inden-2-yl) ,

(5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) , or

(5-ethoxy-2, 3-dihydro-1H-inden-2-yl) .

In some embodiments, A ₁ is 5-to 9-membered heteroaryl, A ₂ is

(wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁) , L ₁ is -C (O) -and L ₂ is a direct bond, A ₃ is a cyclohexyl ring which is unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl.

In some embodiments, A ₁ is 5-to 9-membered heteroaryl, A ₂ is

(wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁) , L ₁ is -C (O) -and L ₂ is a direct bond, A ₃ is a C ₅ or C ₆cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with one or two substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at the phenyl ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at position 5 of the fused ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) . In some embodiments, A ₃ is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group, e.g., a 2, 3-dihydro-1H-inden-2-yl group. In some embodiments, A ₃ is

( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) ,

(2, 3-dihydro-1H-inden-2-yl) ,

(5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) , or

(5-ethoxy-2, 3-dihydro-1H-inden-2-yl) .

In some embodiments, A ₁ is 5-to 9-membered heteroaryl, A ₂ is

(wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁) , L ₁ is -C (O) -and L ₂ is -CH ₂CH ₂-, -CH (CH ₃) -, or -CH (CH ₂OH) -, A ₃ is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C _5-8cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl as defined above.

In some embodiments, the compound is selected from

In some embodiments, the disease mediated by CD38 is neurodegenerative disease selected from dementia, Alzheimer's disease (AD) , Parkinson's disease; tumor selected from glioblastomas, lung cancer, colon cancer, liver cancer, breast cancer, gastric cancer, bladder cancer, melanoma; autoimmune disease selected from diabetes, rheumatoid arthritis (RA) , multiple sclerosis (MS) , systemic lupus erythematosus (SLE) ; inflammatory disease selected from asthma, chronic obstructive pulmonary disease (COPD) , pneumonia, or non-alcoholic steatohepatitis (NASH) .

Definition

The following terms have the indicated meanings throughout the specification:

Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

The following terms have the indicated meanings throughout the specification:

The phase “CD38 inhibitor” includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the CD38 inhibitors described in this invention.

As used herein, including the appended claims, the singular forms of words such as "a" , "an" , and "the" , include their corresponding plural references unless the context clearly indicates otherwise.

The term "or" is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.

The term "alkyl" includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl ( "n-Pr" ) , 2-propyl or isopropyl ( "i-Pr" ) , 1-butyl or n-butyl ( "n-Bu" ) , 2-methyl-1-propyl or isobutyl ( "i-Bu" ) , 1-methylpropyl or s-butyl ( "s-Bu" ) , 1, 1-dimethylethyl or t-butyl ( "t-Bu" ) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups.

The term "halogen” includes fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .

The term "haloalkyl" includes an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo. Examples of the haloalkyl include haloC _1-8alkyl, haloC _1-6alkyl or halo C _1-4alkyl, but not limited to -CF ₃, -CH ₂Cl, -CH ₂CF ₃, -CHCl ₂, -CF ₃, and the like.

The term "cycloalkyl" includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.

For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, examples of the saturated monocyclic cycloalkyl group, e.g., C _3-8cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C _3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems.

The term "heteroaryl" includes a group selected from:

- 5-to 9-membered (e.g., 5-, 6-, 7-, 8-or 9-membered) aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;

- 7-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

- 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.

Examples of the heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, or 1, 3, 4-oxadiazolyl) , phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, or 1, 3, 4-triazolyl) , quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [2, 3-b] pyridin-5-yl) , pyrazolopyridinyl (such as 1H-pyrazolo [3, 4-b] pyridin-5-yl) , benzofuranyl, benzoxazolyl (such as benzo [d] oxazol-6-yl) , pteridinyl, purinyl, 1-oxa-2, 3-diazolyl, 1-oxa-2, 4-diazolyl, 1-oxa-2, 5-diazolyl, 1-oxa-3, 4-diazolyl, 1-thia-2, 3-diazolyl, 1-thia-2, 4-diazolyl, 1-thia-2, 5-diazolyl, 1-thia-3, 4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl) , benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo [d] thiazol-6-yl) , indazolyl (such as 1H-indazol-5-yl) and 5, 6, 7, 8-tetrahydroisoquinoline.

"Heterocyclyl" , "heterocycle" or "heterocyclic" are interchangeable and include a non-aromatic heterocyclyl group comprising one or more, e.g., 1 to 3, heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

Exemplary monocyclic 4 to 9-membered heterocyclyl groups include, but not limited to, (as numbered from the linkage position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1, 4-oxathianyl, 1, 4-dioxepanyl, 1, 4-oxathiepanyl, 1, 4-oxaazepanyl, 1, 4-dithiepanyl, 1, 4-thiazepanyl and 1, 4-diazepanyl, 1, 4-dithianyl, 1, 4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1, 1-dioxo-thiomorpholinyl.

The term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers) , mixtures of mirror image isomers (racemates, racemic mixtures) , geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers) .

Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

When compounds disclosed herein contain a di-substituted cyclic ring system, substituents found on such ring system may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides. For example, the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.

It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ( "SMB" ) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art could select and apply the techniques most likely to achieve the desired separation.

“Diastereomers” refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review. " J. Chromatogr., 113 (3) (1975) : pp. 283-302) . Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

"Pharmaceutically acceptable salts" refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.

In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

As defined herein, "a pharmaceutically acceptable salt thereof" includes salts of at least one compound of Formula (I) , and salts of the stereoisomers of the compound of Formula (I) , such as salts of enantiomers, and/or salts of diastereomers.

The terms “administration” , “administering” , “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as the contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.

The term "effective amount" or “therapeutically effective amount” refers to an amount of the active ingredient, such as a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The term “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject. In the case of combination therapy, the term “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .

Throughout this specification and the claims which follow, unless the context requires otherwise, the term "comprise" , and variations such as "comprises" and "comprising" are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term "comprising" can be substituted with the term "containing" , "including" or sometimes "having" .

Throughout this specification and the claims which follow, the term “C _n-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C _1-8, C _1-6, and the like.

The term “at least one substituent” disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met. For example, “at least one substituent R ₄” disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R ₄ as disclosed herein.

EXAMPLES

Example 1: N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxamide (Compound 1) and 4-amino-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide (Compound 2)

Step 1. Methyl 3-amino-4-bromothiophene-2-carboxylate

A solution of methyl 3-aminothiophene-2-carboxylate (10.0 g, 63.6 mmol) in acetic acid (100 mL) was treated with Br ₂ (30.5 g, 191 mmol) dropwise. The reaction mixture was heated at 60℃ and stirred for 1 hour. The mixture was cooled to room temperature and poured into ice-cold water (200 mL) . The resulting mixture was filtered under reduced pressure. The solid was collected and dried in a vacuum to afford the titled compound (8.39 g, 55.9%yield) as a white solid. MS (ESI) : m/z 235.9 [M+H] ⁺.

Step 2. 7-Bromo-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidin-4 (3H) -one

A solution of methyl 3-amino-4-bromothiophene-2-carboxylate (7.09 g, 30.1 mmol) and isonicotinonitrile (3.1g, 30.1 mmol) in t-BuOH (70 mL) was treated with t-BuOK (8.42 g, 75.1 mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 12 hours. The solution was partitioned between EtOAc (200 mL) and water (200 mL) . The organic layer was separated and the aqueous layer was extracted with EtOAc (200 mL × 2) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA = 10/1 to 1/1, then DCM/MeOH = 50/1) to afford the titled compound (1.00 g, 10.8%yield) as a grey solid. MS (ESI) : m/z 309.9 [M+H] ⁺.

Step 3. Methyl 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxylate

A mixture of 7-bromo-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidin-4 (3H) -one (1.00 g, 3.25 mmol) , triethylamine (0.47 mL, 3.25 mmol) and Pd (dppf) Cl ₂ (2.37 g, 3.25 mmol) in MeOH (20 mL) was degassed with carbon monoxide. The mixture was heated at 120 ℃ under CO atmosphere in an autoclave (6 atm. ) for 2 hours. The mixture was cooled and solvent was removed in a vacuum. The residue was purified by silica gel chromatography (PE/EA = 10/1 to 1/1) to afford the titled compound (900 mg, 96.5%yield) as a grey solid. MS (ESI) : m/z 288.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.95 (s, 1H) , 8.81 (d, J = 6.0 Hz, 2H) , 8.13 (dd, J = 4.6, 1.5 Hz, 2H) , 3.88 (s, 3H) .

Step 4. 4-Oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxylic acid

A solution of methyl 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxylate (900 mg, 3.13 mmol) and LiOH. H ₂O (1.0 g, 10 mmol) in THF (10 mL) and H ₂O (5 mL) was stirred at 50℃ for 12 hours. The resulting mixture was cooled to room temperature and the pH of the mixture was adjusted to 3 with aqueous HCl (1.0 M) . The solvent was removed under reduced pressure to afford the titled compound (800 mg, 93.5%yield) which was used in the next step without purification. MS (ESI) : m/z 274.0 [M+H] ⁺.

