TW202446379A - Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof - Google Patents

Abstract

The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.

Description

Small molecule inhibitors of ubiquitin-specific protease 1 (USP1) and their uses

Ubiquitin-specific protease 1 (USP1) is a gene that plays a role in DNA damage repair. Compounds and pharmaceutical compositions targeting USP1 and methods for treating USP1-related diseases and conditions, such as certain cancers, have not been widely developed. Therefore, there is still a need to seek methods for treating USP1-related diseases.

The present disclosure meets the above needs and also provides additional advantages.

In one aspect, described herein is a compound having a structure of formula (I) or a salt thereof, Formula (I) wherein, Ring A is an aryl group or a heteroaryl group; Ring B is a phenyl group, a phenyl homoelectron array or a heteroaryl group; Ring C is an optionally substituted 5- to 6-membered heteroaryl group; Ring D is an optionally substituted 5- to 6-membered heterocycloalkyl group or an optionally substituted 5- to 6-membered cycloalkyl group; each ^RA is independently selected ^from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC( ₌ O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra , -S(= ^O)2Ra _, -S(=O) ^2NRcRd , -S(=O)(= ^NRb ) ^{Rb , -NRcR d} , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more ^RA1 as the case may be; or two ^RAs together with the intervening atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of them is independently substituted with one or more ^RA1 as the ^case may be; each ^RA1 is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra -S(=O) _2R ^a , -S(=O) _2NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) _2R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein _each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, 4, or 5; each ^RB is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd _, ^-SF5 , -SH _, ^-SRa , -S(=O) ^{Ra ,} -S(=O) _2Ra , -S ⁽ = ^O )2NRcRd ^, -S(=O)(= ^NRb ) ^Rb , ^-NRcRd , ^-NRb C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R ^B1 as appropriate; _n is 0, 1, 2, 3 or 4; each R ^B1 is independently selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(═O)R ^a , -OC(═O)OR ^b , -OC(═O)NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(═O)R ^a , -S(═O) ₂ R ^a , -S(═O) ₂ NR ^c R ^d , -S(═O)(═NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R; _R is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is independently substituted with one or more ^R ; each ^Ra is independently _C1 - _C6 alkyl, C1-C6 haloalkyl, ^C1 _{- C6} hydroxyalkyl, _{C1 -} C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _{C2 - C6} The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; R ^c and R ^d are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C 6 C ₁ -C ₆ alkylene (cycloalkyl), C 1 -C 6 alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl), wherein _each alkyl, alkylene, _alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently substituted with one or more R as the case may be; or R ^c and R _d together with the atoms to which they are attached form a heterocycloalkyl group optionally substituted with one or more R as the case may be; and each ^R is independently halogen, -CN, -OH, -SF ₅ , -SH, -S(═O) C ₁ -C ₃ alkyl, -S(═O) ₂ C ₁ -C ₃ alkyl, -S(═O) _{2 NH2} , -S(=O) _2NHC1 - _C3alkyl , -S(=O) _{2N ( C1} - _C3alkyl ) ₂ , _-S (=O)(= _NC1 -C3alkyl)(C1-C3alkyl _{), -NH2 , -NHC1 -} C3alkyl, -N( _C1 -C3alkyl) ₂ , -N=S(=O)( _{C1 - C3alkyl} ) ₂ , -C(=O) _C1 -C3alkyl, _-C (=O)OH, -C(=O) _{OC1 -} C3alkyl, _-C (=O) _NH2 , -C(=O) _{NHC1 -C3alkyl} , -C(=O)N( _C1 -C3alkyl) ₂ , -P(=O)( _C1 - _C3alkyl ) ₂ , _{C1 - C3alkyl} , _C1 -C C _{1 -C 3 alkoxy, C 1 -C 3 halogenated} alkyl, C ₁ -C ₃ halogenated alkoxy, C 1 -C ₃ hydroxyalkyl, C ₁ -C ₃ aminoalkyl, C ₁ -C ₃ heteroalkyl or C ₃ -C ₆ cycloalkyl; or two R on the same atom form a pendant oxy group.

In some embodiments, the compound has a structure of Formula (IIA) or a pharmaceutically acceptable salt thereof, Formula (IIA).

In some embodiments, the compound has a structure of Formula (IIB) or a pharmaceutically acceptable salt thereof, Formula (IIB).

In one embodiment, described herein is a compound having a structure of formula (IIC) or a pharmaceutically acceptable salt thereof, Formula (IIC).

In one embodiment, described herein is a compound having a structure of formula (IID) or a pharmaceutically acceptable salt thereof, Formula (IID).

In one embodiment, described herein is a compound having a structure of formula (IID') or a pharmaceutically acceptable salt thereof, Formula (IID').

In one embodiment, described herein is a compound having a structure of formula (IID'') or a pharmaceutically acceptable salt thereof, Formula (IID'').

In one embodiment, described herein is a compound having a structure of formula (IIE) or a pharmaceutically acceptable salt thereof, Formula (IIE).

In one embodiment, described herein is a compound having a structure of formula (IIF) or a pharmaceutically acceptable salt thereof, Formula (IIF).

In one embodiment, described herein is a compound having a structure of formula (IIG) or a pharmaceutically acceptable salt thereof, Formula (IIG).

In one aspect, described herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

In one aspect, described herein is a method of regulating ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

In one aspect, described herein is a method of inhibiting ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

In one embodiment, described herein is a method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

In one aspect, described herein is a method of treating a disease or condition associated with ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

In one aspect, described herein is a method of treating a disease or condition associated with ubiquitin-specific protease 1 (USP1) regulation in a subject, the method comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or condition is cancer.

In one aspect, described herein is a method of treating cancer in an individual, comprising administering to an individual in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer or breast cancer.

In some embodiments, the cancer comprises cancer cells with elevated levels of RAD 18. In some embodiments, the cancer is a cancer deficient in a DNA damage repair pathway. In some embodiments, the cancer is a cancer resistant or refractory to PARP inhibitors. In some embodiments, the cancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRAC1 deficient cancer. INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications, patents, or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and/or take precedence over any such conflicting material.

Cross-references to related applications

This application claims priority to PCT patent application No. PCT/CN2023/095070 filed on May 18, 2023, the entire contents of which are incorporated herein by reference.

Although various embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may be devised by those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed. A. Definitions

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this disclosure belongs. All patents and publications mentioned herein are incorporated by reference.

"Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical, and preferably has one to fifteen carbon atoms ( i.e., C ₁ -C ₁₅ alkyl). In certain embodiments, the alkyl group contains one to thirteen carbon atoms ( i.e., C ₁ -C ₁₃ alkyl). In certain embodiments, the alkyl group contains one to eight carbon atoms ( i.e., C ₁ -C ₈ alkyl). In other embodiments, the alkyl group contains one to five carbon atoms ( i.e., C ₁ -C ₅ alkyl). In other embodiments, the alkyl group contains one to four carbon atoms ( i.e., C ₁ -C ₄ alkyl). In other embodiments, the alkyl group contains one to three carbon atoms ( i.e., C ₁ -C ₃ alkyl). In other embodiments, the alkyl group contains one to two carbon atoms ( i.e., C ₁ -C ₂ alkyl). Whenever it appears herein, a numerical range such as "C ₁ -C ₃ alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. In other embodiments, the alkyl group contains one carbon atom ( i.e., C ₁ alkyl). In other embodiments, the alkyl group contains five to fifteen carbon atoms ( i.e., C ₅ -C ₁₅ alkyl). In other embodiments, the alkyl group contains five to eight carbon atoms ( i.e., C ₅ -C ₈ alkyl). In other embodiments, the alkyl group contains two to five carbon atoms ( i.e. , C ₂ -C _{5 alkyl). In other embodiments, the alkyl group contains three to five carbon atoms (i.e., C 3 -C 5} alkyl _{) .} In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). In other embodiments, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise expressly stated in the specification, the alkyl group is optionally substituted with, for example, a pendoxy group, a halogen, an amine group, a nitrile, a nitro group, a hydroxyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, the alkyl group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , -NO ₂ , or -C≡CH. In some embodiments, the alkyl group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen (such as F).

As used herein, C ₁ -C _x (or C _1-x ) includes C ₁ -C ₂ , C ₁ -C ₃ . . . C ₁ -C _x . By way of example only, a group designated as "C ₁ -C ₄ " indicates that there are one to four carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C ₁ -C ₄ alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e. , the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In addition, by way of example, C ₀ -C ₂ alkylene includes direct bonds, -CH ₂ -, and -CH ₂ CH ₂ - linkages.

"Alkoxy" refers to a radical of the formula -O-alkyl bonded through an oxygen atom, wherein alkyl is an alkyl chain as defined above. Unless otherwise expressly stated in the specification, an alkoxy group may be optionally substituted, for example, with a pendoxy group, a halogen, an amine group, a nitrile, a nitro group, a hydroxyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, an alkoxy group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, an alkoxy group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, an alkoxy group is optionally substituted with a halogen.

"Alkenyl" refers to an optionally substituted straight or branched alkyl chain radical containing at least one carbon-carbon double bond and preferably having two to twelve carbon atoms ( i.e. , _C2 - _C12 alkenyl). In certain embodiments, alkenyl contains two to eight carbon atoms ( i.e., _C2 - _C8 alkenyl). In certain embodiments, alkenyl contains two to six carbon atoms ( i.e., _C2 - _C6 alkenyl). In other embodiments, alkenyl contains two to four carbon atoms ( i.e., _C2 - _C4 alkenyl). The radical may be in a cis or trans configuration around the double bond and is understood to include both isomers. Examples include, but are not limited to, vinyl (—CH═CH ₂ ), 1-propenyl (—CH ₂ CH═CH ₂ ), isopropenyl [—C(CH ₃ )═CH ₂ ], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, numerical ranges such as “C ₂ -C ₆ alkenyl” mean that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with, for example, a pendoxy group, a halogen group, an amino group, a nitrile group, a nitro group, a hydroxyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, the alkenyl group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, the alkenyl group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen. The alkenyl group is attached to the rest of the molecule by a single bond, such as ethenyl ( i.e. , vinyl), prop-1-enyl ( i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specifically stated in the specification, alkenyl groups are optionally substituted with, for example, pendoxy groups, halogen groups, amine groups, nitrile groups, nitro groups, hydroxyl groups, halogenated alkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, alkenyl groups are optionally substituted with pendoxy groups, halogen groups, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, alkenyl groups are optionally substituted with pendoxy groups, halogen groups, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, alkenyl groups are optionally substituted with halogen groups.

"Alkynyl" refers to an optionally substituted straight or branched alkyl chain radical containing at least one carbon-carbon triple bond and preferably having two to twelve carbon atoms ( i.e. , _C2 - _C12 alkynyl). In certain embodiments, the alkynyl group contains two to eight carbon atoms ( i.e., _C2 - _C8 alkynyl). In other embodiments, the alkynyl group contains two to six carbon atoms ( i.e., _C2 - _C6 alkynyl). In other embodiments, the alkynyl group contains two to four carbon atoms ( i.e., _C2 - _C4 alkynyl). Whenever it appears herein, a numerical range such as " _C2 - _C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Alkynyl groups are linked to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Unless otherwise specified in the specification, alkynyl groups are optionally substituted, such as with pendoxy groups, halogen, amine, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl groups are optionally substituted with pendoxy groups, halogen, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, alkynyl groups are optionally substituted with pendoxy groups, halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

"Alkylene" or "alkylene chain" refers to an optionally substituted straight or branched divalent hydrocarbon chain that contains no unsaturation and preferably has from one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like, that connects the rest of the molecule. The alkylene chain is connected to the rest of the molecule and to the radical through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical can be achieved through any two carbons within the chain. In certain embodiments, the alkylene contains from one to ten carbon atoms ( i.e., C ₁ -C ₈ alkylene). In certain embodiments, the alkylene contains from one to eight carbon atoms ( i.e., C ₁ -C ₈ alkylene). In other embodiments, the alkylene group contains one to five carbon atoms ( i.e., _C1 - _C5 alkylene). In other embodiments, the alkylene group contains one to four carbon atoms ( i.e., _C1 - _C4 alkylene). In other embodiments, the alkylene group contains one to three carbon atoms ( i.e., _C1 - _C3 alkylene). In other embodiments, the alkylene group contains one to two carbon atoms ( i.e., _C1 - _C2 alkylene). In other embodiments, the alkylene group contains one carbon atom ( i.e., _C1 alkylene). In other embodiments, the alkylene group contains five to eight carbon atoms ( i.e., _C5 - _C8 alkylene). In other embodiments, the alkylene group contains two to five carbon atoms ( i.e., _C2 - _C5 alkylene). In other embodiments, the alkylene group contains three to five carbon atoms ( i.e. , _C3 - _C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene group may be substituted, for example, with a pendoxy group, a halogen, an amine group, a nitrile, a nitro group, a hydroxyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, the alkylene group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH, -OMe, -NH ₂ or -NO _2. In some embodiments, the alkylene group is optionally substituted with a pendoxy group, a halogen, -CN, -CF ₃ , -OH or -OMe. In some embodiments, the alkylene group is optionally substituted with a halogen. In some embodiments, the alkylene group is -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -. In some embodiments, the alkylene group is -CH ₂ -. In some embodiments, the alkylene group is -CH ₂ CH ₂ -. In some embodiments, the alkylene group is -CH ₂ CH ₂ CH ₂ -.

"Aryl" refers to a radical derived from a hydrocarbon ring system comprising at least one aromatic ring. In some embodiments, an aryl group comprises hydrogen and 6 to 30 carbon atoms. An aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, an aryl group is a 6- to 10-membered aryl group. In some embodiments, an aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, those derived from the following cyclic ring systems: anthracenyl, naphthyl, phenanthrenyl, anthracene, azulene, benzene, chrysene, indene, fluoranthene, fluorene, indane, indene, naphthalene, phenanthren, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl group is phenyl. Unless otherwise specifically stated in the specification, the aryl group may be substituted, for example, by halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, halogenated alkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O) ₂ NH-C ₁ -C ₆ alkyl, and the like, as appropriate. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , -NO ₂ , -S(O) ₂ NH ₂ , -S(O) ₂ NHCH ₃ , -S(O) ₂ NHCH ₂ CH ₃ , -S(O) ₂ NHCH ₍ CH ₃ ) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , or -S(O) ₂ NHC(CH ₃ ) _3. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen. In some embodiments, the aryl group is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl group is independently unsubstituted or substituted with halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 .

"Aralkyl" refers to a radical of the formula ^-Rc -aryl, where ^Rc is an alkylene chain as defined above, for example methylene, ethylene and the like.

"Aralkenyl" refers to a radical of the formula ^-Rd -aryl, wherein ^{Rd is} an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula ^-Re -aryl, wherein ^Re is an alkynylene chain as defined above.

"Carbocycle" refers to a saturated, unsaturated or aromatic ring, wherein each atom of the ring is carbon. Carbocycles may include 3-10 membered monocyclic rings and 6-12 membered bicyclic rings (such as spirocyclic, fused or bridged rings). Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. An aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings is included in the definition of carbocycle, if valence permits. In exemplary embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings, if valence permits. Bicyclic carbocyclic rings include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-5 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indenyl, and naphthyl. The term "unsaturated carbocycle" refers to a carbocycle having at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. The term "saturated cycloalkyl" as used herein refers to a saturated carbocycle. Exemplary carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indenyl, norbornane, and naphthyl. The carbocycle may be substituted with one or more substituents, such as those described herein, as appropriate.

As used herein, "phenyl homoelectronic arranger" refers to a moiety or functional group that exhibits physical, biological and/or chemical properties similar to phenyl. Exemplary phenyl homoelectronic arrangers include, but are not limited to, cubane, bicyclo[1.1.1]pentane (BCP), bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, adamantane, norbornene, closed-1,2-carborane, closed-1,7-carborane, closed-1,12-carborane, and ethynyl. In some embodiments, the phenyl homoelectronic arranger is cubane. In some embodiments, the phenyl homoelectronic arranger is ethynyl.

"Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged or spiro ring systems. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms ( _C3 - _C15 cycloalkyl), three to ten carbon atoms ( _C3 - _C10 cycloalkyl), three to eight carbon atoms ( _C3 - _C8 cycloalkyl), three to six carbon atoms ( _C3 - _C6 cycloalkyl), three to five carbon atoms ( _C3 - _C5 cycloalkyl), or three to four carbon atoms ( _C3 - _C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3-6 membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5-6 membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl groups are optionally substituted with, for example, pendoxy groups, halogen groups, amine groups, nitrile groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, halogenated alkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, cycloalkyl groups are optionally substituted with pendoxy groups, halogen groups, methyl groups, ethyl groups, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, cycloalkyl groups are optionally substituted with pendoxy groups, halogen groups, methyl groups, ethyl groups, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, cycloalkyl groups are optionally substituted with halogen groups.

"Cycloalkylalkyl" refers to a radical of the formula ^-Rc -cycloalkyl where ^Rc is an alkylene chain as described above.

"Cycloalkylalkoxy" refers to a radical bonded through the oxygen atom of the formula -OR ^c -cycloalkyl, wherein R ^c is an alkylene chain as described above.

"Halogen" or "halogen" refers to halogen substituents such as bromine, chlorine, fluorine and iodine substituents.

As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of halogen-substituted alkanes ("halogenated alkanes") include halogenated methanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalogenated and trihalogenated methanes (e.g., chloroform, bromoform, trifluoromethane, iodoform), 1-halogenated ethane, 2-halogenated ethane, 1,2-dihalogenated ethane, 1-halogenated propane, 2-halogenated propane, 3-halogenated propane, 1,2-dihalogenated propane, 1,3-dihalogenated propane, 2,3-dihalogenated propane, 1,2,3-trihalogenated propane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted with more than one halogen group, each halogen may be selected independently, for example 1-chloro,2-fluoroethane.

"Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like.

"Hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxylalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

"Aminoalkyl" refers to an alkyl group as defined above substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

The term "heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a _C1 - _C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-) _, sulfur _{, or} a combination thereof, wherein the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. Examples of such _heteroalkyl groups are, for example, _-CH2OCH3 , _{-CH2CH2OCH3 , -CH2CH2OCH2CH2OCH3 ,} or -CH( _{CH3 ) OCH3} . Unless otherwise specifically stated in the specification, the heteroalkyl group is optionally substituted with, for example, a pendoxy group, a halogen, an amine group, a nitrile, a nitro group, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, the heteroalkyl group is optionally substituted with a pendoxy group, a halogen, a methyl group, an ethyl group, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, the heteroalkyl group is optionally substituted with a pendoxy group, a halogen, a methyl group, an ethyl group, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

"Heterocycloalkyl" refers to a stable 3-24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and at least one ring heteroatom. In some embodiments, the heterocycloalkyl contains one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. Unless otherwise clearly stated in the specification, the heterocycloalkyl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring system; and the nitrogen, carbon or sulfur atom in the heterocycloalkyl may be oxidized as appropriate; the nitrogen atom may be quaternarylized as appropriate.

Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms ( _C2 - _C15 heterocycloalkyl groups), two to ten carbon atoms ( _C2 - _C10 heterocycloalkyl groups), two to eight carbon atoms ( _C2 - _C8 heterocycloalkyl groups), two to six carbon atoms ( _C2 - _C6 heterocycloalkyl groups), two to five carbon atoms ( _C2 - _C5 heterocycloalkyl groups), or two to four carbon atoms ( _C2 - _C4 heterocycloalkyl groups). In some embodiments, the heterocycloalkyl group is a 3-6 membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azidobutyl, dioxolanyl, thienyl[1,3]dithiocyclohexanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxolinyl, octahydroindolyl, octahydroisoindolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridinyl, 2-oxopyrrolidinyl, oxazolidinyl, hexahydropyridinyl, hexahydropyrazinyl, 4-hexahydropyridonyl, pyrrolidinyl The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, the heterocycloalkyl group is optionally substituted with, for example, a pendoxy group, a halogen, an amine group, a nitrile, a nitro group, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like. In some embodiments, the heterocycloalkyl group is optionally substituted with a pendoxy group, a halogen, a methyl group, an ethyl group, -CN, -CF ₃ , -OH, -OMe, -NH ₂ or -NO ₂ . In some embodiments, the heterocycloalkyl is optionally substituted with a pendoxy group, a halogen, a methyl group, an ethyl group, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with a halogen.

"Heterocycle" or "heterocyclic group" refers to a saturated, unsaturated or aromatic ring containing one or more ring heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycles include, for example, 3-10 membered monocyclic rings and 6-12 membered bicyclic rings (such as spirocyclic, fused or bridged rings). Unless otherwise explicitly stated in the specification, a heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused, bridged or spirocyclic ring system. Heteroatoms in heterocyclic groups are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclic groups may be partially or fully saturated. Heterocyclic groups are attached to the remainder of the molecule via any atom of one or more rings. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithiocyclohexanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxolinyl, octahydroindolyl, octahydroisoindolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridinyl, 2-oxo In some embodiments, the term "heterocyclic group" includes 1-hydroxy-1-oxo-1-oxo-1-oxo-2 ... For example, the heterocyclic group may be substituted with one or more substituents selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a halogen group, a fluoroalkyl group, a pendo group, a thioketo group, a cyano group, a nitro group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted aralkenyl group, an optionally substituted aralkynyl group, an optionally substituted carbocyclic group, an optionally substituted carbocyclic groupalkyl group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic groupalkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -CN, -R ^b -OR ^e -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxyl, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxyl, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxyl, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxyl, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxyl, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxyl, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy or trifluoromethyl), each ^R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and ^Re is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

"Heteroaryl" or "aromatic heterocycle" refers to a ring system radical comprising carbon atoms and one or more heteroatoms (e.g., selected from the group consisting of nitrogen, oxygen, phosphorus, silicon and sulfur) and at least one aromatic ring. In some embodiments, the heteroaryl is a 5-14 membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. The heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be oxidized as appropriate; the nitrogen atom may be quaternarylated as appropriate. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. Examples include, but are not limited to, azobenzene, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzofuranyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl, benzoxazolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl ...1,4-benzodiazyl, benzonaphthofuranyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl, benzo[b][1,4]dioxolyl, 1,4-benzodiazyl, benzonaphthofuranyl, benzo[b][1,4]dioxolyl, benzothienyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl/benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, oxazolyl, dibenzofuranyl, dibenzothiophenyl, furanyl , furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxazolidinyl, oxazolyl, oxathiophene, 1-pyridyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1- The invention also includes oxadiazine, ... In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , -OH, -OMe, -NH ₂ , or -NO _2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

The term "substituted" refers to a moiety having substituents that replace hydrogens on one or more carbons or substitutable heteroatoms (e.g., NH) of a structure. It is understood that "substitution" or "substituted" includes the implicit precondition that such substitution conforms to the allowed valencies of the substituted atoms and substituents and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having substituents that replace two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with a pendoxy group, an imino group, or a thiol group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of the organic compounds described herein that satisfy the valences of the heteroatoms.

In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxyl, oxo (=O), thioketo (=S), cyano (-CN), nitro ( _-NO2 ), imino (=NH), oxime (=N-OH), hydrazine (=N- _NH2 ), ^-Rb - ^ORa , -Rb ^- OC(O) ^-Ra , -Rb-OC(O) ^-ORa , -Rb ^{- OC} (O)-N( ^Ra ) ₂ , ^-Rb -N( ^Ra ) ₂ , ^-Rb -C(O) ^Ra , ^-Rb- C(O)ORa, -Rb-C(O)N( ^Ra ₎₂ ^{, -Rb} - ^ORc - ^C (O)N( ^Ra ) ₂ , ^-Rb -N( ^Ra )C(O) ^ORa , -Rb ^- N(Ra ⁾ )C(O)R ^a , —R ^b —N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), —R ^b —S(O) _t R ^a (wherein t is 1 or 2), —R ^b —S(O) _t OR ^a (wherein t is 1 or 2), and —R ^b —S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocyclic ring, any of which may be substituted as appropriate with alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, oxime (═O), thioketo (═S), cyano (—CN), nitro (—NO ₂ ), imino (═NH), oxime (═N—OH), hydrazine (═N—NH ₂ ), SF ⁵ , -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _tN ( ^Ra ) ₂ (wherein is 1 or 2); wherein each ^Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl and heterocyclic, wherein when valence permits, each ^Ra may be substituted with alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, oxo (=O), thioketo (=S), cyano (-CN), nitro ( _-NO2 ), imino (=NH), oxime (=N-OH), hydrazine (=N- _NH2 ), -Rb ^{- ORa} , -Rb-OC(O)-Ra, ^{-Rb -} OC(O ^{) -ORa} , -Rb ^- OC(O)-N( ^Ra ) ₂ , ^-Rb- N(Ra) ₂ , -Rb ^{-ORa ;} -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _t R ^a (wherein t is 1 or 2), -R ^b -S(O) _t OR ^a (wherein t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2); and wherein each R ^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain.

As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. "Pharmaceutically acceptable base addition salts" can be formed using inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary amines, diamines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications and commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil and cottonseed oil. , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isosalted water; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

In certain embodiments, the terms "prevent" or "preventing" as used in connection with a disease or disorder may refer to a compound that reduces the occurrence of the disease or disorder in treated samples relative to untreated control samples, or delays the onset of or reduces the severity of one or more symptoms of the disease or disorder relative to untreated control samples in a statistical sample.

As used herein, the terms "treat," "treating," or "treatment" may include alleviating, reducing, or ameliorating symptoms of a disease or disorder, preventing additional symptoms, ameliorating potential causes of symptoms, inhibiting the disease or disorder, e.g., arresting the onset of the disease or disorder, relieving the disease or disorder, causing regression of the disease or disorder, reducing symptoms caused by the disease or disorder, or terminating symptoms of the disease or disorder.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound disclosed herein that is administered sufficient to reduce to some extent one or more symptoms of the disease or condition being treated (e.g., cancer or inflammatory disease). In some embodiments, the result is a reduction and/or alleviation of disease signs, symptoms, or causes, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies.

The term "optionally present" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group may be unsubstituted (e.g. _{, -CH2CH3} ), fully substituted (e.g., _{-CF2CF3 )} , monosubstituted (e.g. _{, -CH2CH2F} ) _, or substituted at any level between fully substituted and monosubstituted (e.g. _{, -CH2CHF2} , _-CH2CF3 , _-CF2CH3 , _{-CFHCHF2 ,} etc.).

As used herein, the term "subject" may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein may be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal.

Ranges provided herein should be understood as shorthand for all values within the range. For example, a range of 1 to 50 should be understood to include any number, combination of numbers, or sub-range selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all intermediate decimal values between the above integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, specifically contemplated are "nested sub-ranges" extending from either end of the range. For example, a nested sub-range of the exemplary range of 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. B. Compounds of the Disclosure

In one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Formula I, wherein, Ring A is an aryl group or a heteroaryl group; Ring B is a phenyl group, a phenyl homoelectron array or a heteroaryl group; Ring C is an optionally substituted 5- to 6-membered heteroaryl group; Ring D is an optionally substituted 5- to 6-membered heterocycloalkyl group or an optionally substituted 5- to 6-membered cycloalkyl group; each ^RA is independently selected ^from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra , ^-S (= ^{O)2Ra ,} _-S (=O ⁾ 2NRcRd, -S(= _O )(= ^NRb ) ^Rb , ^-NRcRd -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more ^RA1 as the case may be; or two ^RAs together with the intervening atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of them is independently substituted with one or more ^RA1 as the ^case may be; each ^RA1 is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra -S(=O) _2R ^a , -S(=O) _2NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) _2R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein _each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, 4, or 5; each ^RB is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd _, ^-SF5 , -SH _, ^-SRa , -S(=O) ^{Ra ,} -S(=O) _2Ra , -S ⁽ = ^O )2NRcRd ^, -S(=O)(= ^NRb ) ^Rb , ^-NRcRd , ^-NRb C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R ^B1 as appropriate; _n is 0, 1, 2, 3 or 4; each R ^B1 is independently selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(═O)R ^a , -OC(═O)OR ^b , -OC(═O)NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(═O)R ^a , -S(═O) ₂ R ^a , -S(═O) ₂ NR ^c R ^d , -S(═O)(═NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R; _R is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is independently substituted with one or more ^R ; each ^Ra is independently _C1 - _C6 alkyl, C1-C6 haloalkyl, ^C1 _{- C6} hydroxyalkyl, _{C1 -} C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _{C2 - C6} The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; R ^c and R ^d are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C 6 C ₁ -C ₆ alkylene (cycloalkyl), C 1 -C 6 alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl), wherein _each alkyl, alkylene, _alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently substituted with one or more R as the case may be; or R ^c and R _d together with the atoms to which they are attached form a heterocycloalkyl group optionally substituted with one or more R as the case may be; and each ^R is independently halogen, -CN, -OH, -SF ₅ , -SH, -S(═O) C ₁ -C ₃ alkyl, -S(═O) ₂ C ₁ -C ₃ alkyl, -S(═O) _{2 NH2} , -S(=O) _2NHC1 - _C3alkyl , -S(=O) _{2N ( C1} - _C3alkyl ) ₂ , _-S (=O)(= _NC1 -C3alkyl)(C1-C3alkyl _{), -NH2 , -NHC1 -} C3alkyl, -N( _C1 -C3alkyl) ₂ , -N=S(=O)( _{C1 - C3alkyl} ) ₂ , -C(=O) _C1 -C3alkyl, _-C (=O)OH, -C(=O) _{OC1 -} C3alkyl, _-C (=O) _NH2 , -C(=O) _{NHC1 -C3alkyl} , -C(=O)N( _C1 -C3alkyl) ₂ , -P(=O)( _C1 - _C3alkyl ) ₂ , _{C1 - C3alkyl} , _C1 -C C ₁ -C ₃ alkoxy, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ halogenated alkoxy, C 1 -C ₃ hydroxyalkyl, C ₁ -C ₃ aminoalkyl, C ₁ -C ₃ heteroalkyl or C ₃ -C ₆ cycloalkyl; or two R on the same atom form a pendant oxy group,

In some embodiments of formula (I), for , , , , , , or , wherein X ¹ is N or CR ^x ; ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyl alkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R; X ² is N or CR ² ; X ³ is N, NR ^1N , CR ¹ , S or O; X ⁴ is N, NR ^2N , CR ² , S or O; X ⁵ is N or C; each of R ¹ and R ² is independently hydrogen, halogen, -CN, OH, -SF ₅ , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C 1 -C 6 hydroxyl alkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C 6 heteroalkyl. wherein each of the alkyl, _{the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; each of R 1N and R 2N is independently hydrogen, C 1-6 alkyl} ^, _{C 1-6} halogenated alkyl, C _1-6 hydroxyalkyl, C 1-C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or the heteroalkyl is optionally substituted with one or more R; each of R 4 and R ^4' is independently selected from hydrogen, halogen, -CN, -OR a , -SR a , -NR c R d , C _1-6 alkyl, C 1-6 halogenated alkyl, C _1-6 hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or the heteroalkyl is optionally substituted with one or more R; each of R ⁴ and R ^4' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁴ and R ^4' together form a pendoxy group; or R ⁴ and R ^4' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; each of R ⁵ and R ^5' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C _{1-6 -C6} haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or ^R5 and R5 ^' together form a pendoxy group; or ^R5 and R5 ^' together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of ^R6 and R6 ^' is independently selected from hydrogen, halogen, -CN, ^{-ORa , -SRa} , ^-NRcRd , _C1-6 alkyl, _{C1-6 -C6} haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or ^R6 and R6 ^' together form a pendooxy group; or ^R6 and R6 ^' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R.

In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for .

In some embodiments of the compound, for , , , , , , , , , , , or In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for .

In some embodiments, for , or .

In some embodiments, Ring C is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted. In some embodiments, Ring C is an optionally substituted 5-membered heteroaryl.

In some embodiments, ring C is a 5-membered heteroaryl and ring D is a 6-membered heteroaryl. In some embodiments, ring C is a 5-membered heteroaryl and ring D is a 6-membered heterocycloalkyl.