Step 5. N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7- carboxamide (Compound 1)

A mixture of 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxylic acid (427 mg, 1.56 mmol) , DIPEA (0.28 mL, 1.56 mmol) and HATU (594 mg, 1.56 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes followed by cyclohexanamine (0.21 mL, 1.88 mmol) was added. The resulting mixture was stirred at room temperature overnight. The solution was partitioned between CH ₂Cl ₂ (30 mL) and water (40 mL) . The organic layer was separated and the aqueous layer was extracted with CH ₂Cl ₂ (30 mL × 2) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 100/1 to 30/1) to afford the titled compound (120 mg, 21.7%yield) . MS m/z (ESI) : 355.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 13.38 (s, 1H) , 9.13 (d, J = 7.6 Hz, 1H) , 8.86 (d, J = 6.0 Hz, 2H) , 8.81 (s, 1H) , 8.00 (d, J = 6.0 Hz, 2H) , 3.88 (s, 1H) , 1.92 (d, J = 5.4 Hz, 2H) , 1.68 (s, 2H) , 1.55 (s, 1H) , 1.46 –1.30 (m, 5H) .

Step 6. 4-Chloro-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide

A solution of N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxamide (100 mg, 0.282 mmol) in POCl ₃ (6.0 mL) was heated at 50 ℃ for 3 hours. The resulting mixture was cooled to room temperature and quenched with ice/water (30 mL) , then extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 100/1-30/1) to afford the titled compound (46 mg, 43.7%yield) as a white solid. MS (ESI) : m/z 373.0 [M+H] ⁺.

Step 7. 4-Amino-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide (Compound 2)

A solution of 4-chloro-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide (46 mg, 0.123 mmol) in NH ₃/MeOH (2 mL, 7.0 M) was heated at 80 ℃ for 8 hours in a microwave reactor. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH = 100/1 to 20/1) to afford the titled compound (19.38 mg, 44.4%yield) . MS m/z (ESI) : 354.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 9.63 (d, J = 7.6 Hz, 1H) , 8.82 –8.77 (m, 3H) , 8.16 (dd, J = 4.5, 1.5 Hz, 2H) , 8.06 (s, 2H) , 3.91 (s, 1H) , 1.99 (s, 2H) , 1.76 (s, 2H) , 1.65 –1.56 (m, 1H) , 1.49 –1.32 (m, 5H) .

Example 2: N- (2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide

Step 1. 2- (pyridin-4-yl) thieno [3, 4-d] pyrimidin-4 (3H) -one

Methyl 4-aminothiophene-3-carboxylate (3.5 g, 22.266 mmol) , isonicotinonitrile (5.1 g, 49.98 mmol) and THF (100 mL) were added to a 250 mL one-neck round-bottom flask. The mixture was stirred and cooled to 0 ～10℃. A solution of t-BuOK (6.2 g, 55.7 mmol) in THF (50 mL) was added drop wise. After addition, the mixture was warmed up to room temperature and stirred for an hour. The resulting mixture was quenched with water (100 mL) and the pH of the mixture was adjusted to 8～9 with HCl (2.0 M, aqueous) . The resulting mixture was extracted with EtOAc (200 mL *3) . The combined organic layers were washed with brine (150 mL) , dried over anhydrous Na ₂SO ₄, filtered in a vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH = 200/1 to 40/1) to give the titled compound (1.85 g, yield: 36%) as an off-white solid. MS m/z (ESI) : 230.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 12.16 (s, 1H) , 8.76 (dd, J = 4.5, 1.6 Hz, 2H) , 8.56 (d, J = 3.2 Hz, 1H) , 8.05 (dd, J = 4.5, 1.6 Hz, 2H) , 7.98 (d, J = 3.2 Hz, 1H) .

Step 2. 7-bromo-2- (pyridin-4-yl) thieno [3, 4-d] pyrimidin-4 (3H) -one

N- (2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide (1.0 g, 4.36 mmol) and DMF (30 mL) were added to a 100 mL one-neck round-bottom flask at room temperature. NBS (1.24 g, 7.0 mmol) was added, the mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL) . The mixture was extracted with EtOAc (200 mL*3) . The organic layers were combined, washed with brine (200 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 200/1 to 40/1) to give the titled compound (560 mg, yield: 41.7 %) as a yellow solid. MS m/z (ESI) : 310.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 12.33 (s, 1H) , 8.79 (d, J = 5.9 Hz, 2H) , 8.65 (s, 1H) , 8.08 (dd, J = 4.6, 1.5 Hz, 1H) .

Step 3. methyl 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxylate

A mixture of 7-bromo-2- (pyridin-4-yl) thieno [3, 4-d] pyrimidin-4 (3H) -one (650 mg, 2.11 mmol) , Pd (dppf) Cl ₂. CH ₂Cl ₂ (150 mg, 0.19 mmol) , TEA (852 mg, 8.44 mmol) and MeOH (80 mL) was heated at 120℃ under an atmosphere of CO (450 psi) for 3 hours. The resulting mixture was cooled and filtered in a vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 200/1 to 40/1) to give the titled compound (600 mg, yield: 99.0 %) as a yellow solid. MS m/z (ESI) : 287.9 [M+H] ⁺.

Step 4. 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxylic acid

A mixture of methyl 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxylate (550 mg, 1.92 mmol) , LiOH. H ₂O (403 mg, 9.6 mmol) , water (15 mL) and MeOH (30 mL) was stirred at 50 ℃ for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (10 mL) and the pH of the mixture was adjusted to 5～6 to obtain a solid. The solid was collected by filtration and dried in a vacuum to give the titled compound (275 mg, yield: 52.6 %) as a yellow solid. MS m/z (ESI) : 274.0 [M+H] ⁺.

Step 5. N- (2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4- d] pyrimidine-7-carboxamide

A mixture of 4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxylic acid (250 mg, 0.91 mmol) , 2, 3-dihydro-1H-inden-2-amine (182 mg, 1.37 mmol) , DIEA (470 mg, 3.64 mmol) and DMF (10 mL) was stirred for 5 minutes before HATU (418 mg, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (60 mL) . The whole was extracted with EtOAc (100 mL *3) . The organic layers were combined, washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 200/1 to 40/1, 300～400 mesh silica gel) to afford the crude compound (410 mg) , which was recrystallized with EtOAc/Petroleum ether (1/1, 5.0 mL) to afford the titled compound (120 mg, yield: 34.0%) . MS m/z (ESI) : 389.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 12.51 (s, 1H) , 9.09 (d, J = 7.7 Hz, 1H) , 8.81 –8.68 (m, 3H) , 7.67 (d, J = 6.1 Hz, 2H) , 7.37 (dd, J = 5.1, 3.3 Hz, 2H) , 7.25 (dd, J = 5.4, 3.2 Hz, 2H) , 4.85 –4.78 (m, 1H) , 3.39 –3.33 (m, 2H) , 2.95 (dd, J = 16.2, 2.3 Hz, 2H) .

The compounds below were synthesized following the procedures described for compound 3.

Example 3: N-cyclohexyl-5- (pyridin-4-yl) benzo [d] isoxazole-3-carboxamide

Step 1. Ethyl 2- (5-bromo-2-fluorophenyl) -2-oxoacetate

A solution of 4-bromo-1-fluoro-2-iodobenzene (5.00 g, 16.6 mmol) in THF (10 mL) was treated with i-PrMgCl (8.31 mL, 16.6 mmol, 1.0 M in THF) dropwise at -30 ℃ to -40 ℃. The resulting mixture was stirred at this temperature for 30 minutes, then cooled to -70 ℃, followed by the addition of (COOEt) ₂ (4.54 mL, 33.2 mmol) in one portion. The reaction mixture was stirred at -10 ℃ for 1 hour. The resulting mixture was quenched with aqueous NH ₄Cl (30 mL) , then extracted with EA (100 mL × 2) . The combined organic layers were washed with brine (50 mL × 3) , dried over anhydrous Na ₂SO ₄, filtered and concentrated to give the titled compound (7.00 g , 100%yield) as a white solid.

Step 2. (E) -ethyl 2- (5-bromo-2-fluorophenyl) -2- (hydroxyimino) acetate

To a solution of ethyl 2- (5-bromo-2-fluorophenyl) -2-oxoacetate (7.00 g, 25.4 mmol) in EtOH (30 mL) was added hydroxylamine hydrochloride (1.95 g, 28.0 mmol) and NaOAc (2.40 g, 29.3 mmol) , and the reaction mixture was stirred at room temperature for 3 hours and then heated to 50 ℃ for 1 hour. The mixture was allowed to cool to room temperature and filtered in a vacuum. The solid was washed with EtOH (20 mL x 3) . The filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EA (100 mL x 3) . The combined organic layers were washed with water (50 mL) , dried over anhydrous Na ₂SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 0/1 to 1/50) to afford the titled compound (3.80 g, 51.5%yield) as a thick oil. MS (ESI) : m/z 290.0 [M+H] ⁺.