In some embodiments, each of Ring C and Ring ^D is optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, ^-ORa , -SH, ^-SRa , ^-NRcRd , optionally substituted _C1-6 alkyl, optionally substituted _C1-6 heteroalkyl, optionally substituted _C2-6 alkenyl, and optionally substituted _C2-6 alkynyl, and wherein the alkyl, the heteroalkyl, the alkenyl or the alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, -OH, _-NO2 , -CN and _C1-3 alkoxy.

In some embodiments, ring D is an aromatic, saturated or partially saturated 6-membered carbon ring or heterocyclic ring, wherein each of the carbon ring or the heterocyclic ring is optionally substituted. In some embodiments, ring D is an aromatic 6-membered carbon ring that is optionally substituted. In some embodiments, ring D is an aromatic 6-membered heterocyclic ring that is optionally substituted. In some embodiments, ring D is an optionally substituted saturated 6-membered carbon ring. In some embodiments, ring D is an optionally substituted saturated 6-membered heterocyclic ring. In some embodiments, ring D is an optionally substituted partially saturated 6-membered carbon ring. In some embodiments, ring D is an optionally substituted partially saturated 6-membered heterocyclic ring.

In some embodiments of the compound of formula (I), for .

In one aspect, the present disclosure provides a compound represented by formula (IIA) or a pharmaceutically acceptable salt thereof: Formula (IIA).

In some embodiments of the compound of formula (I), for .

In one aspect, the present disclosure provides a compound represented by formula (IIB) or a pharmaceutically acceptable salt thereof: Formula (IIB).

In some embodiments, the compound of formula (I) is for .

In one aspect, the present disclosure provides a compound represented by formula (IIC) or a pharmaceutically acceptable salt thereof: Formula (IIC).

In some embodiments, the compound of formula (I) is for .

In one aspect, the present disclosure provides a compound represented by formula (IID) or a pharmaceutically acceptable salt thereof: Formula (IID).

In one aspect, the present disclosure provides a compound represented by formula (IID') or a pharmaceutically acceptable salt thereof: Formula (IID') wherein, ^Z1 is N or CR ^Z1 ; ^Z2 is N or CR ^Z2 ; ^Z3 is N or CR ^Z3 ; ^Z4 is N or CR ^Z4 ; ^Z5 is N or CR ^Z4 ; each of R ^Z1 , R ^Z2 , R ^Z3 , R ^Z4 and R ^Z5 is independently hydrogen or ^RA ; ^R1 is halogen, -CN, OH, _-SF5 , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C 1 -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C _{1 -C 6} heteroalkyl, C _2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or ^{R 4'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; R ⁵ and R ^5' are each independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^5' together form a pendoxy group; or R ⁵ and R ^{R 5'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendoxy group; or R ⁶ and R ^6' together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R groups.

In some embodiments of compounds of Formula (IID'), each of ^RZ1 , ^RZ2 , ^RZ3 , ^RZ4 , and ^RZ5 is independently hydrogen or ^RA , provided that when ^Z1 is ^CRZ1 and ^Z5 is ^CRZ5 , at least one of ^RZ1 and ^RZ5 is selected from ^RA .

In one aspect, the present disclosure provides a compound represented by formula (IID'') or a pharmaceutically acceptable salt thereof: Formula (IID''): Ring A is a 5-membered heteroaryl group; ^Y1 is N or ^CRY1 ; ^Y2 is N or ^CRY2 ; ^Y3 is N or ^CRY3 ; ^Y4 is N or ^CRY4 ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; ^R1 is hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or ^{R 4'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; R ⁵ and R ^5' are each independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^5' together form a pendoxy group; or R ⁵ and R ^{R 5'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendoxy group; or R ⁶ and R ^6' together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R groups.

In some embodiments, the compound of formula (I) is for .

In one aspect, the present disclosure provides a compound represented by formula (IIE) or a pharmaceutically acceptable salt thereof: Formula (IIE): ^Y1 is N or CR ^Y1 ; ^Y2 is N or CR ^Y2 ; ^Y3 is N or CR ^Y3 ; ^Y4 is N or CR ^Y4 ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, C wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; X ¹ is N or ^CRX ; ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C 1-C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl; each of R ⁴ and R ^4' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ The present invention comprises a _{C 2-6} alkenyl, a C _2-6 alkynyl, a cycloalkyl and a heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁴ and R ^4' together form a pendoxy group; or R ⁴ and R ^4' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C 1 -C 6 heteroalkyl, C ₁ -C ₆ The invention also includes _{C 2-6} alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendooxy group; or R ⁶ and R ^6' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R.

In some embodiments, the compound of formula (I) is for .

In one aspect, the present disclosure provides a compound represented by formula (IIF) or a pharmaceutically acceptable salt thereof: Formula (IIF) ^Y1 is N or CR ^Y1 ; ^Y2 is N or CR ^Y2 ; ^Y3 is N or CR ^Y3 ; ^Y4 is N or CR ^Y4 ; ^X2 is N or CR ² ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or R ^{4 '} and R ^4' are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; each of R ⁵ and R ^5' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^R and R ^{5 '} together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R and R ^{6 '} is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R or R ⁶ and R ^{6' together} with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R.

In some embodiments of the compound of formula (I), for .

In one aspect, the present disclosure provides a compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof: Formula (IIG) ^Z1 is N or ^CRZ1 ; ^Z2 is N or ^CRZ2 ; ^Z3 is N or ^CRZ3 ; ^Z4 is N or ^CRZ4 ; ^Z5 is N or ^CRZ4 ; each of ^RZ1 , ^RZ2 , ^RZ3 , ^RZ4 and ^RZ5 is independently hydrogen or ^RA ; ^X3 is N, ^NR1N , ^CR1 , S or O; ^X4 is N, ^NR2N , ^CR2 , S or O; ^X5 is N or C; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, C1-C6 wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; each of ^R1N and ^R2N is independently hydrogen, _C1-6 alkyl, C1 _{- C6} halogenated alkyl, C1-C6 hydroxyalkyl, _C1 - _C6 aminoalkyl or C1- _C6 heteroalkyl; ^X1 is N or ^CRX ; ^RX is hydrogen, halogen, _C1-6 alkyl, _{C1 - C6 halogenated} alkyl, _{C1 - C6 hydroxyalkyl} , C1 _{-C6 aminoalkyl} or _C1 - _{C6 heteroalkyl} ; ^R4 and R ^{R4 and R4'} are each independently selected from hydrogen, halogen, -CN, -ORa, ^{-SRa , -NRcRd} , C1-6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 - _C6 heteroalkyl, C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl ^is optionally substituted with one or more R; or R4 and R4' together form a pendooxy group; or R4 and R4' together with the carbon to which they are attached form a _{3-6 membered} cycloalkyl or a _3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R; and ^R6 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, C1-6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4 ^{' together form a pendooxy group; or R4 and R4' together} with the carbon to which they are attached form a 3-6 membered cycloalkyl or a ^3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R; and Each of ^{R and R '} is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendooxy group; or R ⁶ and R ^6' together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R.

In some embodiments, each of ^RZ1 , ^RZ2 , ^RZ3 , ^RZ4 , and ^RZ5 is independently hydrogen or ^RA , with the proviso that at least one of ^RZ1 and ^RZ5 is present and selected from ^RA .

In one aspect, the present disclosure provides a compound represented by formula (IIH) or a pharmaceutically acceptable salt thereof: Formula (IIH).

In some embodiments, for or In some embodiments, for In some embodiments, for .

In some embodiments, ^X3 is N, ^NR1N , ^CR1 , S or O. In some embodiments, ^X3 is N, ^NR1N or ^CR1 . In some embodiments, ^X3 is N. In some embodiments, ^X3 is ^NR1N . In some embodiments, ^X3 is ^CR1 . In some embodiments, ^X3 is S. In some embodiments, ^X3 is O.

In some embodiments, each of R ^1N and R ^2N is independently hydrogen, C _1-6 alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C 6 heteroalkyl. In some embodiments, R ^1N and R ^2N are independently hydrogen, C _1-6 alkyl, C ₁ - _{C 6 haloalkyl} , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, R ^1N and R ^2N are independently hydrogen, C _1-6 alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl. In some embodiments, each of R ^1N and R ^2N is independently hydrogen, C _1-6 alkyl, C ₁ - _{C 6} haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl.

In some embodiments, R ^1N is hydrogen, C _1-6 alkyl or C ₁ -C ₆ haloalkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ^1N is hydrogen, C _1-6 alkyl or C ₁ -C ₆ haloalkyl. In some embodiments, R ^1N is hydrogen. In some embodiments, R ^1N is C _1-6 alkyl. In some embodiments, R ^1N is CH _3. In some embodiments, R ^1N is C ₁ -C ₆ haloalkyl.

In some embodiments, R ^2N is hydrogen, C _1-6 alkyl or C ₁ -C ₆ haloalkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ^2N is hydrogen, C _1-6 alkyl or C ₁ -C ₆ haloalkyl. In some embodiments, R ^2N is hydrogen. In some embodiments, R ^2N is C _1-6 alkyl. In some embodiments, R ^2N is CH _3. In some embodiments, R ^2N is C ₁ -C ₆ haloalkyl.

In some embodiments, ^R1 and ^R2 are independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, C1- _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted _with one or more R. In some embodiments, ^R1 and ^R2 are independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _{C1 - C6} heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl or heterocycloalkyl.

In some embodiments, R ¹ is halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ¹ is halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is C _1-6 alkyl. In some embodiments, R ¹ is CH ₃ . In some embodiments, R ^{1 is halogen. In some embodiments, R 1 is} F. In some embodiments, R ¹ is Cl. In some embodiments, R ¹ is C ₁ -C ₆ halogenated alkyl. In some embodiments, R ¹ is CF ₃ .

In some embodiments, R ² is halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ² is halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl. In some embodiments, R ² is halogen. In some embodiments, R ² is C _1-6 alkyl. In some embodiments, R ² is CH ₃ . In some embodiments, R ^{2 is halogen. In some embodiments, R 2 is} F. In some embodiments, R ² is Cl. In some embodiments, R ² is C ₁ -C ₆ halogenated alkyl. In some embodiments, R ² is CF ₃ .

In some embodiments, R ¹ is halogen, -CN, OH, -SF ₅ , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ¹ is halogen, -CN, OH, -SF ₅ , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl or heterocycloalkyl.

In some embodiments, ^R2 is halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ² is halogen, -CN, OH, -SF ₅ , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl or heterocycloalkyl.

In some embodiments, ^X4 is N, ^NR2N , ^CR2 , S or O. In some embodiments, ^X4 is N, ^NR2N or ^CR2 . In some embodiments, ^X4 is N. In some embodiments, ^X4 is ^NR2N . In some embodiments, ^X4 is ^CR2 . In some embodiments, ^X4 is S.

In some embodiments, ^X4 is O. In some embodiments, ^X5 is N or C. In some embodiments, ^X5 is N. In some embodiments, ^X5 is C.

In some embodiments, ^X1 is N or ^CRX . In some embodiments, ^X1 is N. In some embodiments, ^X1 is ^CRX .

In some embodiments, ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl. In some embodiments, ^RX is hydrogen. In some embodiments, ^RX is halogen. In some embodiments, ^RX is C _1-6 alkyl. In some embodiments, ^RX is C ₁ -C ₆ halogenated alkyl. In some embodiments, ^RX is C ₁ -C ₆ hydroxyalkyl. In some embodiments, ^RX is C ₁ -C ₆ aminoalkyl. In some embodiments, ^RX is C ₁ -C ₆ heteroalkyl.

In some embodiments, ^Z1 is N or CR ^Z1 . In some embodiments, ^Z1 is N. In some embodiments, ^Z1 is CR ^Z1 . In some embodiments, ^Z2 is N or CR ^Z2 . In some embodiments, ^Z2 is N. In some embodiments, ^Z2 is CR ^Z2 . In some embodiments, ^Z3 is N or CR ^Z3 . In some embodiments, ^Z3 is N. In some embodiments, ^Z3 is CR ^Z3 . In some embodiments, ^Z4 is N or CR ^Z4 . In some embodiments, ^Z4 is N. In some embodiments, ^Z4 is CR ^Z4 . In some embodiments, ^Z5 is N or CR ^Z5 . In some embodiments, ^Z5 is N. In some embodiments, ^Z5 is CR ^Z5 .

In some embodiments, each of R ^Z1 , R ^Z2 , R ^Z3 , R ^Z4 , and R ^Z5 is independently hydrogen or ^RA . In some embodiments, each of R ^Z1 , R ^Z2 , R ^Z3 , and R ^Z4 is hydrogen.

In some embodiments, R ^Z1 is or ^RA . In some embodiments, R ^Z1 is hydrogen. In some embodiments, R ^Z1 is ^RA . In some embodiments, R ^Z1 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with one or more ^RA1 . In some embodiments, R ^Z1 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH _3. In some embodiments, ^RA is CH(CH ₃ ) ₂ . In some embodiments, ^RA is ^-ORa . In some embodiments, ^RA is _-OCH3 . In some embodiments, ^RA is _-OCF2H . In some embodiments, ^RA is cycloalkyl. In some embodiments, ^RA is .

In some embodiments, R ^Z2 is hydrogen or ^RA . In some embodiments, R ^Z2 is hydrogen. In some embodiments, R ^Z2 is ^RA . In some embodiments, R ^Z2 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with one or more ^RA1 . In some embodiments, R ^Z2 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH _3. In some embodiments, ^RA is CH(CH ₃ ) ₂ . In some embodiments, ^RA is ^-ORa . In some embodiments, ^RA is _-OCH3 . In some embodiments, ^RA is _-OCF2H . In some embodiments, ^RA is cycloalkyl. In some embodiments, ^RA is .

In some embodiments, R ^Z3 is hydrogen or ^RA . In some embodiments, R ^Z3 is hydrogen. In some embodiments, R ^Z3 is ^RA . In some embodiments, R ^Z3 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with one or more ^RA1 . In some embodiments, R ^Z3 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH _3. In some embodiments, ^RA is CH(CH ₃ ) ₂ . In some embodiments, ^RA is ^-ORa . In some embodiments, ^RA is _-OCH3 . In some embodiments, ^RA is _-OCF2H . In some embodiments, ^RA is cycloalkyl. In some embodiments, ^RA is .

In some embodiments, R ^Z4 is hydrogen or ^RA . In some embodiments, R ^Z4 is hydrogen. In some embodiments, R ^Z4 is ^RA . In some embodiments, R ^Z4 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with one or more ^RA1 . In some embodiments, R ^Z4 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH _3. In some embodiments, ^RA is CH(CH ₃ ) ₂ . In some embodiments, ^RA is ^-ORa . In some embodiments, ^RA is _-OCH3 . In some embodiments, ^RA is _-OCF2H . In some embodiments, ^RA is cycloalkyl. In some embodiments, ^RA is .

In some embodiments, R ^Z5 is hydrogen or ^RA . In some embodiments, R ^Z5 is hydrogen. In some embodiments, R ^Z5 is ^RA . In some embodiments, R ^Z5 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl, wherein the alkyl or the cycloalkyl is optionally substituted with one or more ^RA1 . In some embodiments, R ^Z5 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH _3. In some embodiments, ^RA is CH(CH ₃ ) ₂ . In some embodiments, ^RA is ^-ORa . In some embodiments, ^RA is _-OCH3 . In some embodiments, ^RA is _-OCF2H . In some embodiments, ^RA is cycloalkyl. In some embodiments, ^RA is .

In some embodiments, ^Y1 is N or CR ^Y1 . In some embodiments, ^Y1 is N. In some embodiments, ^Y1 is CR ^Y1 . In some embodiments, ^Y2 is N or CR ^Y2 . In some embodiments, ^Y2 is N. In some embodiments, ^Y2 is CR ^Y2 . In some embodiments, ^Y3 is N or CR ^Y3 . In some embodiments, ^Y3 is N. In some embodiments, ^Y3 is CR ^{Y3. In some embodiments, Y4 is N or CR Y4 . In} some embodiments, ^Y4 is N. In some embodiments, ^Z4 is CR ^Y4 .