Step 3. Ethyl 5-bromobenzo [d] isoxazole-3-carboxylate

To a solution of (E) -ethyl 2- (5-bromo-2-fluorophenyl) -2- (hydroxyimino) acetate (3.90 g, 13.4 mmol) in DMF (10 mL) and THF (10 mL) was added NaH (810 mg, 20.2 mmol, 60%in oil) in portions. The resulting mixture was stirred at 70 ℃ for 4 hours. The mixture was allowed to cool to RT and filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with water (100 mL) and extracted with EA (100 mL × 3) . The combined organic layers were washed with water (50 mL) , dried over anhydrous Na ₂SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 0/1 to 1/60) to afford the titled compound (1.17 g, 32.2%yield) as a white solid.

Step 4. Ethyl 5- (pyridin-4-yl) benzo [d] isoxazole-3-carboxylate

A mixture of ethyl 5-bromobenzo [d] isoxazole-3-carboxylate (300 mg, 1.11 mmol) , pyridin-4-ylboronic acid (205 mg, 1.67 mmol) , Pd (PPh ₃) ₄ (128 mg, 0.111 mmol) , Na ₂CO ₃ (294 mg, 2.78 mmol) , dioxane (8.0 mL) and H ₂O (1.0 mL) was degassed with argon for 3 times and stirred at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature, diluted with EA (100 mL) and washed with brine (100 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was slurried with EA/PE (1/10, 22 mL) to afford the titled compound (100 mg, 33.6%yield) as a light-yellow solid. MS (ESI) : m/z 269.0 [M+H] ⁺.

Step 5. N-cyclohexyl-5- (pyridin-4-yl) benzo [d] isoxazole-3-carboxamide

A mixture of ethyl 5- (pyridin-4-yl) benzo [d] isoxazole-3-carboxylate (90 mg, 0.335 mmol) , cyclohexylamine (0.15 mL, 1.342 mmol) and EtOH (4.0 mL) was stirred at 100 ℃ for 2 hours. The resulting mixture was purified by prep-HPLC (Basi method: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10um 20*250 nm, Mobile Phase A: 0.1%NH ₄OH in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (3.97 mg, 3.7%yield) . MS (ESI) : m/z 322.5 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 9.01 (d, J = 8.2 Hz, 1H) , 8.68 (d, J = 5.9 Hz, 2H) , 8.39 (d, J = 1.0 Hz, 1H) , 8.16 (dd, J = 8.9, 1.6 Hz, 1H) , 8.02 (d, J = 8.8 Hz, 1H) , 7.78 (d, J = 6.0 Hz, 2H) , 3.85 (s, 1H) , 1.86 (d, J = 12.5 Hz, 2H) , 1.76 (d, J = 12.3 Hz, 2H) , 1.62 (d, J = 13.5 Hz, 1H) , 1.46 –1.27 (m, 4H) , 1.19 –1.09 (m, 1H) .

Example 4: N-cyclohexyl-2- (pyridin-4-yl) -1H-indole-4-carboxamide

Step 1. N-cyclohexyl-1H-indole-4-carboxamide

To a mixture of 1H-indole-4-carboxylic acid (2.00 g, 12.4 mmol) , HATU (5.66 g, 14.9 mmol) , DIEA (6.10 mL, 37.2 mmol) in DCM (20 mL) was added cyclohexanamine (1.70 mL, 14.9 mmol) . The reaction mixture was stirred at room temperature for 2 hours before diluting with EA (100 mL) and washed with brine (100 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE = 0/1 -1/10) to afford the titled compound (1.30 g, 43.2%yield) as a white solid. MS (ESI) : m/z 243.1 [M+H] ⁺.

Step 2. tert-butyl 4- (cyclohexylcarbamoyl) -1H-indole-1-carboxylate

To a solution of N-cyclohexyl-1H-indole-4-carboxamide (1.10 g, 4.54 mmol) in THF (25 mL) were added t-BuOK (356 mg, 3.18 mmol) and Boc ₂O (1.08 g, 4.99 mmol) , and the mixture was stirred at 70 ℃ for 3 hours. The reaction solution was cooled to room temperature before EA (100 mL) and H ₂O (50 mL) were added. The organic layer was separated, washed with brine (30 mL) and dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with EA /PE (1/5, 18 mL) to afford the titled compound (1.2 g, 77.2%yield) as a white solid. MS (ESI) : m/z 343.1 [M+H] ⁺.

Step 3. tert-butyl 2-bromo-4- (cyclohexylcarbamoyl) -1H-indole-1-carboxylate

To a solution of tert-butyl 4- (cyclohexylcarbamoyl) -1H-indole-1-carboxylate (700 mg, 2.04 mmol) in THF (10 mL) at -78 ℃ under N ₂ atmosphere was added LDA (3.07 mL, 6.14 mmol, 2.0 M in THF) dropwise. The reaction mixture was stirred at -78 ℃ for 30 minutes and added a solution of 1, 2-dibromo-1, 1, 2, 2-tetrachloroethane (2.00 g, 6.14 mmol) in THF (5.0 mL) . The mixture was stirred at the same temperature for 2 hours and aqueous NH ₄Cl (10 mL) was added dropwise to quench the reaction. The resulting mixture was mixed with EA (100 mL) and brine (50 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting (EA/PE = 0/1 to 1/5) to afford the titled compound (550 mg, 1.31 mmol, 64.0%yield) as a white solid. MS (ESI) : m/z 421.1 [M+H] ⁺.

Step 4. N-cyclohexyl-2- (pyridin-4-yl) -1H-indole-4-carboxamide

A mixture of tert-butyl 2-bromo-4- (cyclohexylcarbamoyl) -1H-indole-1-carboxylate (150 mg, 0.356 mmol) , pyridin-4-ylboronic acid (65.6 mg, 0.534 mmol) , Pd (PPh ₃) ₄ (41.1 mg, 0.036 mmol) , Na ₂CO ₃ (75.5 mg, 0.712 mmol) in dioxane (2 mL) and H ₂O (0.5 mL) was degassed with argon for 3 times. The mixture was stirred at 120 ℃ for 30 minutes. The mixture was cooled and concentrated under reduced pressure. The residue was purified by prep-HPLC (system: Waters 2767/2545/2489/Qda, Inertsil ODS-3 10um 20*250nm, Mobile Phase A: 0.1%FA in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (13.7 mg, 0.04 mmol, 12.0%yield) . MS (ESI) : m/z 320.5 [M+H] ⁺; ¹H NMR (400MHz, DMSO-d6) δ 11.95 (s, 1H) , 8.63 (d, J = 5.9 Hz, 2H) , 8.09 (d, J = 7.9 Hz, 1H) , 7.83 (d, J = 6.0 Hz, 2H) , 7.56 (d, J = 8.2 Hz, 1H) , 7.49 (s, 1H) , 7.42 (d, J = 7.3 Hz, 1H) , 7.22 (t, J = 7.7 Hz, 1H) , 3.89 –3.77 (m, 1H) , 1.93 –1.84 (m, 2H) , 1.80 –1.70 (m, 2H) , 1.63 (d, J = 12.2 Hz, 1H) , 1.45 –1.27 (m, 4H) , 1.22 –1.08 (m, 1H) .

Example 5: N-cyclohexyl-3- (pyridin-4-yl) -1H-indole-5-carboxamide

Step 1. Methyl 3-bromo-1H-indole-5-carboxylate

To a solution of methyl 1H-indole-5-carboxylate (2.00 g, 11.4 mmol) in DMF (50 mL) was added NBS (3.05 g, 17.1 mmol) by portions and the mixture was stirred at room temperature for 4.0 hours. Water (60 mL) was added and the resulting mixture was extracted with EA (50 mL × 2) . The combined organic layers were washed with NaHCO ₃ solution (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was slurried with PE/EA (90 mL, PE/EA=15/1) . The resulting mixture was filtered and the solid was collected and dried in a vacuum to give the titled compound (2.40 g, 82.8%yield) as a yellow solid. MS (ESI) : m/z 254.0 [M+H] ⁺.

Step 2. 1-tert-butyl 5-methyl 3-bromo-1H-indole-1, 5-dicarboxylate

To a solution of methyl 3-bromo-1H-indole-5-carboxylate (1.40 g, 5.51 mmol) in THF (30 mL) was added Boc ₂O (3.56 g, 16.5 mmol) , DIEA (3.89 mL, 22.0 mmol) and DMAP (340 mg, 2.75 mmol) . The reaction mixture was stirred at room temperature for 1 hour and was diluted with EA (100 mL) and washed with brine (80 mL) . The organic layer was separated, washed with aqueous HCl (0.1 M, 50 mL) and brine (50 mL) and concentrated. The residue was slurried with EA/PE (1/4, 50 mL) to afford the titled compound (2.00 g, 100 %yield) as a yellow solid.

Step 3. Methyl 3- (pyridin-4-yl) -1H-indole-5-carboxylate

A mixture of 1-tert-butyl 5-methyl 3-bromo-1H-indole-1, 5-dicarboxylate (500 mg, 1.41 mmol) , pyridin-4-ylboronic acid (260 mg, 2.12 mmol) , Na ₂CO ₃ (299 mg, 2.82 mmol) , Pd (PPh ₃) ₄ (82 mg, 0.07 mmol) in dioxane (12 mL) and water (3.0 mL) was bubbled with N ₂ for 3 minutes. The reaction tube was sealed and heat under microwave at 120 ℃ for 30 minutes. The mixture was cooled to room temperature and diluted with water (60 mL) , extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA = 2/1 –1/3) to afford the titled compound (99.0 mg, 27.8%yield) as a yellow solid. MS (ESI) : m/z 253.0 [M+H] ⁺.

Step 4. 3- (pyridin-4-yl) -1H-indole-5-carboxylic acid

To a solution of methyl 3- (pyridin-4-yl) -1H-indole-5-carboxylate (99.0 mg, 0.39 mmol) in MeOH (10 mL) was added NaOH (31.4 mg, 0.78 mmol) . The reaction mixture was heated at 80 ℃ for 2.0 hours. The mixture was cooled room temperature and the pH was adjusted to 7～8 with aqueous HCl (1.0 M) . The mixture was concentrated under vacuum to afford the titled compound (94 mg, 100%yield) as a yellow solid, which was used for next step without further purification. LC-MS (ESI) : m/z 239.0 [M+H] ⁺.

Step 5. N-cyclohexyl-3- (pyridin-4-yl) -1H-indole-5-carboxamide

To a solution of 3- (pyridin-4-yl) -1H-indole-5-carboxylic acid (93.5 mg, 0.39 mmol) in DMF (10 mL) were added DIEA (0.290 mL, 1.73 mmol) and HATU (1.79 g, 0.47 mmol) . The reaction was stirred at room temperature for 30 minutes and cyclohexanamine (200 mg, 0.74 mmol) was added. The resulting mixture was stirred at room temperature for 3.5 hours. The resulting mixture was diluted with water (60 mL) , extracted with ethyl acetate (50 mL × 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (DCM/MeOH = 200/1 –20/1) to afford the titled compound (60.4 mg, 48.2%yield) . MS (ESI) : m/z 320.5 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ11.88 (s, 1H) , 8.59 (d, J = 5.6 Hz, 2H) , 8.45 (2, 1H) , 8.21 (d, J = 8.0 Hz, 1H) , 8.10 (d, J = 2.8 Hz, 1H) , 7.79 (d, J = 6.0 Hz, 2H) , 7.73 (d, J = 8.8 Hz, 1H) , 7.50 (d, J = 8.4 Hz, 1H) , 3.82 (s, 1H) , 1.86 –1.74 (m, 3H) , 1.65 –1.61 (m, 1H) , 1.38 –1.14 (m, 5H) .

The compounds below were synthesized following procedures described for Compound 23.

Example 6: N-cyclohexyl-2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxamide

Step 1. methyl 2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxylate

To a solution of NaHSO ₃ (2.51 g, 24.1 mmol) in water (15 mL) were added methyl 2, 3-diaminobenzoate (1.00 g, 6.02 mmol) and a solution of isonicotinaldehyde (0.57 mL, 6.02 mmol) in EtOH (2.0 mL) at room temperature. The reaction mixture was stirred at that temperature for 1 hour and then heated to 100 ℃ for 18 hours. The mixture was cooled to room temperature and mixed with ethyl acetate (100 mL) and washed with water (50 mL) . The organic layer was separated, washed with brine (5.0 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 0/1 –1/1) to afford the titled compound (700 mg, 46.1%yield) as a yellow solid. MS (ESI) : m/z 252.1 [M+H] ⁺.

Step 2. 2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxylic acid

To a solution of methyl 2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxylate (700 mg, 2.76 mmol) in MeOH (20 mL) and H ₂O (5.0 mL) was added NaOH (444 mg, 11.1 mmol) and the reaction mixture was stirred at 80℃ for 18 hours. The mixture was cooled to room temperature and adjusted the pH of the mixture to 7～8 with aqueous HCl (1.0 M) and concentrated under reduced pressure. The pH of the mixture was further adjusted to 3～4 with aqueous HCl (4.0 M) and concentrated to afford the titled compound (600 mg, 90.7%yield) as a brown solid. MS (ESI) : m/z 240.4 [M+H] ⁺.

Step 3. N-cyclohexyl-2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxamide

To a solution of 2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxylic acid (350 mg, 1.46 mmol) in DMF (10 mL) was added DIEA (0.48 mL, 2.93 mmol) , HATU (723 mg, 1.90 mmol) and cyclohexanamine (0.20 mL, 1.76 mmol) . The mixture was stirred at room temperature for 1 hr and diluted with H ₂O (20 mL) , then extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column (PE/EA = 100/1 to 1/3) to afford the titled compound (102 mg, 22.0%yield) as a pink solid. MS (ESI) : m/z 321.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) 13.80 (s, 1H) , 9.93 (d, J = 7.7 Hz, 1H) , 8.87 –8.82 (m, 2H) , 8.12 (dd, J = 4.6, 1.5 Hz, 2H) , 7.93 (d, J = 7.5 Hz, 1H) , 7.80 (d, J = 7.3 Hz, 1H) , 7.43 (t, J = 7.8 Hz, 1H) , 3.99 (s, 1H) , 1.98 (d, J = 12.7 Hz, 2H) , 1.79 (d, J = 3.7 Hz, 2H) , 1.60 (d, J = 6.9 Hz, 1H) , 1.55 –1.37 (m, 5H) .

Example 7: N-cyclohexyl-8- (pyridin-4-yl) -9H-purin-6-amine

A mixture of 6-chloro-8- (pyridin-4-yl) -9H-purine (50.0 mg, 0.216 mmol) , cyclohexanamine (0.15 mL, 1.30 mmol) and n-BuOH (3.0 mL) was degassed with argon for 3 times, then heated to 120 ℃ for 3.0 hours. The resulting mixture was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10um OBD 19*250 mm, Mobile Phase A: 0.1%NH ₄OH in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min, Column temp: RT) to afford the titled compound (26.43 mg, 41.6%yield) . MS (ESI) : m/z 321.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) 8.72 (dd, J = 4.6, 1.5 Hz, 2H) , 8.20 (s, 1H) , 8.05 (dd, J = 4.6, 1.6 Hz, 2H) , 7.55 (d, J = 8.0 Hz, 1H) , 4.12 (s, 1H) , 1.91 (s, 2H) , 1.76 (d, J = 12.1 Hz, 2H) , 1.64 (d, J = 12.5 Hz, 1H) , 1.44 –1.32 (m, 4H) , 1.16 (d, J = 9.9 Hz, 1H) .

Example 8: N-cyclohexyl-7- (pyridin-4-yl) -5H-pyrrolo [3, 2-d] pyrimidin-2-amine

Step 1. 7-bromo-N-cyclohexyl-5H-pyrrolo [3, 2-d] pyrimidin-2-amine

A mixture of 7-bromo-2-chloro-5H-pyrrolo [3, 2-d] pyrimidine (1.00 g, 4.30 mmol) , cyclohexanamine (2.94 mL, 25.8 mmol) in NMP (6.0 mL) was degassed with argon for 3 times. The reaction mixture was stirred at 180℃ for 6 hours. The resulting mixture was cooled to room temperature and diluted with H ₂O (20 mL) , extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE/EA = 50: 1 to 1: 1) to afford the titled compound (474 mg, 37.3%yield) as a white solid. MS (ESI) : m/z 295.2 [M+H] ⁺.

Step 2. tert-butyl 7-bromo-2- (cyclohexylamino) -5H-pyrrolo [3, 2-d] pyrimidine-5-carboxylate

To a solution of 7-bromo-N-cyclohexyl-5H-pyrrolo [3, 2-d] pyrimidin-2-amine (474 mg, 1.60 mmol) in THF (10 mL) was added DIEA (2.13 mL, 12.8 mmol) , DMAP (392 mg, 3.21 mmol) and Boc ₂O (2.10 g, 9.64 mmol) . The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with aqueous NaHCO ₃ (10 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by slurring (PE/EA = 5/1) to afford the titled compound (400 mg, 63.0%yield) as a yellow solid. MS (ESI) : m/z 333.9 [M+H] ⁺.