In some embodiments, each of ^RY1 , ^RY2 , ^RY3 , and R ^Z4 is independently hydrogen or ^RB . In some embodiments, each of ^RY1 , ^RY2 , ^RY3 , and ^RY4 is hydrogen.

In some embodiments, R ^Y1 is hydrogen or ^RB . In some embodiments, R ^Y1 is hydrogen. In some embodiments, R ^Y1 is ^RB . In some embodiments, R ^Y1 is ^RB , wherein ^RB is selected from halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . In some embodiments, ^RB is F.

In some embodiments, ^RY2 is hydrogen or ^RB . In some embodiments, ^RY2 is hydrogen. In some embodiments, ^RY2 is ^RB . In some embodiments, ^RZY is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . In some embodiments, ^RB is F.

In some embodiments, ^RY3 is hydrogen or ^RB . In some embodiments, ^RY3 is hydrogen. In some embodiments, ^RY3 is ^RB . In some embodiments, ^RY3 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . In some embodiments, ^RB is F.

In some embodiments, ^RY4 is hydrogen or ^RB . In some embodiments, ^RY4 is hydrogen. In some embodiments, ^RY4 is ^RB . In some embodiments, ^RY4 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . In some embodiments, ^RB is F.

In some embodiments, R ⁴ and R ^4′ are independently selected from hydrogen, halogen, —CN, —OR ^a , —SR ^a , —NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ⁴ and R ^{4 '} are independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl. In some embodiments, R ^{4 and R 4 'together form a pendoxy group. In some embodiments, R 4 and} R ^{4 '} together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, R ⁴ and R ^4′ together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl.

In some embodiments, ^R is selected from hydrogen, halogen, -CN, -ORa, ^{-SRa , -NRcRd} , _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 ^- _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with _one or more R. In some embodiments, ^R is selected from hydrogen, halogen, _C1-6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, ^R is hydrogen. In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is C _1-6 alkyl. In some embodiments, R ⁴ is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ⁴ is C ₁ -C ₆ halogenated alkyl.

In some embodiments, R ^4′ is selected from hydrogen, halogen, —CN, —OR ^a , —SR ^a , —NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl, or the heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ^4′ is selected from hydrogen, halogen, C _1-6 alkyl, and C ₁ - _{C 6} halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ^4′ is hydrogen. In some embodiments, R ^4' is halogen. In some embodiments, R ^4' is C _1-6 alkyl. In some embodiments, R ^4' is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ^4' is C ₁ -C ₆ halogenated alkyl.

In some embodiments, R ⁵ and R ^5′ are independently selected from hydrogen, halogen, —CN, —OR ^a , —SR ^a , —NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ⁵ and R ^5' are independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl. In some embodiments, R ⁵ and R ^5' together form a pendoxy group. In some embodiments, R ⁵ and R ^5' together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, R ⁵ and R ^5′ together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl.

In some embodiments, ^R is selected from hydrogen, halogen, -CN, -ORa, ^{-SRa , -NRcRd} , _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 ^- _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with _one or more R. In some embodiments, ^R is selected from hydrogen, halogen, _C1-6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, ^R is hydrogen. In some embodiments, R ⁵ is halogen. In some embodiments, R ⁵ is C _1-6 alkyl. In some embodiments, R ⁵ is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ⁵ is C ₁ -C ₆ halogenated alkyl.

In some embodiments, R ^5′ is selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ^5′ is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ^5′ is hydrogen. In some embodiments, R ^5' is halogen. In some embodiments, R ^5' is C _1-6 alkyl. In some embodiments, R ^5' is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ^5' is C ₁ -C ₆ halogenated alkyl.

In some embodiments, ^R and ^R are independently selected from hydrogen, halogen, -CN, ^-OR , ^{-SR , -NRcR} , _C1-6 alkyl, C1 _{- C6} haloalkyl, C1- _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more _R. In some embodiments, R ⁵ and R ^5' are independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl. In some embodiments, R ^{6 and R 6' together form a pendoxy group. In some embodiments, R 6 and} R ^{6 '} together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, R ⁶ and R ^6′ together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl.

In some embodiments, ^R is selected from hydrogen, halogen, -CN, -ORa, ^{-SRa , -NRcRd} , _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 ^- _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with _one or more R. In some embodiments, ^R is selected from hydrogen, halogen, _C1-6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, ^R is hydrogen. In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is C _1-6 alkyl. In some embodiments, R ⁶ is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ⁶ is C ₁ -C ₆ halogenated alkyl.

In some embodiments, R ^6′ is selected from hydrogen, halogen, —CN, —OR ^a , —SR ^a , —NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R ^6′ is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ^6' is halogen. In some embodiments, R ^6' is C _1-6 alkyl. In some embodiments, R ^6' is C _1-6 alkyl optionally substituted with one or more R. In some embodiments, R ^6' is C ₁ -C ₆ halogenated alkyl.

In some embodiments, ^RA is selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, the heteroalkyl, the Each of the alkenyl, the alkynyl, the cycloalkyl, the heterocycloalkyl, the aryl and the heteroaryl is independently optionally substituted with one or more R ^A1 . In some embodiments, ^RA is selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ ^heteroalkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. The intervening atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, ^or heteroaryl, each of which is independently substituted with one or more R ^A1 as appropriate. is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl. In some embodiments, ^RA is C ₁ -C ₆ alkyl. In some embodiments, ^RA is CH ₃ . In some embodiments, ^RA is CH(CH ₃ ) ₂ . , ^RA is -OR ^a . In some embodiments, ^RA is -OCH ₃ . In some embodiments, ^RA is -OCF ₂ H. In some embodiments, ^RA is cycloalkyl. In the embodiment, ^RA is .

In some embodiments, ^RA is not _C1-6 alkoxy. In some embodiments, ^RA is not Cl. In some embodiments, ^RA is not halogen.

In some embodiments, each ^RA is independently selected from halogen, OH, -NO ₂ , oxo, -CN, C _1-6 alkyl, C _1-6 alkoxy, C 1-6 halogenated alkyl, C 1-6 heteroalkyl, and C _3-6 cycloalkyl. In some embodiments, each ^{RA is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 halogenated alkyl, and C 3-6 cycloalkyl. In some embodiments, each RA} _{is independently selected from C 1-6 alkyl , C 1-6 alkoxy, C 1-6} ^halogenated _{alkoxy , C 1-6 halogenated} alkyl, and C _3-6 cycloalkyl. In some embodiments, each ^RA is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, and C _3-6 cycloalkyl, wherein the alkyl, the alkoxy, and the cycloalkyl are optionally substituted with one or more halogens (e.g., 1 to 3 fluorines). In some embodiments, each ^RA is independently selected from methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl, -O-butyl, cyclopropyl, CN, OH, -O-CHF ₂ , -O-CH ₂ F, CHF ₂ , CH ₂ F, and CF ₃ . In some embodiments, ^{RA is a halogen. In some embodiments, RA is} -NO ₂ . In some embodiments, ^RA is a pendoxy group. In some embodiments, ^RA is -CN. In some embodiments, ^RA is C _1-6 alkyl, which may be substituted. In some embodiments, ^RA is C ₁ -alkyl. In some embodiments, ^RA is C ₂ alkyl. In some embodiments, ^RA is C ₃ alkyl. In some embodiments, ^RA is C _1-6 heteroalkyl, which may be substituted. In some embodiments, ^RA is C ₃ heteroalkyl. In some embodiments, ^RA is C _3-8 cycloalkyl, which may be substituted. In some embodiments, ^RA is C ₃ cycloalkyl. In some embodiments, ^RA is C _2-7 heterocycloalkyl, which may be substituted. In some embodiments, ^RA is C ₂ heterocycloalkyl.

In some embodiments, each ^RA is independently substituted with one or more substituents independently selected from the group consisting of halogen, -OH, _-NO2 , amino, -CN, _C1-6 alkoxy, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-6 carbocycle, and 3-6 membered heterocycle, wherein the _C3-6 carbocycle and the 3-6 membered heterocycle are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, _oxo , -CN, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 halogenated alkyl.

In some embodiments, ^RA is independently substituted with one or more substituents independently selected from the group consisting of halogen, -OH, _-NO2 , amino, -CN, _C1-6 alkoxy, _C1-6 alkyl, _C1-6 halogenated alkyl, C3-6 carbocycle, and _3-6 membered heterocycle, wherein the _C3-6 carbocycle and the 3-6 membered heterocycle are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, _-NO2 , pentooxy, -CN, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 halogenated alkyl. In some embodiments, each ^RA is independently selected from halogen, -NO ₂ , oxo, CN, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-8 cycloalkyl, or optionally substituted C _2-7 heterocycloalkyl. In some embodiments, ^RA is halogen. In some embodiments, ^RA is -NO ₂ . In some embodiments, ^RA is oxo. In some embodiments, ^RA is CN. In some embodiments, ^RA is _optionally substituted C _1-6 alkyl. In some embodiments, ^RA is optionally substituted C _1-3 alkyl. In some embodiments, ^RA is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF ₃ , -CH ₂ CF ₃ or -CH ₂ CH ₂ F. In some embodiments, ^RA is an optionally substituted C _{2-6 alkenyl. In some embodiments, RA is an optionally substituted C 2-6 alkynyl} . In some embodiments, ^RA is an optionally substituted C _1-6 heteroalkyl. In some embodiments, ^RA is an optionally substituted C _3-8 cycloalkyl. In some embodiments, ^RA is ^an optionally substituted C _3-6 cycloalkyl, such as cyclopropyl. In some embodiments, ^RA is , , or In some embodiments, ^RA is an optionally substituted C _2-7 heterocycloalkyl. In some embodiments, ^RA is an optionally substituted C _2-5 heterocycloalkyl. In some embodiments, ^RA is -OC _1-3 alkyl. In some embodiments, ^RA is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ OMe, -OCH ₂ CH ₂ OH, -OC(CH ₃ ) ₃ or -OCH ₂ CH ₂ OCH ₃ . In some embodiments, ^RA is -OCH ₃ . In some embodiments, ^RA is In some embodiments, -OCH ₃ is -OCD ₃ .

In some embodiments, each ^RA is independently OH, _C1-6 alkoxy (eg, _-OCH3 ), _C1-6 alkyl, _C1-6 haloalkyl, or _C3 - _C6 cycloalkyl (eg, cyclopropyl).

In some embodiments, each ^RA is independently OH, C _1-3 alkyl, C _1-3 alkoxy (e.g., -OCH ₃ ), C _1-3 halogenated alkyl, or C ₃ -C ₆ cycloalkyl (e.g., cyclopropyl). In some embodiments, each ^RA is independently C _1-3 alkoxy (e.g., -OCH ₃ ) or C ₃ -C ₆ cycloalkyl (e.g., cyclopropyl). In some embodiments, each ^RA is independently -OCH ₃ , C _1-3 alkyl, C 1-3 halogenated alkyl, or cyclopropyl. In some embodiments, each ^RA is independently C _1-3 alkoxy, C _1-3 alkyl, C _{1-3 halogenated} alkyl, or cyclopropyl. In some embodiments, -OCH ₃ is -OCD ₃ .

In some embodiments, R ^A1 is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, the heteroalkyl, the The alkenyl, the alkynyl, the cycloalkyl, the heterocycloalkyl, the aryl and the heteroaryl are independently optionally substituted with one or more R. In some embodiments, R ^A1 is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R ^A1 is halogen, C ₁ -C ₆ alkyl, cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by one or more R groups.

In some embodiments of the compound of formula (I), Ring A is an aryl or heteroaryl group. In some embodiments, Ring A is a phenyl group or a 5-6 membered monocyclic heteroaryl group. In some embodiments, Ring A is a phenyl group or a 5-6 membered monocyclic heteroaryl group. In some embodiments, Ring A is a pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, thiophene or thiazole.

In some embodiments, for , , , , , , , , , , , , , , , , , or .

In some embodiments, Select from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, Selected from , , , and .

In some embodiments, Select from: , , , , , , , and .

In some embodiments, for or .

In some embodiments, for , , , , or .

In some embodiments, for , , , , , , or . In some embodiments, Ring A is an unsubstituted aryl group (e.g., phenyl). In some embodiments, Ring A is an aryl group (e.g., phenyl) optionally substituted with 1 to 5 ^RAs . In some embodiments, Ring A is an aryl group (e.g., phenyl) substituted with 1 ^RA . In some embodiments, Ring A is an aryl group (e.g., phenyl) substituted with 2 ^RAs . In some embodiments, Ring A is an aryl group (e.g., phenyl) substituted with 3 ^RAs . In some embodiments, Ring A is an aryl group (e.g., phenyl) substituted with 4 ^RAs . In some embodiments, Ring A is an aryl group (e.g., phenyl) substituted with 5 ^RAs .

In some embodiments, Ring A is a monocyclic heteroaryl or a bicyclic heteroaryl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a bicyclic heteroaryl.

In some embodiments, Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is monocyclic heteroaryl. In some embodiments, Ring A is bicyclic heteroaryl.

In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms.

In some embodiments, Ring A is a 5-membered monocyclic heteroaryl. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms. In some embodiments, Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole or thiophene. In some embodiments, for , , , , , , , , , , , , , , , , , or In some embodiments, for , , or In some embodiments, for , , ,or In some embodiments, for or In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for , or In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for , or In some embodiments, for , , , , , , , or In some embodiments, Ring A is a bicyclic heteroaryl. In some embodiments, Ring A is a fused 5-6, 6-6 or 6-5 bicyclic heteroaryl.

In some embodiments, Select from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for .

In some embodiments, Select from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for .

In some embodiments, for , , or .

In some embodiments, ring B is phenyl, phenyl homoelectronic arrangement or heteroaryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is phenyl homoelectronic arrangement. In some embodiments, phenyl homoelectronic arrangement is cubane. In some embodiments, ring B is heteroaryl. In some embodiments, ring B is 5-6 membered monocyclic heteroaryl. In some embodiments, ring B is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, thiophene or thiazole. In some embodiments, ring B is 5-6 membered monocyclic heteroaryl. In some embodiments, ring B is pyridine. In some embodiments, ring B is pyrimidine. In some embodiments, Ring B is pyrazine. In some embodiments, Ring B is pyridazine. In some embodiments, Ring B is triazine. In some embodiments, Ring B is imidazole. In some embodiments, Ring B is pyrazole. In some embodiments, Ring B is triazole. In some embodiments, Ring B is oxazole. In some embodiments, Ring B is isoxazole. In some embodiments, Ring B is thiophene. In some embodiments, Ring B is thiazole.

In some embodiments, Select from: , , , and .

In some embodiments, R ¹⁰ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is independently substituted with one or more R ^B1 . In some embodiments, R 10 is heteroaryl, wherein the heteroaryl is optionally substituted with one or more R ^B1 . In some embodiments, R ¹⁰ is a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms selected from N, O, S and P, which is optionally substituted. In some embodiments, R ¹⁰ is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. In some embodiments, R ¹⁰ is a fused 5-6, 6-6 or 6-5 heteroaryl ^, which is optionally substituted. In some embodiments, R ¹⁰ is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. In some embodiments, R ¹⁰ is optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

In some embodiments, ^R10 is selected from: , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, ^R10 is selected from: , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, R ¹⁰ is , , or In some embodiments, R ¹⁰ is , , , or In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is .