Step 3. N-cyclohexyl-7- (pyridin-4-yl) -5H-pyrrolo [3, 2-d] pyrimidin-2-amine

A mixture of tert-butyl 7-bromo-2- (cyclohexylamino) -5H-pyrrolo [3, 2-d] pyrimidine-5-carboxylate (200 mg, 0.50 mmol) , pyridin-4-ylboronic acid (93.3 mg, 0.76 mmol) , Pd (PPh ₃) ₄ (58.5 mg, 0.05 mmol) , K ₂CO ₃ (140 mg, 1.01 mmol) in dioxane (4.0 mL) and H ₂O (0.8 mL) was degassed with argon for 3 times, and the mixture was heated at 120 ℃ for 4 hours. The mixture was cooled to room temperature, diluted with H ₂O (20 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Base method: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10um 20*250nm, Mobile Phase A: 0.1%NH ₄OH in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (5.05 mg, 3.4%yield) . MS (ESI) : m/z 294.5 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 11.72 (s, 1H) , 8.53 (s, 1H) , 8.48 (d, J = 6.0 Hz, 2H) , 8.33 (s, 1H) , 8.19 (d, J = 6.0 Hz, 2H) , 6.44 (d, J = 7.7 Hz, 1H) , 3.82 –3.72 (m, 1H) , 2.00 (d, J = 10.9 Hz, 2H) , 1.76 (d, J = 12.7 Hz, 2H) , 1.62 (s, 1H) , 1.38 –1.23 (m, 5H) .

The compounds below were synthesized following procedures described for Compound 28

Example 9: N-cyclohexyl-6- (pyridin-4-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-amine

Step 1. 6-bromo-4-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2, 3-d] pyrimidine.

To a solution of 4-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2, 3-d] pyrimidine (2.00 g, 6.80 mmol) in THF (40 mL) at -78 ～ -70 ℃ under N ₂ atmosphere was added LDA (6.80 mL, 13.6 mmol, 2.0 M in THF) dropwise. The mixture was stirred at -78 ～ -70 ℃ for 30 minutes followed by adding a solution of 1, 2-dibromo-1, 1, 2, 2-tetrachloroethane (4.43 g, 13.6 mmol) in THF (20 mL) . The reaction mixture was stirred at -78 ～ -70 ℃ for 2 hours. Aqueous NH ₄Cl (10 mL) was added and the resulting mixture was diluted with EA (100 mL) and washed with brine (50 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was slurried with EA/PE (1/1, 60 mL) to afford the titled compound (1.26 g, 49.5%yield) as a brown solid. MS (ESI) : m/z 371.8 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.86 (s, 1H) , 8.13 –8.09 (m, 2H) , 7.81 (d, J = 7.5 Hz, 1H) , 7.71 (t, J = 7.9 Hz, 2H) , 7.32 (s, 1H) .

Step 2. 6-Bromo-N-cyclohexyl-7H-pyrrolo [2, 3-d] pyrimidin-4-amine

A mixture of 6-bromo-4-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2, 3-d] pyrimidine (650 mg, 1.74 mmol) , cyclohexanamine (865 mg, 8.72 mmol) , DIEA (450 mg, 3.49 mmol) in n-BuOH (30 mL) was stirred at 120℃ for 4 hours. The resulting mixture was cooled to room temperature and diluted with EA (100 mL) and washed with brine (100 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA/PE = 0/1 to 2/3) to afford the titled compound (260 mg, 26.1%yield) as a brown solid. MS (ESI) : m/z 294.9 [M+H] ⁺.

Step 3. N-cyclohexyl-6- (pyridin-4-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-amine

A mixture of 6-bromo-N-cyclohexyl-7H-pyrrolo [2, 3-d] pyrimidin-4-amine (150 mg, 0.51 mmol) , pyridin-4-ylboronic acid (93.7 mg, 0.76 mmol) , Pd (PPh ₃) ₄ (58.7 mg, 0.05 mmol) , Na ₂CO ₃ (108 mg, 1.02 mmol) in dioxane (6.0 mL) and water (2.0 mL) was bubbled with N ₂ for 3 minutes. The reaction tube was sealed and heated at 150 ℃ for 30 minutes under a microwave reactor. The resulting mixture was cooled to room temperature and diluted with EA (40 mL) and brine (30 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (Base method: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10um 20*250 nm, Mobile Phase A: 0.1%NH ₄OH in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (26.36 mg, 17.7%yield) . MS (ESI) : m/z 294.5 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 12.26 (s, 1H) , 8.58 (d, J = 4.1 Hz, 2H) , 8.15 (s, 1H) , 7.71 (d, J = 4.8 Hz, 2H) , 7.44 (d, J = 7.8 Hz, 1H) , 7.30 (s, 1H) , 4.06 (s, 1H) , 1.96 (d, J = 9.5 Hz, 2H) , 1.75 (s, 2H) , 1.64 (d, J = 12.2 Hz, 1H) , 1.41 –1.14 (m, 6H) .

The compounds below were synthesized following procedures described for Compound 9.

Example 10: 2- (cyclohexylamino) -7- (1H-imidazol-1-yl) thieno [3, 2-d] pyrimidin-4 (3H) -one

Step 1. 7-bromo-2- (cyclohexylamino) thieno [3, 2-d] pyrimidin-4 (3H) -one

A mixture of 7-bromo-2-chlorothieno [3, 2-d] pyrimidin-4 (3H) -one (322 mg, 1.21 mmol) and cyclohexanamine (1.38 mL, 12.1 mmol) in NMP (3 mL) was heated at 180 ℃ for 3 hours. The resulting mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL × 3) . The combined organic phases were washed with brine (60 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA = 20/1 -2/1) to afford the titled compound (400 mg, 87.5%yield) as a brown solid. MS (ESI) : m/z 330.1 [M+H] ⁺.

Step 2. 2- (cyclohexylamino) -7- (1H-imidazol-1-yl) thieno [3, 2-d] pyrimidin-4 (3H) -one

A mixture of 7-bromo-2- (cyclohexylamino) thieno [3, 2-d] pyrimidin-4 (3H) -one (100 mg, 0.31 mmol) , imidazole (41.1 mg, 0.609 mmol) , Cs ₂CO ₃ (198 mg, 0.609 mmol) , CuI (6 mg, 0.030 mmol) and (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (4 μL, 0.030 mmol) in DMF (1 mL) was heated at 120 ℃ under N ₂ atmosphere in a microwave reactor for 0.5 h. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL × 2) . The combined organic phases were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 100/1 -20/1) to afford the titled compound (10.43 mg, 10.9%yield) . MS (ESI) : m/z 316.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 10.88 (s, 1H) , 8.53 (s, 1H) , 8.20 (s, 1H) , 7.88 (s, 1H) , 7.09 (s, 1H) , 6.50 (s, 1H) , 3.73 –3.70 (m, 1H) , 1.94 (d, J = 10.9 Hz, 2H) , 1.72 –1.67 (m, 2H) , 1.60 –1.56 (m, 1H) , 1.40 –1.19 (m, 5H) .

Example 11: N-cyclohexyl-5- (thiazol-5-yl) -1H-indazol-3-amine (compound 33) and 1- (3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazol-1-yl) ethanone (compound 34)

Step 1. 5-bromo-N-cyclohexyl-1H-indazol-3-amine

To a mixture of cyclohexanone (1.17 mL, 11.3 mmol) , 5-bromo-1H-indazol-3-amine (2.00 g, 9.43 mmol) in AcOH (20 mL) was added NaCNBH ₃ (1.19 g, 18.9 mmol) . The reaction mixture was heated at 50 ℃ under N ₂ atmosphere for 12 hours. The mixture was cooled to room temperature, diluted with H ₂O (50 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column (PE/EA = 50/1 to 1/1) to afford the titled compound (900 mg, 32.5%yield) as a white solid. MS (ESI) : m/z 296.0 [M+H] ⁺.

Step 2. tert-butyl 5-bromo-3- (cyclohexylamino) -1H-indazole-1-carboxylate

To a solution of 5-bromo-N-cyclohexyl-1H-indazol-3-amine (0.90 g, 3.06 mmol) in THF (20 mL) were added DIEA (2.53 mL, 15.3 mmol) , DMAP (190 mg, 1.53 mmol) and Boc ₂O (2.67 g, 12.2 mmol) . The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with aqueous NaHCO ₃ (10 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by slurring (PE/EA = 5/1, 5.0 mL) to afford the titled compound (900 mg, 74.6%yield) as a white solid. MS (ESI) : m/z 394.0 [M+H] ⁺.

Step 3. tert-butyl 3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazole-1-carboxylate.

A mixture of tert-butyl 5-bromo-3- (cyclohexylamino) -1H-indazole-1-carboxylate (300 mg, 0.76 mmol) , 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (161 mg, 0.76 mmol) , Pd (PPh ₃) ₄ (87.9 mg, 0.076 mmol) , Na ₂CO ₃ (161 mg, 1.52 mmol) in dioxane (8.0 mL) and H ₂O (2.0 mL) was bubbled with N ₂ for 3 minutes. The mixture was heated at 120℃ for 30 minutes with a microwave reactor. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and washed with brine (30 mL) . The organic layer was separated, dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA/PE = 1/100 to 1/4) to afford the titled compound (120 mg, 39.6%yield) as a yellow solid. MS (ESI) : m/z 399.1 [M+H] ⁺.

Step 4. N-cyclohexyl-5- (thiazol-5-yl) -1H-indazol-3-amine (Compound 33)

A mixture of tert-butyl 3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazole-1-carboxylate (170 mg, 0.43 mmol) and HCl/MeOH (4.0 M, 5.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10um OBD 19*250 mm, Mobile Phase A: 0.1%HCl in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min, Column temp: RT) to afford the titled compound (17.63 mg, 12.3%yield) . MS (ESI) : m/z 299.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ13.26 (s, 1H) , 9.10 (s, 1H) , 8.50 (d, J = 9.6 Hz, 1H) , 8.29 (s, 1H) , 7.98 (d, J = 8.8 Hz, 1H) , 7.49 (d, J = 8.8 Hz, 1H) , 3.61 (s, 1H) , 2.05 (s, 2H) , 1.77 (s, 2H) , 1.64 (d, J = 11.5 Hz, 1H) , 1.46 –1.28 (m, 4H) , 1.21 (s, 1H) .

Step 5. 1- (3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazol-1-yl) ethanone (Compound 34)

A mixture of N-cyclohexyl-5- (thiazol-5-yl) -1H-indazol-3-amine (83.0 mg, 0.280 mmol) , DIEA (0.120 mL, 0.690 mmol) , acetic anhydride (0.03 mL, 0.28 mmol) and DMAP (3.40 mg, 0.028 mmol) in THF (10 mL) was stirred at room temperature for 5 hours. The mixture was diluted with H ₂O (20 mL) and the resulting mixture was extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column (PE/EA = 50/1 to 5/1) to afford the titled compound (16.60 mg, 17.5%yield) . MS (ESI) : m/z 341.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) 9.11 (s, 1H) , 8.30 (d, J = 6.0 Hz, 2H) , 8.24 (d, J = 8.6 Hz, 1H) , 7.93 (dd, J = 8.6, 1.4 Hz, 1H) , 6.91 (d, J = 7.2 Hz, 1H) , 3.62 (s, 1H) , 2.52 (d, J = 12.9 Hz, 3H) , 2.11 (d, J = 9.0 Hz, 2H) , 1.77 (s, 2H) , 1.64 (d, J = 12.1 Hz, 1H) , 1.40 –1.15 (m, 5H) .

The compounds below were synthesized following procedures described for Compound 34.

Example 12: N-cyclohexyl-7- (thiazol-5-yl) benzo [d] oxazol-2-amine

Step 1. 7-bromo-N-cyclohexylbenzo [d] oxazol-2-amine

A mixture of 2-amino-6-bromophenol (200 mg, 1.06 mmol) , isocyanocyclohexane (139 mg, 1.27 mmol) , Pd (PPh ₃) ₄ (123 mg, 0.106 mmol) in dioxane (5.0 mL) was degassed with argon 3 times and the mixture was heated at 50 ℃ for 8 hours. The mixture was diluted with H ₂O (20 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column (PE/EA = 100/1 to 15/1) to afford the titled compound (170 mg, 54.1%yield) as a white solid. MS (ESI) : m/z 295.0 [M+H] ⁺.

Step 2. N-cyclohexyl-7- (thiazol-5-yl) benzo [d] oxazol-2-amine

A mixture of 7-bromo-N-cyclohexylbenzo [d] oxazol-2-amine (140 mg, 0.47 mmol) , 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (140 mg, 0.66 mmol) , Pd (PPh ₃) ₄ (54.8 mg, 0.047 mmol) , Na ₂CO ₃ (101 mg, 0.95 mmol) in dioxane (2.0 mL) and H ₂O (0.50 mL) was bubbled with argon for 3 minutes. The reaction tube was sealed and heated at 150 ℃ for 30 minutes in a microwave reactor. The mixture was cooled to room temperature, diluted with H ₂O (20 mL) and extracted with EA (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10um OBD 19*250 mm, Mobile Phase A: 0.1%FA in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min, Column temp: RT) to afford the titled compound (6.11 mg, 4.3%yield) . MS (ESI) : m/z 300.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) 9.20 (s, 1H) , 8.47 (s, 1H) , 8.12 (d, J = 7.8 Hz, 1H) , 7.30 (d, J = 7.6 Hz, 1H) , 7.24 (d, J = 6.6 Hz, 1H) , 7.18 (t, J = 7.7 Hz, 1H) , 3.58 (s, 1H) , 2.00 (s, 2H) , 1.75 (s, 2H) , 1.60 (d, J = 11.3 Hz, 1H) , 1.32 (d, J = 9.2 Hz, 4H) , 1.21 (d, J = 15.3 Hz, 1H) .

Example 13: 4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methyl-6- (1H-pyrazol-4-yl) quinolin-2 (1H) -one

Step1. Ethyl 3- ( (4-bromophenyl) (methyl) amino) -3-oxopropanoate.

A solution of 4-bromo-N-methylaniline (116 g, 623 mmol) and DIEA (332 mL, 1.87 mol) in DCM (500 mL) was cooled to 0 ～ 10 ℃ followed by adding a solution of ethyl 3-chloro-3-oxopropanoate (96.3 mL, 748 mmol) in DCM (500 mL) dropwise. The reaction mixture was warmed up to room temperature and stirred at that temperature for 2 h. Diluted the mixture with DCM (1L) and brine (500 mL) . The organic layer was separated, washed with brine (500 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE = 0/1 -2/3) to afford the titled compound (79.6 g, 42.5%yield) as an off-white solid. MS (ESI) : m/z 299.9 [M+H] ⁺.

Step 2. 3- ( (4-bromophenyl) (methyl) amino) -3-oxopropanoic acid

To a solution of ethyl 3- ( (4-bromophenyl) (methyl) amino) -3-oxopropanoate (71.0 g, 237 mmol) in THF (700 mL) was added a solution of LiOH. H ₂O (20.0 g, 473 mmol) in H ₂O (700 mL) . The reaction mixture was stirred at room temperature for 4 hours. The pH of reaction mixture was adjusted to 1～2 with HCl (10 M) and extracted with ethyl acetate (1L) . The organic layer was separated, washed with brine (400 mL) , dried over Na ₂SO ₄ and filtered in a vacuum. The filtrate was concentrated under reduced pressure. The residue was slurried with EA/PE (EA/PE = 1/10, 1L) to afford the titled compound (58.7 g, 85.8%yield) as an off-white solid. MS (ESI) : m/z 272.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 12.54 (s, 1H) , 7.66 (d, J = 7.9 Hz, 2H) , 7.32 (d, J = 8.0 Hz, 2H) , 3.62 -3.13 (m, 5H) .

Step 3. 6-bromo-4-hydroxy-1-methylquinolin-2 (1H) -one

A mixture of 3- ( (4-bromophenyl) (methyl) amino) -3-oxopropanoic acid (65.0 g, 239 mmol) and PPA (200 mL) was stirred at 100 ℃ for 18 hours before being cooled to room temperature and poured into ice/water (1.5 L) . The mixture was stirred at room temperature for 2 hours and filtered in a vacuum. The solid was washed with water (500 mL×2) , collected and dried in a vacuum at 50 ℃ for 16 hours to afford the titled compound (63.52 g, 100%yield) as an off-white solid. MS (ESI) : m/z 254.4 [M+H] ⁺.

Step 4. 6-bromo-4-chloro-1-methylquinolin-2 (1H) -one

A mixture of 6-bromo-4-hydroxy-1-methylquinolin-2 (1H) -one (50.0 g, 197 mmol) and POCl ₃ (400 mL) was heated at 100 ℃ for 3 hours. Then the reaction mixture was cooled to room temperature, poured into ice/water (2L) and stirred for 1 hour. The pH of resulting mixture was adjusted to 3～4 with NaOH (aqueous, 1M) . Collected the solid formed by filtration and washed with water (1L) , dried under vacuum to afford the titled compound (45.7 g, 85.2%yield) as a yellow solid. MS (ESI) : m/z 274.3 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.00 (d, J = 2.3 Hz, 1H) , 7.89 (dd, J = 9.0, 2.3 Hz, 1H) , 7.59 (d, J = 9.1 Hz, 1H) , 7.02 (s, 1H) , 3.60 (s, 3H) .

Step 5. 6-bromo-4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methylquinolin-2 (1H) -one

To a solution of 6-bromo-4-chloro-1-methylquinolin-2 (1H) -one (3 g, 11.0 mmol) in NMP (30 mL) was added (1r, 4r) -4-methoxycyclohexanamine hydrochloride (2.70 g, 20.9 mmol) and DIEA (6.00 mL, 36.2 mmol) , and the reaction mixture was stirred at 160 ℃ for 48 hours. The resulting mixture was cooled to room temperature, diluted with EA (100 mL) and brine (100 mL) . The organic layer was separated, washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 20/1 to 2/1) to afford the title compound (500 mg, 12.4%yield) as a brown solid. MS (ESI) : m/z 365.0 [M+H] ⁺.