In some embodiments, R ¹⁰ is an optionally substituted C _3-8 cycloalkyl or an optionally substituted phenyl. In some embodiments, R ¹⁰ is an optionally substituted C _2-9 heterocycloalkyl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic heteroaryl, each of which contains 1 to 4 heteroatoms selected from O, S, N, P, and Si. In some embodiments, R ¹⁰ is an optionally substituted C _3-8 cycloalkyl. In some embodiments, R ¹⁰ is a C ₃ cycloalkyl. In some embodiments, R ¹⁰ is a C ₅ cycloalkyl. In some embodiments, R ¹⁰ is a C ₆ cycloalkyl. In some embodiments, R ¹⁰ is an optionally substituted phenyl. In some embodiments, R ¹⁰ is an optionally substituted C _2-9 heterocycloalkyl. In some embodiments, R ¹⁰ is a C ₃ heterocycloalkyl. In some embodiments, R ¹⁰ is a C ₅ heterocycloalkyl. In some embodiments, R ¹⁰ is a C ₆ heterocycloalkyl. In some embodiments, R ¹⁰ is an optionally substituted monocyclic heteroaryl. In some embodiments, R ^{10 is an optionally substituted bicyclic heteroaryl. In some embodiments, R 10 is} imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. In some embodiments, R ¹⁰ is imidazole. In some embodiments, R ¹⁰ is pyrazole. In some embodiments, R ¹⁰ is triazole. In some embodiments, R ¹⁰ is tetrazole. In some embodiments, R ¹⁰ is optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl. In some embodiments, R ¹⁰ is substituted with halogen. In some embodiments, R ¹⁰ is substituted with -OR ^11. In some embodiments, R ¹⁰ is substituted with -NO _2. In some embodiments, R ¹⁰ is substituted with pendoxy. In some embodiments, R ¹⁰ is substituted with -CN. In some embodiments, R ¹⁰ is substituted with optionally substituted C _1-6 haloalkyl. In some embodiments, R ¹⁰ is substituted with optionally substituted C _1-6 alkyl. In some embodiments, R ¹⁰ is substituted with an optionally substituted C _1-6 aminoalkyl.

In some embodiments, R ¹⁰ is an optionally substituted monocyclic heteroaryl or an optionally substituted bicyclic heteroaryl. In some embodiments, R ¹⁰ is an optionally substituted monocyclic heteroaryl (e.g., a 5-membered heteroaryl). In some embodiments, R ¹⁰ is a substituted monocyclic heteroaryl.

In some embodiments, R ¹⁰ is , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ¹⁰ is , , , or In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is In some embodiments, R ¹⁰ is .

In some embodiments, R ¹⁰ is a 5-membered heteroaryl group optionally substituted with one or more substituents selected from C _1-3 halogenated alkyl and C _1-3 alkyl (e.g., , , ,or In some embodiments, R ¹⁰ is substituted with 1 or 2 substituents selected from C _1-3 halogenated alkyl and C _1-3 alkyl.

In some embodiments, R ¹⁰ is an optionally substituted C _3-8 cycloalkyl, an optionally substituted C _2-9 heterocycloalkyl, an optionally substituted naphthyl, an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic heteroaryl. In some embodiments, R ¹⁰ is an optionally substituted C _3-8 cycloalkyl. In some embodiments, R ¹⁰ is an optionally substituted C _2-9 heterocycloalkyl. In some embodiments, R ¹⁰ is an optionally substituted 5-6 membered heterocycloalkyl. In some embodiments, R ¹⁰ is an optionally substituted naphthyl. In some embodiments, R ¹⁰ is an optionally substituted phenyl group. In some embodiments, R ¹⁰ is an optionally substituted monocyclic heteroaryl group. In some embodiments, R ¹⁰ is an optionally substituted bicyclic heteroaryl group.

In some embodiments, R ¹⁰ is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms selected from N, O, S and P. In some embodiments, R ^{10 is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. In some embodiments, R 10 is} an optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

In some embodiments, R ¹⁰ is optionally substituted with one or more substituents independently selected from halogen, -OR ^a , -NO ₂ , oxo, -CN, optionally substituted C _1-6 haloalkyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 aminoalkyl, optionally substituted C _1-6 hydroxyalkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-8 cycloalkyl, and optionally substituted C _2-7 heterocycloalkyl. In some embodiments, R ¹⁰ is optionally substituted with one or more substituents independently selected from the following: halogen, -OR ¹¹ , -NO ₂ , oxo, -CN, C _1-3 halogenated alkyl, C _1-3 alkyl, C _1-3 aminoalkyl, C _1-3 hydroxyalkyl, optionally substituted C _1-4 heteroalkyl (e.g., -CH ₂ C(=O)N(CH ₃ ) ₂ ), optionally substituted C _3-6 cycloalkyl, and optionally substituted C _2-5 heterocycloalkyl. In some embodiments, R ¹⁰ is optionally substituted C _3-8 cycloalkyl. In some embodiments, R ¹⁰ is C ₃ cycloalkyl. In some embodiments, R ¹⁰ is C ₅ cycloalkyl. In some embodiments, R ¹⁰ is C ₆ cycloalkyl. In some embodiments, R ¹⁰ is phenyl, which may be substituted. In some embodiments, R ¹⁰ is C _2-9 heterocycloalkyl, which may be substituted. In some embodiments, R ¹⁰ is C ₃ heterocycloalkyl. In some embodiments, R ¹⁰ is C ₅ heterocycloalkyl. In some embodiments, R ¹⁰ is C ₆ heterocycloalkyl. In some embodiments, R ¹⁰ is 5 to 6 membered heterocycloalkyl or heteroaryl, which may be substituted. In some embodiments, R ^{10 is monocyclic heteroaryl, which may be substituted. In some embodiments, R 10 is} bicyclic heteroaryl, which may be substituted. In some embodiments, R ¹⁰ is imidazole, pyrazole, triazole, or tetrazole, each of which is optionally substituted. In some embodiments, R ¹⁰ is imidazole. In some embodiments, R ¹⁰ is pyrazole. In some embodiments, R ^B is triazole. In some embodiments, R ¹⁰ is tetrazole.

In some embodiments, R ^B is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, the heteroalkyl, the Each of the alkenyl, the alkynyl, the cycloalkyl, the heterocycloalkyl, the aryl and the heteroaryl is independently optionally substituted with one or more R ^B1 . In some embodiments, R ^B is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, ^RB is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R ^B1 . In some embodiments, R ^B is halogen. In some embodiments, R ^B is F. In some embodiments, ^RB is _C1 - _C6 alkyl optionally substituted with one or more ^RB1 . In some embodiments, ^RB is _C1 - _C6 alkyl. In some embodiments, ^RB is _C1 - _C6 halogenated alkyl.

In some embodiments, R ^B1 is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, the heteroalkyl, the The alkenyl, the alkynyl, the cycloalkyl, the heterocycloalkyl, the aryl and the heteroaryl are independently optionally substituted with one or more R. In some embodiments, R ^B1 is selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O) NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C( =O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b ,-C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R ^B1 is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ halogenated alkyl; wherein the alkyl is optionally substituted by one or more R. In some embodiments, R ^B1 is halogen. In some embodiments, R ^B1 is In some embodiments, R B1 is C ₁ -C ₆ alkyl substituted with one or more R. In some embodiments, R ^B1 is C ₁ -C ₆ alkyl. In some embodiments, R ^B1 is CH ₃ . In some embodiments, R ^B1 is CH ₂ CH ₃ . In some embodiments, R ^B1 is CH(CH ₃ ) ₂ . In some embodiments, R ^B1 is CH 2 CH 3 . is C ₁ -C ₆ halogenated alkyl. In some embodiments, R ^B1 is CF ₃ .

In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, ^Ra is _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, C2- _{C6 alkenyl, C2-C6 alkynyl ,} cycloalkyl, heterocycloalkyl _, aryl, heteroaryl, _C1 - _C6 alkylene (cycloalkyl), _C1 - _C6 alkylene (heterocycloalkyl), _C1 - _C6 alkylene (aryl) or _C1 - _C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with one or more R. In some embodiments, ^Ra is hydrogen, C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, C1- _C6 heteroalkyl, _C2 - _{C6 alkenyl, C2-C6 alkynyl , cycloalkyl} , heterocycloalkyl, aryl, heteroaryl _{, C1-C6} alkylene (cycloalkyl), _C1 - _{C6 alkylene} (heterocycloalkyl), _C1 - _C6 alkylene (aryl) or _C1 - _C6 alkylene (heteroaryl). In some embodiments, ^Ra is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl or cycloalkyl, wherein each alkyl, heteroalkyl or cycloalkyl is optionally substituted with one or more R. In some embodiments, ^Ra is C ₁ -C ₆ alkyl optionally substituted with one or more R. In some embodiments, ^Ra is C ₁ -C ₆ alkyl. In some embodiments, ^Ra is CH ₃ . In some embodiments, ^Ra is C ₁ -C ₆ haloalkyl. In some embodiments, ^Ra is CHF ₂ . In some embodiments, ^Ra is C ₁ -C ₆ heteroalkyl. In some embodiments, ^Ra is cycloalkyl optionally substituted with one or more R. In some embodiments, ^Ra is cycloalkyl.

In some embodiments, R ^b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), C ₁ -C ₆ alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with one or more R. In some embodiments, R ^b is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), C ₁ -C ₆ alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl). In some embodiments, R ^b is C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ heteroalkyl or cycloalkyl, wherein each alkyl, heteroalkyl or cycloalkyl is optionally substituted with one or more R. In some embodiments, R ^b is C ₁ -C ₆ alkyl optionally substituted with one or more R. In some embodiments, R ^b is C ₁ -C ₆ alkyl. In some embodiments, R ^b is CH ₃ . In some embodiments, R ^b is C ₁ -C ₆ halogenated alkyl. In some embodiments, R ^b is CHF ₂ . In some embodiments, R ^b is C ₁ -C ₆ heteroalkyl. In some embodiments, R ^b is cycloalkyl optionally substituted with one or more R. In some embodiments, R ^b is cycloalkyl.

In some embodiments, R ^c and R ^d are independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C 1 -C 6 heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), _{C 1 -C 6 alkylene (heterocycloalkyl), C 1 -C 6 alkylene (aryl) or C 1 -C 6 alkylene ( heteroaryl ) , wherein each} alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be. In some embodiments, R ^c and R ^d are independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C 1 -C _{6 heteroalkyl, C 2 -C 6 alkenyl ,} C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), _{C 1 -C 6 alkylene (heterocycloalkyl), C 1 -C 6 alkylene (aryl) or C 1 -C 6 alkylene ( heteroaryl ) . In} some embodiments, R ^c and R ^d together with the atoms to which they are attached form a heterocycloalkyl group optionally substituted with one or more R. In some embodiments, R ^c and R ^d together with the atoms to which they are attached form a bond to form a heterocycloalkyl.

In some embodiments, R ^c is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), C ₁ -C ₆ alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently substituted with one or more R as the case may be. In some embodiments, R ^c is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ alkylene (cycloalkyl), C ₁ -C ₆ alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl). In some embodiments, R ^c is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl or cycloalkyl, wherein each alkyl, heteroalkyl or cycloalkyl is optionally substituted with one or more R. In some embodiments, R ^c is C ₁ -C ₆ alkyl optionally substituted with one or more R. In some embodiments, R ^c is C ₁ -C ₆ alkyl. In some embodiments, R ^c is CH ₃ . In some embodiments, R ^b is C ₁ -C ₆ haloalkyl. In some embodiments, R ^c is CHF ₂ . In some embodiments, R ^c is C ₁ -C ₆ heteroalkyl. In some embodiments, R ^c is cycloalkyl optionally substituted with one or more R. In some embodiments, R ^c is cycloalkyl.

In some embodiments, ^Rd is hydrogen, C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 - _C6 heteroalkyl, C2- _{C6 alkenyl, C2-C6 alkynyl ,} cycloalkyl, heterocycloalkyl, aryl, heteroaryl _{, C1} - _C6 alkylene (cycloalkyl), _C1 - _C6 alkylene (heterocycloalkyl), _C1 - _C6 alkylene (aryl) or _C1 - _C6 alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with _one or more R as the case may be. In some embodiments, ^Rd is hydrogen, C1 _{- C6} alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, C1- _C6 aminoalkyl, _C1 - _C6 heteroalkyl, C2- _{C6 alkenyl, C2-C6 alkynyl , cycloalkyl} , heterocycloalkyl, aryl, heteroaryl _{, C1-C6} alkylene (cycloalkyl), _C1 - _{C6 alkylene} (heterocycloalkyl), _C1 - _C6 alkylene (aryl) or _C1 - _C6 alkylene (heteroaryl). In some embodiments, R ^d is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl or cycloalkyl, wherein each alkyl, heteroalkyl or cycloalkyl is optionally substituted with one or more R. In some embodiments, R ^d is C ₁ -C ₆ alkyl optionally substituted with one or more R. In some embodiments, R ^d is C ₁ -C ₆ alkyl. In some embodiments, R ^d is CH ₃ . In some embodiments, R ^b is C ₁ -C ₆ haloalkyl. In some embodiments, R ^d is CHF ₂ . In some embodiments, R ^d is C ₁ -C ₆ heteroalkyl. In some embodiments, R ^d is cycloalkyl optionally substituted with one or more R. In some embodiments, ^Rd is cycloalkyl.

In some embodiments, R is halogen, -CN, -OH, _-SF5 , -SH, -S(=O) _C1 - _C3 alkyl, -S(=O) _{2C1 - C3} alkyl, -S(=O)2NH2, -S(=O) _{2NH1 - C3} alkyl, -S(=O) _2N ( _C1 -C3 alkyl) ₂ , -S(=O)(= _NC1 - _C3 alkyl)( _C1 -C3 _{alkyl ), -NH2 , -NHC1 -C3 alkyl} , -N( _C1 - _C3 alkyl) ₂ , -N=S(=O)( _{C1 - C3} alkyl) ₂ , -C(=O) _C1 - _C3 alkyl, -C(=O)OH, -C(=O) _OC1 - _C3 alkyl, -C(=O) _NH2 , -C(=O)NHC ₁ -C ₃ alkyl, -C(=O)N(C ₁ -C ₃ alkyl) ₂ , -P(=O)(C ₁ -C ₃ alkyl) ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ halogenated alkoxy, C ₁ -C ₃ hydroxyl alkyl, C ₁ -C ₃ aminoalkyl, C ₁ -C ₃ heteroalkyl or C ₃ -C ₆ cycloalkyl. In some embodiments, two R on the same atom form a pendoxy group. In some embodiments, R is a halogen. In some embodiments, R is F. In some embodiments, R is -CN. In some embodiments, R is -OH. In some embodiments, R is -SF ₅ . In some embodiments, R is -SH. In some embodiments, R is -S(=O)C ₁ -C ₃ alkyl. In some embodiments, R is -S(=O) ₂ C ₁ -C ₃ alkyl. In some embodiments, R is -S(=O) ₂ NH ₂ . In some embodiments, R is -S(=O) ₂ NHC ₁ -C ₃ alkyl. In some embodiments, R is -S(=O) ₂ N(C ₁ -C ₃ alkyl) ₂ . In some embodiments, R is -S(=O)(=NC ₁ -C ₃ alkyl)(C ₁ -C ₃ alkyl). In some embodiments, R is -NH ₂ . In some embodiments, R is -NHC ₁ -C ₃ alkyl. In some embodiments, R is -N(C ₁ -C ₃ alkyl) ₂ . In some embodiments, R is -N=S(=O)(C ₁ -C ₃ alkyl) ₂ . In some embodiments, R is -C(=O)C ₁ -C ₃ alkyl. In some embodiments, R is -C(=O)OH. In some embodiments, R is -C(=O)OC ₁ -C ₃ alkyl. In some embodiments, R is -C(=O)NH ₂ . In some embodiments, R is -C(=O)NHC ₁ -C ₃ alkyl. In some embodiments, R is -C(=O)N(C ₁ -C ₃ alkyl) ₂ . In some embodiments, R is -P(=O)(C ₁ -C ₃ alkyl) ₂ . In some embodiments, R is C ₁ -C ₃ alkyl. In some embodiments, R is C ₁ -C ₃ alkoxy. In some embodiments, R is C ₁ -C ₃ haloalkyl. In some embodiments, R is C ₁ -C ₃ haloalkoxy. In some embodiments, R is C ₁ -C ₃ hydroxyalkyl. In some embodiments, R is C _{1 -C 3 aminoalkyl. In some embodiments, R is C 1 -C 3 heteroalkyl .} In some embodiments, R is C ₃ -C ₆ cycloalkyl.

Non-limiting examples of compounds described herein are the compounds presented in Table 1 and their pharmaceutically acceptable salts. In some embodiments, the compound is selected from Table 1. Table 1. Exemplary compounds of the present disclosure Compound No. Structure IUPAC 1 4-(2-isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2 8-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine 3 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine 4 2-(3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole 5 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 6 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 7 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 8 2-(3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole 9 2-(3-(2-isopropylpyridin-3-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole 10 5-(3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole 11 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 12 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 13 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 14 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 15 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 16 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 17 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 18 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 19 1-(2-isopropylphenyl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 20 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(5-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine twenty one 2-(1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole twenty two 2-(1-(2-isopropylphenyl)-3-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole twenty three 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine twenty four 1-(4-cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 25 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(6-fluoro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 26 1-(2-isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridine 27 1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 28 3-Chloro-1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 29 6-(5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 30 6-(3-Fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine 31 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine 32 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Additional non-limiting examples of compounds described herein are the compounds presented in Table 2 and their pharmaceutically acceptable salts. In some embodiments, the compound is selected from Table 2. Table 2. Exemplary compounds of the present disclosure Compound No. Structure IUPAC 33 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Table 3 presents the corresponding biological data of USP1 IC50 (nM) and MDA-MB-436 IC50 (nM) of the compounds presented in Table 1. Table 3: Compound No. USP1 IC ₅₀ (nM) MDA-MB-436 IC ₅₀ (nM) 1 C C 2 B B 3 B B 4 B B 5 C 6 C 7 B 8 B B 9 B 10 B B 11 B A 12 B A 13 B B 14 B B 15 A A 16 B B 17 A A 18 B A 19 A A 20 B B twenty one B B twenty two B C twenty three B B twenty four B B 25 A A 26 A B 27 A A 28 A A 29 A A 30 A A 31 B C 32 A B IC ₅₀ (nM): 0＜A≤50; 50 ＜ B≤1,000; 1,000＜C≤10,000 Other isomers/stereoisomers of the compounds disclosed herein

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers and each center exists in the R configuration or the S configuration. The compounds described herein include all non-mirror isomers, mirror isomers, and epimers and corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of mirror image isomers and/or non-mirror image isomers produced by a single preparative step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of non-mirror image isomers, separating the non-mirror image isomers, and recovering the optically pure mirror image isomers. In some embodiments, resolvable complexes are preferred. In some embodiments, non-mirror image isomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by exploiting these anisotropies. In some embodiments, non-mirror image isomers are separated by palm chromatography or, preferably, by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure mirror image isomers are then recovered with the resolving agent by any practical means that will not result in racemization. Isotopically Enriched Compounds

Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, represented by ¹ H (protium), ² H (deuterium), and ³ H (tritium). Protium is the most abundant hydrogen isotope in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide compounds that can be used to study in vivo pathways of drug elimination and metabolism.

For example, the compounds described herein can be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes selected from the group consisting of deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from ² H, ¹¹ C, ¹³ C, 14 C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ O, ¹⁷ O, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹³¹ I, and ¹²⁵ I. In some embodiments, the abundance of the enriched isotopes is independently at least 1 molar%, at least ¹⁰ molar%, at least 20 molar%, at least 30 molar%, at least 40 molar%, at least 50 molar%, at least 60 molar%, at least 70 molar%, at least 80 molar%, at least 90 molar%, or 100 molar%.

In some embodiments, the compounds are deuterated at least one position. In some embodiments, the compounds disclosed herein have some or all of ^the1H atoms replaced ^with2H atoms.

Methods for the synthesis of deuterated compounds are known in the art and include, by way of non-limiting example only, the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997, as well as the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods such as those described in Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000 , p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989 , 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981 , 64(1-2), 9-32. Pharmaceutically acceptable salts

In some embodiments, the compounds described herein exist in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by separately reacting the purified compound in free form with the appropriate acid or base and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with minerals, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, Salt, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, caproate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate Acid salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonic acid salt, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitic acid salt, pectinate, persulfate, 3- Phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate and xylenesulfonate.

In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, apple acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzene Formic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamine, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids such as oxalic acid, while not themselves pharmaceutically acceptable, are used to prepare salts useful as intermediates in obtaining the compounds disclosed herein or their stereoisomers and pharmaceutically acceptable acid addition salts thereof.

In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base of a pharmaceutically acceptable metal cation, such as hydroxide, carbonate, bicarbonate, sulfate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkaline metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 alkyl) ₄ and the like.

Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, hexahydropyrazine, and the like. It should be understood that the compounds described herein also include quaternary ammoniation of any basic nitrogen-containing groups contained therein. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternary ammoniation. Tautomers

In some cases, compounds exist as tautomeric isomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, with concomitant switching of single bonds and adjacent double bonds. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Administration

In certain embodiments, compositions containing one or more compounds described herein are administered for therapeutic treatment. In certain therapeutic applications, compositions are administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or disorder. Amounts effective for this use depend on the severity and course of the disease or disorder, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Routes of Administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection. Pharmaceutical compositions/formulations

According to standard pharmaceutical practice, the compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition. In some embodiments, the compounds described herein are administered to animals.

In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a customary manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically usable formulation. Appropriate formulation depends on the chosen route of administration. For a general overview of the pharmaceutical compositions described herein, see, for example, Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure. C. Methods of Treatment

Ubiquitin-specific protease 1 (USP1) is a member of the ubiquitin-specific processing protease family. USP1 is a deubiquitinating enzyme ("DUB") and regulates its function by deubiquitinating substrates involved in key oncogenic pathways. Among its actions, USP1 can exhibit DNA-mediated activation at replication forks, protecting the forks and promoting survival in BRCA1-deficient cells. Because loss of both USP1 and BRCA1 leads to replication fork degradation, inhibition of USP1 can selectively reduce the viability of or kill tumor cells with BRCA deficiency without affecting the survival of cells with normal BRCA function.

In the United States (US), it is estimated that hereditary BRCA1 and BRCA2 mutations are present in 5%-10% of breast cancers and 10%-15% of ovarian cancers. Breast cancer is the most common cancer in the world and the most common malignancy in women. BRCA1 and BRCA2 can be detected in at least 5% of unselected breast cancer patients and approximately 30% of patients with a family history of developing breast or ovarian cancer. Currently, there are limited treatment options for breast cancer patients with germline BRCA mutations, more aggressive progression and a higher risk of recurrence, including chemotherapy and immune checkpoint inhibitors. Although PARP inhibitors have been approved by the US Food and Drug Administration (FDA) as monotherapy for deleterious/suspected deleterious germline BRCA mutation, HER2-negative breast cancer, in some cases, rapid development of resistance to PARP inhibitors can be observed in breast cancer patients. Ovarian cancer represents a heterogeneous group of solid tumors. On average, one in five ovarian cancers may be associated with germline mutations. Of those ovarian cancers with germline mutations, 65-85% may be associated with germline BRCA mutations. Similar to the breast cancer context, although PARP inhibitors can be a first-line maintenance therapy for patients with BRCA mutation ovarian cancer, these patients may develop resistance to PARP inhibitors.

The compounds described herein can be used as inhibitors of USP1. Such compounds can exhibit BRCA1 and/or BRCA2 mutant selective antiproliferative activity. The compounds described herein can be used to treat BRCA1 and/or BRCA2 mutation or homologous recombination (HRD) positive cancers. The compounds described herein can exhibit antiproliferative activity in cancer cells with BRCA1 and/or BRCA2 mutations, especially MDA-MB-436 cells. The compounds described herein may not exhibit similar antiproliferative activity in cancer cells with wild-type BRCA, especially SNG-M cells. In some embodiments, the compounds described herein may exhibit at least 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold or more selectivity for mutant BRCA1 and/or BRCA2 over wild-type BRCA.

The compounds described herein can be used to prepare a medicament for preventing or treating a disease or disorder. In some embodiments, the compounds described herein are used in a method of regulating USP1 in an individual. In some embodiments, the compounds described herein are used in a method of inhibiting USP1 in an individual. In some embodiments, the compounds described herein are used in a method of inhibiting or reducing DNA repair activity regulated by USP1 in an individual. In some embodiments, the compounds described herein are used in a method of treating a disease or disorder associated with USP1 in an individual. In some embodiments, the compounds described herein are used in a method of treating a disease or disorder associated with USP regulation in an individual. Additionally, methods for modulating, inhibiting or treating any of the diseases or disorders described herein in a subject in need of such treatment involve administering to the subject a pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

In the event that the patient's condition does not improve, the compound may be administered chronically, that is, for extended periods of time, including throughout the patient's life span, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder, at the physician's discretion.

After the patient's disease has improved, a maintenance dose is administered as necessary. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, may be reduced to a level that retains the improved disease, disorder, or condition. However, after any recurrence of symptoms, the patient may require intermittent treatment on a long-term basis.

The amount of a given dose that will correspond to this amount will vary depending on factors such as the specific compound, the disease or disorder and its severity, the identity (e.g., weight) of the individual or subject to be treated, but nonetheless can be determined in a manner recognized in the art based on the specific circumstances surrounding the case (including, for example, the specific agent being administered, the route of administration, the disorder being treated, and the individual or subject being treated). However, in general, dosages for adult human treatment will generally be in the range of about 0.02 to about 5000 mg per day, in some embodiments about 1 to about 1500 mg per day. The desired dose may conveniently be presented in a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals (for example as two, three, four or more sub-doses per day).

In one aspect, the disclosure provides a method of regulating USP1 in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure provides a method of inhibiting USP1 in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure provides a method of inhibiting or reducing DNA repair activity regulated by USP1 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, the present disclosure provides a method for treating a disease or condition associated with USP1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. In some embodiments, the disease or condition is cancer.

In one aspect, the disclosure provides a method for treating a disease or condition associated with USP1 regulation in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. In some embodiments, the disease or condition is cancer.

In one aspect, the present disclosure provides a method for treating cancer in an individual, comprising administering to the individual in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, the present disclosure provides a method for treating cancer in an individual, comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) or multiple myeloma (MM).

In some embodiments, the cancer is carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anorectal region, melanoma, kidney cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, neuroglioblastoma, neuroglioma, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, blood cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, the cancer to be treated by the methods of the present disclosure includes, for example, carcinomas, squamous carcinomas (e.g., cervical canal, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, and esophagus) and adenocarcinomas (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, and ovary). In some embodiments, the cancer to be treated by the methods of the present disclosure further includes sarcomas (e.g., myogenic sarcomas), leukemias, neuromas, melanomas, and lymphomas. In some embodiments, the cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, the cancer to be treated by the treatment methods of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, the cancer to be treated by the treatment methods of the present disclosure is ovarian cancer. In some embodiments, the cancer to be treated by the treatment methods of the present disclosure is colorectal cancer. In some embodiments, the cancer is a homologous recombination-deficient cancer. In some embodiments, the cancer comprises cancer cells having a mutation in the gene encoding p53.

In some embodiments, the patient or patient group to be treated with the pharmaceutical composition of the present disclosure suffers from a solid tumor. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer or Merkel cell carcinoma. In some embodiments, the patient or patient group to be treated with the pharmaceutical composition of the present disclosure suffers from a blood cancer. In some embodiments, the patient has a blood cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), or multiple myeloma ("MM"). In some embodiments, the patient or group of patients to be treated has a cancer selected from the group consisting of ovarian cancer, lung cancer, and melanoma.

Specific examples of cancers that may be prevented and/or treated according to the present disclosure include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast cancer; breast sarcoma; neurofibroma; neurofibromatosis; childhood tumors; neuroblastoma; malignant melanoma; epidermal cancer; leukemias, such as, but not limited to, acute leukemias, acute lymphocytic leukemias, acute myelocytic leukemias (such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, and myeloproliferative abnormal syndrome), chronic leukemia (such as but not limited to chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia), hairy cell leukemia; polycythemia vera; lymphoma, such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, such as but not limited to depressed multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia (Waldenstrom's macroglobulinemia; monoclonal gammaglobulinemia of undetermined significance; benign monoclonal gammaglobulinopathy; heavy chain disease; bone cancer and connective tissue sarcomas, such as but not limited to osteosarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced osteosarcoma of bone, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma (Kaposi's sarcoma), sarcoma), leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurothecoma, rhabdomyosarcoma and synovial sarcoma; brain tumors, such as but not limited to neuroglioma, astrocytoma, brain stem neuroglioma, ependymoma, oligodendroglioma, non-neuronal glioma, acoustic neurothectomy, craniophysoma, medulloblastoma, meningioma, pinealoma, pineoblastoma and primary brain lymphoma; breast cancer, including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast carcinoma, myxoma carcinoma, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease) and inflammatory breast cancer; adrenal cancer, such as but not limited to pheochromocytoma and adrenal cortical carcinoma; thyroid cancer, such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer, such as but not limited to insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor and carcinoid or islet cell tumor; pituitary cancer, such as but not limited to Cushing's disease (Cushing's disease), prolactin-secreting tumors, acromegaly and diabetic diabetes insipidus; eye cancers such as, but not limited to, ocular melanomas (such as iris melanoma, choroidal melanoma and ciliary body melanoma), and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma and melanoma; vulvar cancers such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma and Paget's disease; cervical cancers such as, but not limited to, squamous cell carcinoma and adenocarcinoma; uterine cancers such as, but not limited to, endometrial carcinoma and uterine sarcoma; ovarian cancers such as, but not limited to, epithelial ovarian cancer, ovarian sarcoma, borderline tumors, germ cell tumors, and stromal tumors; cervical cancer; esophageal cancer, such as but not limited to squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; gastric cancer, such as but not limited to adenocarcinoma, Mycosis fungoides (polypoid), ulcerative, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; colon cancer; colorectal cancer, KRAS mutant colorectal cancer; colorectal carcinoma; rectal cancer; liver cancer, such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancer, such as adenocarcinoma; bile duct cancer, such as but not limited to papillary, nodular and diffuse; lung cancer, such as KRAS mutant non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma and small cell lung cancer; lung cancer; testicular cancer, such as but not limited to germinal tumor, seminoma, anaplastic, classical (classical), seminoma, non-seminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk sac tumor), prostate cancer (such as but not limited to androgen-independent prostate cancer, androgen-dependent prostate cancer), adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma; Penile cancer; oral cancer, such as but not limited to squamous cell carcinoma; basal carcinoma; salivary gland cancer, such as but not limited to adenocarcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma; pharyngeal cancer, such as but not limited to squamous cell carcinoma and verrucous carcinoma; skin cancer, such as but not limited to basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentigo melanoma; kidney cancer, such as but not limited to renal cell carcinoma, adenocarcinoma, adrenal adenoid tumor, fibrosarcoma, transitional cell carcinoma (renal pelvis and/or uterus); kidney carcinoma; Wilms’ tumor (Wilms’ tumor); bladder cancer, such as but not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma. In addition, cancer includes myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinoma.

In one aspect, the present disclosure provides a method for treating cancer in an individual, comprising administering to an individual in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. In some embodiments, the cancer may comprise cancer cells having elevated RAD 18 mRNA expression levels. In some embodiments, the elevated RAD 18 levels are elevated RAD 18 protein levels. In some embodiments, RAD 18 levels can be detected using quantitative methods such as microarrays, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, the level of RAD 18 in cancer cells can be detected prior to administering the compounds described herein. In some embodiments, RAD 18 levels can be detected in cancer samples obtained from an individual. In some embodiments, if a subject has elevated levels of RAD 18, the subject can be treated with a compound described herein. In some embodiments, elevated levels of RAD 18 in cancer cells indicate that the subject to which the compound or pharmaceutical composition described herein is administered is responsive to treatment with the compound or pharmaceutical composition described herein. In some embodiments, a compound described herein is not administered to a subject with elevated levels of RAD 18.

In some embodiments, the cancer is a cancer with defects in DNA damage repair pathways. In some embodiments, the cancer is a BRCA1 or BRCA2 mutant cancer that is resistant or refractory to PARP inhibitors. In some embodiments, the cancer comprises cells with elevated RAD 18 levels, wherein the elevated RAD 18 levels are at least as high as the RAD 18 mRNA and/or protein levels in ES2 cells or HEP3B217 cells.

In some embodiments, the cancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wild-type cancer. In some embodiments, the cancer is a BRCA1 deficient cancer. In some embodiments, the cancer is a BRCA2 deficient cancer. In some embodiments, the cancer comprises cancer cells having mutations in the genes encoding BRCA1 and/or BRCA2. In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and a BRCA2 mutant cancer. In some embodiments, the cancer comprises cells having elevated levels of RAD 18, wherein the elevated levels of RAD 18 are at least as high as the levels of RAD 18 mRNA and/or protein in ES2 cells or HEP3B217 cells. EXAMPLES

The following examples are provided to illustrate, but not to limit, the claimed disclosure. The following examples further illustrate the present disclosure, but should certainly not be construed as limiting its scope in any way.