Step 6. 4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methyl-6- (1H-pyrazol-4-yl) quinolin- 2 (1H) -one

A mixture of 6-bromo-4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methylquinolin-2 (1H) -one (100 mg, 0.274 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (106 mg, 0.548 mmol) , Pd (PPh ₃) ₄ (158 mg, 0.137 mmol) , CsF (125 mg, 0.821 mmol) , CuI (104 mg, 0.548 mmol) and dioxane (5.0 mL) was degassed with N ₂ for 3 times, then heated at 90 ℃ for 4 hours. The mixture was filtered and the solvent was evaporated. The resulting mixture was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10um OBD 19*250mm, Mobile Phase A: 0.1%NH ₄OH in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min, Column temp: RT) to afford the title compound (7.28 mg, 7.5%yield) . LC-MS (ESI) : m/z 353.2 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.53 (d, J = 2.4 Hz, 0.5H) , 8.40 (d, J = 2.4 Hz, 0.5H) , 8.08 (d, J = 2.4 Hz, 1H) , 8.05 –8.02 (m, 0.6H) , 7.78 –7.76 (m, 1H) , 7.74 (d, J = 2.4 Hz, 0.4H) , 7.63 (s, 1H) , 7.56 –7.53 (m, 0.5H) , 7.53 –7.49 (m, 1H) , 6.67 –7.59 (m, 1.5H) , 5.56 (s, 0.5H) , 4.79 –4.76 (m, 1H) , 3.70 –3.64.

Example 14: N- (5- (thiazol-5-yl) -1H-indazol-3-yl) cyclohexanecarboxamide

Step 1. tert-butyl 5-bromo-3- (cyclohexanecarboxamido) -1H-indazole-1-carboxylate.

To a solution of tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate (400 mg, 1.28 mmol) , TEA (0.360 mL, 2.56 mmol) in DCM (10 mL) was added cyclohexanecarbonyl chloride (0.21 mL, 1.54 mmol) at 0℃ under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with aqueous NaHCO ₃ (50 mL) and extracted with ethyl acetate (50 mL ×2) . The combined organic layers were washed with HCl (0.1 M, 20 mL) , then brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by silica gel column (PE/EA =50/1 to 10/1) to afford the titled compound (410 mg, 75.8%yield) as a white solid. MS (ESI) : m/z 422.1 [M+H] ⁺.

Step 2. N- (5- (thiazol-5-yl) -1H-indazol-3-yl) cyclohexanecarboxamide

A mixture of tert-butyl 5-bromo-3- (cyclohexanecarboxamido) -1H-indazole-1-carboxylate (380 mg, 0.90 mmol) , 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (285 mg, 1.35 mmol) , Pd (PPh ₃) ₄ (208 mg, 0.180 mmol) , Na ₂CO ₃ (95.4 mg, 0.90 mmol) in dioxane (4.0 mL) and H ₂O (1.0 mL) was bubbled with argon for 3 minutes. The mixture was sealed and heated at 120 ℃ for 30 minutes in a microwave reactor. The mixture was diluted with H ₂O (20 mL) and extracted with ethyl acetate (50 mL × 2) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. To the residue was added HCl/EtOH (2.0 M, 6.0 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column (PE/EA = 100/1 to 1/1) to afford the titled compound (27.02 mg, 9.2%yield) . MS (ESI) : m/z 327.1 [M+H] ^+; ¹H NMR (400 MHz, DMSO-d ₆) δ 12.80 (s, 1H) , 10.32 (s, 1H) , 9.04 (s, 1H) , 8.21 (s, 1H) , 8.02 (s, 1H) , 7.70 (dd, J = 4.8, 1.6 Hz, 1H) , 7.51 (d, J = 4.8 Hz, 1H) , 1.88 (d, J = 12.0 Hz, 2H) , 1.78 (d, J = 12.0 Hz, 2H) , 1.67 (d, J = 9.2 Hz, 1H) , 1.54 –1.41 (m, 2H) , 1.34 –1.19 (m, 4H) .

Example 15: N-cyclohexyl-2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxamide

Step 1. methyl 2-oxo-2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylate.

A mixture of 2-oxo-2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylic acid (300 mg, 1.68 mmol) , concentrated H ₂SO ₄ (3.0 mL) in MeOH (15 mL) was degassed with argon for 3 times. The mixture was heated at 75 ℃ for 18 hours. The mixture was diluted with H ₂O (20 mL) , filtered. The solid was collected and dried in a vacuum to afford the titled compound (280 mg, 1.46 mmol, 86.5%yield) . MS (ESI) : m/z 193.1 [M+H] ⁺.

Step 2. methyl 2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylate.

A mixture of methyl 2-oxo-2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylate (280 mg, 1.46 mmol) , 4-iodopyridine (597 mg, 2.91 mmol) , CuI (20.7 mg, 0.146 mmol) , Cs ₂CO ₃ (1.42 g, 4.37 mmol) , (1R, 2R) -N ¹, N ²-dimethylcyclohexane-1, 2-diamine (0.010 mL, 0.094 mmol) in DMF (10 mL) was degassed with argon for 3 times, then heated at 100 ℃ under argon atmosphere for 12 hours. The reaction mixture was cooled to room temperature, diluted with EA (20 mL) and washed with brine (30 mL × 2) . The combined organic layers were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound (230 mg, 58.6%yield) . MS (ESI) : m/z 270.0 [M+H] ⁺.

Step 3. 2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylic acid

To a solution of methyl 2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylate (230 mg, 0.854 mmol) in MeOH (10 mL) and H ₂O (10 mL) was added LiOH. H ₂O (359 mg, 8.54 mmol) , and the reaction mixture was stirred at 80 ℃ for 6 hours. The resulting mixture was cooled to rt and adjusted to pH = 2～3 with diluted HCl (2.0 M) . MeOH was removed under reduced pressure. The residue was filtered and the solid was collected, dried in a vacuum to afford the titled compound (46 mg, 21.1%yield) . MS (ESI) : m/z 256.0 [M+H] ⁺.

Step 4. N-cyclohexyl-2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5- carboxamide To a solution of 2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylic acid (46 mg, 0.180 mmol) in DMF (10 mL) was added HATU (178 mg, 0.469 mmol) , DIEA (0.12 mL, 0.721 mmol) and cyclohexanamine (0.04mL, 0.360 mmol) , and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (50 mL) and washed with brine (50 mL) . The organic phase was separated and dried over anhydrous Na ₂SO ₄, filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (Method: Waters 2767/2545/2489/Qame: Inertsil ODS-3 10um 20*250 nm, Mobile Phase A: 0.1%FA in water, Mobile Phase B: CH ₃CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (2.98 mg, 4.9%yield) . MS (ESI) : m/z 337.1 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 337.1 δ 8.75 (d, J = 6.2 Hz, 2H) , 8.45 (s, 1H) , 8.22 (s, 1H) , 7.69 (d, J = 6.2 Hz, 2H) , 7.65 –7.58 (m, 2H) , 7.31 (d, J = 8.2 Hz, 1H) , 3.75 (d, J = 11.7 Hz, 1H) , 1.82 (s, 2H) , 1.73 (s, 2H) , 1.61 (d, J = 10.8 Hz, 1H) , 1.31 (t, J = 9.9 Hz, 4H) , 1.16 –1.07 (m, 1H) .

The compounds below were synthesized following procedures described for Compound 42.

CD38 hydrolase enzymatic assay

A dilution of the test compounds 4× of the desired final concentration in sucrose buffer (0.25 M sucrose, 40 mM tris base) was prepared. Also, a blank sample was prepared with 50 μl of sucrose buffer and no test compounds. A CD38 inhibitor 78c (as disclosed in J. Med. Chem. 2015, 58, 3548-3571) was used as a control for the CD38 activity and the compounds disclosed herein were tested.

2.5X rhCD38 enzyme working fluid (10818-H08H, Sino Biological Inc, 0.125 ng/μl; BSA, 500 ng/μl) in sucrose buffer (0.25 M sucrose, 40 mM tris base) was prepared. 2.5x substrate working fluid (ε-NAD, N2630-25MG, Sigma-Aldrich, 125 μM) in sucrose buffer (0.25 M sucrose, 40 mM tris base) was also prepared.

The dynamic reading was performed at 25℃ with excitation light of 300 nm and emission light of 410 nm on the enzyme marker. The readings were recorded for a total of 1 hour, and the data were analyzed with the point reading time of 20min.

The microplate reader records fluorescence. Individual excel files containing fluorescence data are exported and the results are plotter against various drug concentrations and analyzed in GraphPad Prism 7.0 for concentration curve generation.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.