The following synthetic schemes are provided for purposes of illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It is understood that one skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art will be able to prepare in a similar manner as described below by using appropriate starting materials and modifying the synthetic pathways as necessary. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to one skilled in the art or prepared as described herein.

The compounds and salts described herein can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or to any specific substituents used for illustrative purposes. Although various steps are described and depicted in the synthetic schemes below, in some cases, the steps may be performed in an order different from the order shown below. The numbers or R groups in each scheme do not necessarily correspond to the numbers or R groups in the scope of the application or other schemes or tables herein. Abbreviations: ACN Acetonitrile Ar Argon BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl DBU 1,8-Diaza-7-bicyclo[5.4.0]undecene DCE 1,2-Dichloroethane DCM Dichloromethane DIEA, DIPEA Diisopropylethylamine DMF N,N -Dimethylformamide DMSO Dimethyl sulfoxide EtOAc, EA Ethyl acetate EtOH Ethanol hr(s) Hours IPA Isopropyl alcohol LC-MS LC-MS m-CPBA m-Chloroperbenzoic acid MeOH Methanol N OAc Sodium acetate NBS N- Bromobutyrimide NIS N- Iodosuccinimide PE Petroleum ether Preparative TLC Preparative TLC RT, rt, rt Room temperature TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran Example A_Bioanalysis Example A1: Enzymatic Analysis

Human recombinant USP1/UAF1 expressed in bacillary virus-infected Sf21 cells (R&D, E-568-050) was used. Test compounds and/or vehicle were incubated with 2 nM USP1/UAF1 in modified HEPES buffer pH 8.0 at RT for 15 minutes. The reaction was initiated by adding 500 nM Ubiquitin Rhodon 110 (R&D, U-555-050) for kinetic reading. The slope change of fluorescence intensity was read spectrofluorescence at 485 nm/535 nm. The dose response of the test compound or reference compound ML-323 was analyzed by nonlinear regression using GraphPad prism software. The analysis results are shown in Table 3. Example A2: MDA-MB-436 breast cancer cell culture

MDA-MB-436 cells were grown in Leibovitz L-15 medium containing 10 μg/ml insulin, 16 μg/ml glutathione, 10% FBS. Cells were passaged at subconfluence after trypsinization and maintained in an incubator at 37°C in a humidified atmosphere with 5% _CO2 . Example A3: MDA-MB-436 breast cancer cell proliferation analysis

Cell proliferation was determined using the CellTiter-Glo® luminescent cell viability assay (Promega, No. G7573). MDA-MB-436 cells were seeded in 384-well plates and allowed to attach for 24 h. Compounds were added to the 384-well plates by ECHO and incubated at 37°C in a humidified atmosphere with 5% _CO2 . After 7 days, CellTiter-Glo® was added to the 384-well plates, the contents were mixed at 400 g on an orbital oscillator for 2 min, and the plates were then centrifuged at 1000 rpm for 2 min. After incubation at RT for 30 min, luminescence was read on the envision. The results of the analysis are shown in Table 3. Example B_Chemical Synthesis Example B: Synthesis of Intermediate C 2- Fluoro -5-(4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridine

To a solution of sodium acetate (13.11 g, 159.88 mmol) in water (100 mL) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (32.36 g, 119.91 mmol) dropwise at 0°C. The mixture was stirred at 100°C for 1 hr. A solution of 6-fluoronicotinoaldehyde (10.00 g, 79.94 mmol), MeOH (150 mL) and ammonium hydroxide (approximately 25-28 wt%) (150 mL) was added to the cooled mixture at 0°C. The mixture was stirred at room temperature for 16 hr. The volatiles were removed in vacuo to give a residue. The residue was diluted with water (100 mL) and extracted with EtOAc (80 mL×5). The combined organic fractions were washed with brine (100 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound (18.0 g, 77.87 mmol, 97% yield) as a yellow solid which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.80 (d, J = 2.4 Hz, 1 H), 8.60 - 8.43 (m, 1 H), 8.03 (s, 1 H), 7.41 - 7.28 (m, 1 H). 2- Fluoro -5-(1- methyl -4-( trifluoromethyl )-1 H -imidazol -2- yl ) pyridine

To a solution of 2-fluoro-5-(4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (5.00 g, 21.63 mmol) in DMF (50 mL) was added Cs ₂ CO ₃ (14.09 g, 43.26 mmol) and CH ₃ I (4.61 g, 32.45 mmol) at 0° C. The mixture was stirred at room temperature under Ar for 16 hr. Water (60 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (4.1 g, 16.72 mmol, 77% yield) as a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.63 - 8.59 (m, 1 H), 8.45 - 8.26 (m, 1 H), 8.05 - 8.00 (m, 1 H), 7.45 - 7.28 (m, 1 H), 3.82 (s, 3 H). Example B2: Synthesis of Intermediate E:

The synthetic route for intermediate E was analogous to that for intermediate C by replacing 6-fluoronicotinaldehyde with 5-bromopyridine-2-carbaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 16%) in petroleum ether to give the title compound (300 mg, 0.98 mmol, 14% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.65 - 8.50 (m, 1 H), 8.14 - 8.01 (m, 1 H), 7.85 - 7.75 (m, 1 H), 7.22 (s, 1 H), 4.05 (s, 3 H). Example B3: Synthesis of Intermediate G:

The synthetic route for intermediate G was analogous to that of intermediate C by replacing iodomethane with iodoethane. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 17%) in petroleum ether to give the title compound (1.90 g, 7.33 mmol, 56% yield) as a yellow oil.

LC-MS (ESI+): m/z 260.0 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.49 - 8.41 (m, 1 H), 8.18 - 8.02 (m, 1 H), 7.50 - 7.38 (m, 1 H), 7.15 - 7.05 (m, 1 H), 4.15 - 4.03 (m, 2 H), 1.49 (t, J = 7.2 Hz, 3 H). Example B4: Synthesis of Intermediate H: 2- Fluoro-5-(1-isopropyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine

To a solution of 2-fluoro-5-(4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (3.00 g, 12.98 mmol) and Cs ₂ CO ₃ (12.70 g, 38.98 mmol) in DMF (50 mL) was added 2-iodopropane (11.05 g, 65.00 mmol). The mixture was stirred at 75° C. for 24 hr. To the cooled reaction mixture was added water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL x 3), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (1.7 g, 6.22 mmol, 48% yield) as a yellow oil.

LC-MS (ESI+): m/z 274.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.45 - 8.37 (m, 1 H), 8.13 - 8.02 (m, 1 H), 7.47 (s, 1 H), 7.13 - 7.05 (m, 1 H), 4.54 - 4.43 (m, 1 H), 1.53 - 1.45 (m, 6 H). Example B5: Synthesis of Intermediate I:

The synthetic route for intermediate I was analogous to that of intermediate C by replacing 6-fluoronicotinaldehyde with 5-chloropyrazine-2-carbaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether to give the title compound (550.0 mg, 2.09 mmol, 74% yield) as a white solid.

LC-MS (ESI+): m/z 262.9 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.21 - 9.13 (m, 1 H), 8.51 - 8.43 (m, 1 H), 7.29 (s, 1 H), 4.05 (s, 3 H). Example B6: Synthesis of Intermediate J:

The synthetic route for intermediate J was similar to that of intermediate C by replacing 6-fluoronicotinaldehyde with 2-chloropyrimidine-5-carbaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (420.0 mg, 1.60 mmol, 57% yield) as a yellow solid.

LC-MS (ESI+): m/z 263.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.19 (s, 2 H), 8.15 (s, 1 H), 3.93 (s, 3 H). Example B7: Synthesis of Intermediate K:

The synthetic route for intermediate K was similar to that of intermediate C by replacing 6-fluoronicotinaldehyde with 4-bromo-2-fluorobenzaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether to give the title compound (720.0 mg, 2.23 mmol, 76% yield) as a yellow solid.

LC-MS (ESI+): m/z 322.8 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.07 - 8.00 (m, 1 H), 7.86 - 7.74 (m, 1 H), 7.68 - 7.52 (m, 2 H), 3.61 (d, J =1.6 Hz, 3 H). Example B8: Synthesis of Intermediate L:

The synthetic route for intermediate L was analogous to that of intermediate C by replacing 6-fluoronicotinaldehyde with 4-bromo-3-fluorobenzaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (822 mg, 2.54 mmol, 78% yield) as a yellow solid.

LC-MS (ESI+): m/z 322.9 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.99 (s, 1 H), 8.15 - 8.05 (m, 1 H), 7.80 - 7.71 (m,1 H), 7.58 - 7.51 (m,1 H), 3.82 (s, 3 H). Example B9: Synthesis of Intermediate M:

The synthetic route for intermediate M was analogous to that for intermediate C by replacing 6-fluoronicotinaldehyde with 6-bromonicotinaldehyde. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (2.91 g, 9.50 mmol, 55% yield) as a yellow solid.

LC-MS (ESI+): m/z 305.9 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.74 (d, J = 2.4 Hz, 1 H), 8.13 - 8.10 (m, 1 H), 8.04 (s, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 3.83 (s, 3 H). Example B10: Synthesis of Compound 1: 4-(2- Isopropylpyridin-3-yl)-7,8-dihydropyrido[4,3- d ]pyrimidine-6(5 H )-carboxylic acid tert-butyl ester

To a solution of tert- _butyl 4-chloro- 5H , 6H , 7H , 8H -pyrido[4,3- d ]pyrimidine-6-carboxylate (409.0 mg, 1.52 mmol) in dioxane (10 mL) and water (2 mL) was added 2-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridine (562.1 mg, 2.27 mmol), Pd(dppf) _Cl2 (111.0 mg, 0.15 mmol) and _Na2CO3 (321.4 _mg , 3.03 mmol) under N2. The mixture was stirred at 100°C for 16 hr. Water (30 mL) was added to the cooled reaction mixture and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (400.0 mg, 1.13 mmol, 74% yield) as a yellow oil.

LC-MS (ESI+): m/z 355.2 (M+H) ⁺ . 4-(2- Isopropylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidine

A mixture of 4-[2-(propan-2-yl)pyridin-3-yl] -5H , 6H , 7H , 8H -pyrido[4,3- d ]pyrimidine-6-carboxylic acid tert-butyl ester (400.0 mg, 1.13 mmol) in HCl/MeOH (3 mol/L, 3 mL) was stirred at room temperature for 6 hr. The mixture was concentrated in vacuo to give a residue. Then, EtOAc (20 mL) and water (10 mL) were added to the residue. The aqueous phase was alkalized with saturated _NaHCO3 solution and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (30 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase column chromatography ( _H2O /ACN = 100/0 to 9/1) to give the title compound (200.0 mg, 0.79 mmol, 70% yield) as a yellow solid.

LC-MS (ESI+): m/z 255.1 (M+H) ⁺ . 4-(2- isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidine

To a _solution of 2-(propan-2-yl)-3-{ 5H , 6H , 7H , 8H -pyrido[4,3- d ]pyrimidin-4-yl}pyridine (50.0 mg, 0.20 mmol) in toluene (5 mL) was added 2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl) -1H -imidazole (50.0 mg, 0.16 mmol), sodium tert-butoxide (15.7 mg, 0.16 mmol) and Pd-PEPPSI™-IPent catalyst (0.83 mg, 0.001 mmol) under N2. The mixture was stirred at 100°C for 16 hr. Water (10 mL) was added to the cooled reaction mixture and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EA=1/3) to give the title compound.

LC-MS (ESI+): m/z 479.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.09 (s, 1 H)- 8.74 - 8.73 (m, 1 H), 7.84 (s, 1 H), 7-80 - 7.76 (m, 1 H ), 7.55 (d, J = 8.8 Hz, 2 H)- 7.43 - 7.40 (m, 1 H), 6.93 (d, J = 9.2 Hz, 2 H)- 4.24 - 4.05 (m, 2 H)- 3.95 - 3.75 (m, 2 H), 3.72 (s, 3 H)- 3.23 - 3.14 (m, 2 H) - 2.79 - 2.60 (m, 1 H), 1.16 (d, J = 6.8 Hz, 6 H). Example B11: Synthesis of Compound 2: 2- Methoxy-4-((trimethylsilyl)ethynyl)nicotinaldehyde

To a solution of 4-iodo-2-methoxypyridine-3-carbaldehyde (1.00 g, 3.80 mmol) and trimethylsilyl acetylene (747.0 mg, 7.61 mmol) in THF (10 mL) was added TEA (1.15 g, 11.41 mmol), CuI (72.0 mg, 0.38 mmol) and bis(triphenylphosphine)palladium(II) chloride (267.0 mg, 0.38 mmol). The mixture was degassed and refilled with _N2 three times, then the reaction mixture was stirred at 60 °C for 3 hr. The mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 2%) in petroleum ether to afford the title compound (770.0 mg, 3.30 mmol, 87% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.53 (s, 1 H), 8.26 (d, J = 5.2 Hz, 1 H), 7.03 (d, J = 5.2 Hz, 1 H), 4.06 (s, 3 H), 0.29 (s, 9 H). 1- Methoxy-2,7-naphthyridine

To a solution of 2-methoxy-4-((trimethylsilyl)ethynyl)nicotinaldehyde (770.0 mg, 3.30 mmol) in MeOH (5 mL) was added _NH3 /MeOH (14M, 5 mL). The mixture was stirred at 50 °C for 3 hr. The mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (280.0 mg, 1.75 mmol, 53% yield) as a yellow solid.

LC-MS (ESI+): m/z 161.1 (M+H) ⁺ . 8- Methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine

To a solution of 1-methoxy-2,7-naphthyridine (280.0 mg, 1.75 mmol) in MeOH/HOAc (3 mL/1 mL) was added Pd/C 10% (150.0 mg). The mixture was stirred at 35 °C under _H2 for 18 hr. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo to give the title compound (200.0 mg, 1.22 mmol, 70% yield) as a brown oil which was used directly in the next step.

LC-MS (ESI+): m/z 165.0 (M+H) ⁺ . 8- Methoxy -2-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2 -yl )-1,2,3,4- tetrahydro -2,7- naphthyridine

To a solution of 8-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine (200.0 mg, 1.22 mmol) and 2-fluoro-5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyridine (388.0 mg, 1.58 mmol) in DMSO (3 mL) was added DIEA (315.0 mg, 2.44 mmol) at room temperature. The mixture was stirred at 130°C for 16 hr. Water (10 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/1) to give the title compound (230.0 mg, 0.59 mmol, 48% yield) as a yellow oil.

LC-MS (ESI+): m/z 390.1 (M+H) ⁺ . 7-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2- yl )-5,6,7,8 -tetrahydro -2,7- naphthyridin -1- ol

To a solution of 8-methoxy-2-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (200.0 mg, 0.51 mmol) in DMF (6 mL) was added toluene-4-sulfonic acid (442.0 mg, 2.57 mmol) and LiCl (109.0 mg, 2.57 mmol). The mixture was stirred at 120° C. for 2 hr. Water (15 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with methanol (0% to 5%) in dichloromethane to give the title compound (180.0 mg, 0.48 mmol, 94% yield) as a yellow oil.

LC-MS (ESI+): m/z 376.0 (M+H) ⁺ . 8- Chloro -2-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2 -yl )-1,2,3,4- tetrahydro -2,7- naphthyridine

To a solution of 7-(5-(1-methyl-4-(trifluoromethyl) -1H- imidazol-2-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-1-ol (180.0 mg, 0.48 mmol) in acetonitrile (4 mL) was added POCl ₃ (367.0 mg, 2.40 mmol). The mixture was stirred at 90° C. for 5 hr. The mixture was concentrated in vacuo to give a residue. The residue was diluted with DCM and aqueous NaHCO ₃ solution. The aqueous phase was extracted with DCM (10 mL×2). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EA = 0/1) to give the title compound (110.0 mg, 0.28 mmol, 58% yield) as a yellow solid.