Claims

A compound of formula (I)

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

wherein

A ₁ is C _1-6alkyl, phenyl or 5-to 9-membered heteroaryl;

A ₂ is

each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C _1- ₆alkyl, -C _2-6alkenyl, -C _2-6alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR _aR _b, -C (O) R _a, -C (O) OR _a, -NO ₂, -OR _a, -SO ₂R _a, -CONR _aR _b, -NR _aCOR _b, -NR _aCO ₂R _b, or -NR _aSO ₂R _b, wherein R _a and R _b are each independently hydrogen or C _1-4alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH ₂, -C (O) CH ₃, or CH ₃, wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁;

L ₁ and L ₂ are each independently a direct bond, -C (O) -, or - (CR _cR _d) _n-, wherein R _c and R _d are each independently hydrogen, C _1-4alkyl, hydroxyC _1-4alkyl, or -C (O) OR _e, wherein R _e is hydroxy or C _1-4alkyl, and n is a number of 1, 2, 3 or 4;

R is H or C _1-6alkyl; and

A ₃ is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C _5- ₈cycloalkyl ring, a C _5-8cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, or a bridged bicyclic cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl.
The compound of claim 1, wherein A ₁ is a monocyclic 5-to 9-membered heteroaryl comprising from 1 to 3 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , preferably monocyclic 5-to 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen as the ring member (s) .
The compound of claim 1 or 2, wherein A ₁ is pyridyl, thiazolyl, imidazolyl, pyrazinyl, or pyrazolyl.
The compound of any one of claims 1-3, wherein A ₁ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl.
The compound of any one of claims 1-4, wherein A ₂ is

each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C _1- ₆alkyl, -C _2-6alkenyl, -C _2-6alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR _aR _b, -C (O) R _a, -C (O) OR _a, -NO ₂, -OR _a, -SO ₂R _a, -CONR _aR _b, -NR _aCOR _b, -NR _aCO ₂R _b, or -NR _aSO ₂R _b, wherein Ra and Rb are each independently hydrogen or C _1-4alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH ₂, -C (O) CH ₃, or CH ₃, wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁.
The compound of any one of claims 1-5, wherein A ₂ is
The compound of any one of claims 1-6, wherein L ₁ is a direct bond or -C (O) -; and L ₂ is a direct bond, -C (O) -, or - (CR _cR _d) _n-, wherein R _c and R _d are each independently hydrogen, C _1-4alkyl, hydroxyC _1- ₄alkyl, or -C (O) OR _e, wherein R _e is hydroxy or C _1-4alkyl, and n is a number of 1, 2, 3 or 4.
The compound of any one of claims 1-7, wherein L ₁ is -C (O) -, and L ₂ is a direct bond, -CH ₂-, -CH ₂CH ₂-, -CH (CH ₃) -, -CH (CH ₂OH) -, or -CH (COOMe) -.
The compound of any one of claims 1-8, wherein A ₃ is a C ₅ or C ₆cycloalkyl ring or a C ₅ or C ₆cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1- ₆alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 9, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, said fused ring is unsubstituted or substituted with one or two substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 9, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, said fused ring is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at position 5 of the fused ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 10 or 11, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group.
The compound of claim 9, wherein A ₃ is Cyclohexyl, (1r, 4r) -4-hydroxycyclohexyl, (1r, 4r) -4-methoxycyclohexyl,
tetrahydro-2H-pyran-4-yl, phenyl or pyridin-3-yl.
The compound of claim 1, wherein A ₁ is 5-to 9-membered heteroaryl, A ₂ is

(wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁) , L ₁ is -C (O) -and L ₂ is a direct bond, A ₃ is a cyclohexyl ring which is unsubstituted or substituted with one or two or three substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl.
The compound of claim 1, wherein A ₁ is 5-to 9-membered heteroaryl, A ₂ is

(wherein the left attaching position is attached to A ₁ and the right attaching position is attached to L ₁) , L ₁ is -C (O) -and L ₂ is a direct bond, A ₃ is a C ₅ or C ₆cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 14, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with one or two substituents selected from halogen, C _1-6alkyl, or -OR _f, wherein R _f is hydrogen, C _1-6alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 14, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at the phenyl ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 14, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR _f at position 5 of the fused ring, wherein R _f is hydrogen, C _1-6alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
The compound of claim 14, wherein A ₃ is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group, e.g., a 2, 3-dihydro-1H-inden-2-yl group.
The compound of claim 14, wherein A ₃ is
The compound of claim 1, the compound is selected from

N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxamide;

4-amino-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide;

N- ( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- (2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

4-oxo-2- (pyridin-4-yl) -N- ( (2R) -5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-cyclohexyl-4-oxo-2- (thiazol-5-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-cyclohexyl-2-methyl-4-oxo-3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

4-oxo-2- (pyridin-4-yl) -N- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- ( (1r, 4r) -4-hydroxycyclohexyl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-benzyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

4-oxo-N-phenethyl-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

4-oxo-N- (pyridin-3-ylmethyl) -2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- (5-ethoxy-2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-cyclohexyl-4-oxo-2-phenyl-3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N-cyclohexyl-4-oxo-2- (pyridin-3-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- (1-cyclohexylethyl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- (bicyclo [2.2.2] octan-1-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

N- (1-cyclohexyl-2-hydroxyethyl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide;

methyl 2-cyclohexyl-2- (4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamido) acetate;

N-cyclohexyl-5- (pyridin-4-yl) benzo [d] isoxazole-3-carboxamide;

N-cyclohexyl-2- (pyridin-4-yl) -1H-indole-4-carboxamide;

N-cyclohexyl-3- (pyridin-4-yl) -1H-indole-5-carboxamide;

N-cyclohexyl-3- (pyridin-4-yl) -1H-indazole-5-carboxamide;

N- ( (1r, 4r) -4-methoxycyclohexyl) -3- (thiazol-5-yl) -1H-indazole-5-carboxamide;

N-cyclohexyl-2- (pyridin-4-yl) -1H-benzo [d] imidazole-4-carboxamide;

N-cyclohexyl-8- (pyridin-4-yl) -9H-purin-6-amine;

N-cyclohexyl-7- (pyridin-4-yl) -5H-pyrrolo [3, 2-d] pyrimidin-2-amine;

N-cyclohexyl-7- (thiazol-5-yl) thieno [3, 2-d] pyrimidin-2-amine;

N-cyclohexyl-6- (pyridin-4-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-amine;

N-cyclohexyl-6- (thiazol-5-yl) thieno [2, 3-d] pyrimidin-4-amine;

2- (cyclohexylamino) -7- (1H-imidazol-1-yl) thieno [3, 2-d] pyrimidin-4 (3H) -one;

N-cyclohexyl-5- (thiazol-5-yl) -1H-indazol-3-amine;

1- (3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazol-1-yl) ethanone;

N-cyclohexyl-1-methyl-5- (thiazol-5-yl) -1H-indazol-3-amine;

N-cyclohexyl-5- (pyridin-4-yl) -1H-indazol-3-amine;

N-cyclohexyl-5- (pyrazin-2-yl) -1H-indazol-3-amine;

N- (cyclohexylmethyl) -5- (thiazol-5-yl) -1H-indazol-3-amine;

N-cyclohexyl-7- (thiazol-5-yl) benzo [d] oxazol-2-amine;

4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methyl-6- (1H-pyrazol-4-yl) quinolin-2 (1H) -one;

N- (5- (thiazol-5-yl) -1H-indazol-3-yl) cyclohexanecarboxamide;

N-cyclohexyl-2-oxo-3- (pyridin-4-yl) -2, 3-dihydro-1H-benzo [d] imidazole-5-carboxamide; or

N- (1- (pyridin-4-yl) -1H-benzo [d] imidazol-6-yl) cyclohexanecarboxamide.
A pharmaceutical composition, comprising a compound of any one of claims 1 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
A method of treating a disease mediated by CD38 in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of any one of claims 1 to 20 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 22, wherein the disease mediated by CD38 is

neurodegenerative disease selected from dementia, Alzheimer's disease (AD) , Parkinson's disease;

tumor selected from glioblastomas, lung cancer, colon cancer, liver cancer, breast cancer, gastric cancer, bladder cancer, melanoma;

autoimmune disease selected from diabetes, rheumatoid arthritis (RA) , multiple sclerosis (MS) , systemic lupus erythematosus (SLE) ;

inflammatory disease selected from asthma, chronic obstructive pulmonary disease (COPD) , pneumonia, non-alcoholic steatohepatitis (NASH) ; and

metabolic disease.
A method of inhibiting CD38 function, comprising contacting a compound of any one of claims 1 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, with the CD38.
The method of claim 24, wherein the CD38 is in a cell.
The method of claim 24, wherein the contacting occurs in vitro.
The method of claim 24, wherein the contacting occurs in vivo.