LC-MS (ESI+): m/z 394.1 (M+H) ⁺ . 8-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-2-(5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine

To a _solution of 8-chloro-2-(5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (50.0 mg, 0.13 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (70.0 mg, 0.25 mmol) in dioxane/H ₂ O (1 mL/0.2 mL) was added Pd(dppf)Cl ₂ (19.0 mg, 0.03 mmol) and K ₂ CO ₃ (35.0 mg, 0.25 mmol) under N 2. The mixture was stirred at 90 °C under Ar for 16 hr. To the cooled reaction mixture was added water (15 mL) and the aqueous phase was extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over _Na2SO4 , _filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EA = 0/1) to give the title compound.

LC-MS (ESI+): m/z 508.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.74 (s, 1 H), 8.48 (d, J = 5.2 Hz, 1 H), 8.40 (d, J = 2.0 Hz, 1 H), 7.90 - 7.80 (m, 2 H), 7.31 (d, J = 4.8 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 4.55 - 4.44 (m, 2 H), 3.95 - 3.87 (m, 2 H), 3.85 (s, 3 H), 3.74 (s, 3 H), 3.10 - 2.97 (m, 2 H), 1.51 - 1.42 (m, 1 H), 1.11 - 1.01 (m, 2 H), 0.91 - 0.84 (m, 2 H). Example B12: Synthesis of Compound 3: 3- Bromo-6,7-dihydro-[1,2,3]triazolo[1,5- a ] pyrazine -5(4 H ) -carboxylic acid tert-butyl ester

To a solution of 2-methylpropan-2-yl 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5- a ]pyrazine-5-carboxylate (500.0 mg, 2.23 mmol) in _CH3CN (10 mL) was added NBS (476.2 mg, 2.68 mmol) at 0°C. The mixture was stirred at room temperature for 16 hr. The mixture was concentrated to give a residue which was purified by flash column chromatography eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (230.0 mg, 0.76 mmol, 34% yield) as a yellow solid.

LC-MS (ESI+): m/z 303.1 (M+H) ⁺ . 3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ] pyrazine -5(4 H ) -carboxylic acid tert-butyl ester

A mixture of 2-methylpropan-2-yl 3-bromo-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5- a ]pyrazine-5-carboxylate (190.0 mg, 0.63 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyrimidine (259.6 mg, 0.94 mmol), CataCXium® A Pd G3 (CAS: 1651823-59-4, 45.6 mg, 0.06 mmol) and K ₃ PO ₄ (399.1 mg, 1.88 mmol) in THF/H ₂ O (5 mL/0.5 mL) was stirred at 80 °C under N ₂ for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with ethyl acetate (0% to 50%) in petroleum ether) to give the title compound (140.0 mg, 0.38 mmol, 60% yield) as a yellow solid.

LC-MS (ESI+): m/z 373.1 (M+H) ⁺ . 3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5- a ] pyrazine

To a solution of 2-methylpropan-2-yl 3-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5- a ]pyrazine-5-carboxylate (130.0 mg, 0.35 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hr. The volatiles were removed in vacuo. The residue was dissolved in DCM (15 mL) and the pH was adjusted to 7-8 by adding NaHCO ₃ powder. The mixture was filtered through a Celite® pad and the filtrate was concentrated to give a residue which was purified by flash column chromatography on silica gel eluting with MeOH (0% to 5%) in DCM to give the title compound (90.0 mg, 0.33 mmol, 94% yield) as a yellow oil.

LC-MS (ESI+): m/z 273.1 (M+H) ⁺ . 3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5- a ] pyrazine

To a _mixture of 3-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5- a ]pyrazine (85.0 mg, 0.31 mmol), 2-(4-bromophenyl)-3-methyl-5-(trifluoromethyl)imidazole (190.5 mg, 0.62 mmol), tert-BuONa (240.0 mg, 2.50 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS) (297.6 mg, 0.62 mmol) in toluene (5 mL) was added Pd(OAc) ₂ (7.0 mg, 0.03 mmol) under N 2. The mixture was stirred at 100 °C for 16 hr. To the reaction mixture was added water (10 mL) and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/3) to give the title compound.

LC-MS (ESI+): m/z 497.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.68 (s, 1 H), 7.86 (s, 1 H), 7.59 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 9.2 Hz, 2 H), 4.64 - 4.47 (m, 4 H), 4.10 - 3.97 (m, 2 H), 3.94 (s, 3 H), 3.75 (s, 3 H), 2.20 - 2.07 (m, 1 H), 1.13 - 1.04 (m, 2 H), 0.98 - 0.88 (m, 2 H). Example B13: Synthesis of Compound 4: 2- Bromo -5-(4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

To a solution of sodium acetate (0.85 g, 10.42 mmol) in water (15 mL) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.11 g, 7.81 mmol) dropwise at 0°C. Then, the mixture was stirred at 100°C for 1 hr. After cooling to room temperature, a mixture of 2-bromo-1,3-thiazole-5-carbaldehyde (1.00 g, 5.21 mmol), MeOH (30 mL) and ammonium hydroxide (28%, 10 mL) was added to the solution and the resulting mixture was stirred at room temperature for 16 hr. The mixture was concentrated to remove MeOH. The residue was diluted with water (20 mL) and extracted with EtOAc (25 mL×3). The combined organic fractions were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (0% to 25% ethyl acetate in petroleum ether) to give the title compound (470.0 mg, 1.58 mmol, 30% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.87 (br.s, 1 H), 7.79 (s, 1 H), 7.37 (s, 1 H). 2- Bromo -5-(1- methyl -4-( trifluoromethyl )-1 H -imidazol -2- yl ) thiazole

To a solution of 2-(2-bromo-1,3-thiazol-5-yl)-5-(trifluoromethyl) -3H -imidazole (470 mg, 1.58 mmol) and Cs ₂ CO ₃ (1284.2 mg, 3.94 mmol) in DMF (10 mL) was added MeI (447.5 mg, 3.15 mmol) dropwise at 0°C. The mixture was gradually warmed to room temperature and stirred for 16 hr. Water (10 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (350.0 mg, 1.12 mmol, 71% yield) as a yellow solid.

LC-MS (ESI+): m/z 313.9 (M+H) ⁺ . 3- Iodo -4,6- dihydropyrrolo [3,4- c ] pyrazole -5(1 H ) -carboxylic acid tert-butyl ester

To a solution of 2-methylpropan-2-yl 1,4,5,6-tetrahydropyrrolo[4,3- c ]pyrazole-5-carboxylate (2.50 g, 11.95 mmol) in DMF (30 mL) was added NIS (3.49 g, 15.53 mmol). The mixture was stirred at 60°C for 6 hr. After cooling to room temperature, saturated Na ₂ SO ₃ solution (50 mL) was slowly added to the mixture, and then the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic fractions were washed with brine (60 mL x 3), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was recrystallized from _Et2O (30 mL) to give the title compound (2.85 g, 8.50 mmol, 71% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.65 - 4.50 (m, 2 H), 4.44 - 4.30 (m, 2 H), 1.51 (s, 9 H). 3 - Iodo -1- methyl -4,6- dihydropyrrolo [3,4-c] pyrazole -5(1 H ) -carboxylic acid tert-butyl ester

To _a solution of 2-methylpropan-2-yl 3-iodo-1,4,5,6-tetrahydropyrrolo[4,3- c ]pyrazole-5-carboxylate (2.85 g, 8.50 mmol) and _Cs2CO3 (5.54 g, 17.01 mmol) in DMF (30 mL) was added iodomethane (2.41 g, 17.01 mmol) dropwise at 0°C. The mixture was gradually warmed to room temperature and stirred for 16 hr. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 30%) in petroleum ether to give the title compound (760.0 mg, 2.18 mmol, 26% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.45 - 4.41 (m, 2 H), 4.26 - 4.22 (m, 2 H), 3.75 (s, 3 H), 1.43 (s, 9 H). 3-(4- Cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1 H )-carboxylic acid tert-butyl ester

A mixture of 2-methylpropan-2-yl 3-iodo-1-methyl-5,6-dihydro- 4H -pyrrolo[4,3- c ]pyrazole-5-carboxylate (600.0 mg, 1.72 mmol), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyrimidine (949.0 mg, 3.44 mmol), cataCXium® A Pd G3 (12.5 mg, 0.017 mmol) and K ₃ PO ₄ (730.0 mg, 3.44 mmol) in THF/water (10 mL/1.5 mL) was stirred at 80 °C under N ₂ for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with ethyl acetate (0% to 60%) in petroleum ether) to give the title compound (600.0 mg, 1.62 mmol, 94% yield) as a yellow oil.

LC-MS (ESI+): m/z 372.2 (M+H) ⁺ . 3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole

To a solution of 2-methylpropan-2-yl 3-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-1-methyl-5,6-dihydro- 4H -pyrrolo[4,3- c ]pyrazole-5-carboxylate (200.0 mg, 0.54 mmol) in DCM (20 mL) was added TFA (3 mL) at 0°C. The mixture was stirred at room temperature for 5 hr. The mixture was concentrated to give the title compound (140.0 mg, 0.52 mmol, 96% yield) as a yellow oil, which was used in the next step without further work-up.

LC-MS (ESI+): m/z 272.1 (M+H) ⁺ . 2-(3-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-1- methyl -4,6- dihydropyrrolo [3,4-c] pyrazol -5( 1H )-yl ) -5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

A mixture of 3-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-1-methyl-5,6-dihydro- 4H -pyrrolo[4,3- c ]pyrazole (146.0 mg, 0.54 mmol), 2-(2-bromo-1,3-thiazol-5-yl)-3-methyl-5-(trifluoromethyl)imidazole (218.3 mg, 0.70 mmol) and DIEA (139.6 mg, 1.08 mmol) in DMSO (3 mL) was stirred at 90° C. for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on a C18 column (eluted with ACN (0% to 100%) in water) to give the title compound.

LC-MS (ESI+): m/z 503.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.59 (s, 1 H), 7.85 (s, 1 H), 7.69 (s, 1 H), 4.79 (s, 2 H), 4.49 (s, 2 H), 3.94 (s, 3 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 2.81 - 2.60 (m, 1 H), 1.15 - 0.88 (m, 4 H). Example B14: Synthesis of Compound 5: 3-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-1 -methyl -5-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2 -yl ) pyridin -2- yl )-1,4,5,6- tetrahydropyrrolo [3,4-c] pyrazole

To a solution of 3-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-1-methyl-5,6-dihydro- 4H -pyrrolo[4,3-c]pyrazole (80.0 mg, 0.30 mmol) and DIEA (76.3 mg, 0.59 mmol) in DMSO (2 mL) was added 2-fluoro-5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyridine (144.7 mg, 0.59 mmol). The mixture was stirred at 130° C. for 6 hr. After cooling to room temperature, water (10 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography on a C18 column eluting with ACN (0% to 100%) in water to give the title compound.

LC-MS (ESI-): m/z 497.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.59 (s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 7.92 - 7.89 (m, 2 H), 6.67 (d, J = 8.8 Hz, 1 H), 4.78 (s, 2 H), 4.49 (s, 2 H), 3.94 (s, 3 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 2.72 - 2.60 (m, 1 H), 1.10 - 0.96 (m, 4 H). Example B15: Synthesis of Compound 6: 3-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-1- methyl -5-(6-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -3- yl )-1,4,5,6- tetrahydropyrrolo [3,4-c] pyrazole

To a solution of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole (85.0 mg, 0.31 mmol) and 5-bromo-2-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyridine (144.0 mg, 0.47 mmol) in toluene (3 mL) were added Pd(OAc) ₂ (7.0 mg, 0.03 mmol), X-PHOS (299.0 mg, 0.63 mmol) and sodium tert-butoxide (60.0 mg, 0.63 mmol). The mixture was stirred at 100° C. under Ar for 16 hr. Water (15 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 497.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.60 (s, 1 H), 8.07 (d, J = 2.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.87 (s, 1 H), 7.09 - 7.21 (m, 1 H), 4.69 (s, 2 H), 4.44 (s, 2 H), 4.05 (s, 3 H), 3.95 (s, 3 H), 3.90 (s, 3 H), 2.70 - 2.58 (m, 1 H), 1.08 - 1.04 (m, 2 H), 0.99 - 0.95 (m, 2 H). Example B16: Synthesis of Compound 7: 3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole

To a solution of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole (85.0 mg, 0.31 mmol) and 2-(4-bromophenyl)-3-methyl-5-(trifluoromethyl)imidazole (143.0 mg, 0.47 mmol) in toluene (3 mL) were added Pd(OAc) ₂ (7.0 mg, 0.03 mmol), X-PHOS (299.0 mg, 0.63 mmol) and sodium tert-butoxide (60.0 mg, 0.63 mmol). The mixture was stirred at 100° C. under Ar for 16 hr. Water (15 mL) was added to the cooled reaction mixture and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 496.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.60 (s, 1 H), 7.83 (d, J = 1.2 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 2 H), 6.73 (d, J = 8.8 Hz, 2 H), 4.64 (s, 2 H), 4.38 (s, 2 H), 3.94 (s, 3 H), 3.90 (s, 3 H), 3.76 (s, 3 H), 2.70 - 2.55 (m, 1 H), 1.16 - 1.02 (m, 2 H), 0.99 - 0.90 (m, 2 H). Example B17: Synthesis of Compound 8: 2- Bromo-5-(1-isopropyl-4-(trifluoromethyl) -1H -imidazol-2-yl)thiazole

To a solution of 2-(2-bromo-1,3-thiazol-5-yl)-5-(trifluoromethyl) -3H -imidazole (300.0 mg, 1.01 mmol) in DMF (4 mL) was added Cs ₂ CO ₃ (819.7 mg, 2.52 mmol) and 2-iodopropane (341.7 mg, 2.01 mmol) at room temperature. The mixture was stirred at 60° C. for 16 hr. To the cooled reaction mixture was added water (10 mL) and the aqueous phase was extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 12%) in petroleum ether to give the title compound (150.0 mg, 0.44 mmol, 44% yield) as a yellow oil.

LC-MS (ESI+): m/z 340.0 (M+H) ⁺ . 2-(3-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H )-yl)-5-(1-isopropyl-4-(trifluoromethyl) -1H -imidazol-2-yl)thiazole

To a solution of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole (50.0 mg, 0.18 mmol) in DMSO (2 mL) was added 2-(2-bromo-1,3-thiazol-5-yl)-3-(propan-2-yl)-5-(trifluoromethyl)imidazole (81.0 mg, 0.24 mmol) and DIEA (48.0 mg, 0.37 mmol) at room temperature. The mixture was stirred at 90° C. for 16 hours. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 531.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.59 (s, 1 H), 8.08 (s, 1 H), 7.61 (s 1 H), 4.79 (s, 2 H), 4.75 - 4.68 (m, 1 H), 4.49 (s, 2 H), 3.94 (s, 3 H), 3.89 (s, 3 H), 2.71 - 2.67 (m, 1 H), 1.45 (d, J = 6.4 Hz, 6 H ), 1.07 - 1.04 (m, 2 H), 0.99 - 0.95 (m, 2 H). Example B18: Synthesis of Compound 9:

The synthetic route for compound 9 was similar to that for compound 4 by replacing intermediate D with 2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridine ( intermediate F ). The crude product was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 474.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.53 (m, 1 H), 7.86 (s, 1 H), 7.76 - 7.70 (m, 1 H), 7.70 (s, 1 H), 7.32 - 7.25 (m, 1 H), 4.79 (s, 2 H), 4.65 (s, 2 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 3.78 - 3.71 (m, 1 H), 1.23 - 1.18 (m, 6 H). Example B19: Synthesis of Compound 10: 2-(1,3- dioxolan-2-yl)thiazole

To a solution of ethylene glycol (5.50 g, 88.42 mmol), 1,3-thiazole-2-carbaldehyde (5.00 g, 44.21 mmol) in toluene (50 mL) was added toluene-4-sulfonic acid (800.0 mg, 4.65 mmol). The reactants were stirred at 120°C for 16 hr. Water (100 mL) was added to the cooled reaction mixture and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (80 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 15%) in petroleum ether to give the title compound (5.20 g, 33.08 mmol, 75% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.83 (d, J = 3.2 Hz, 1 H), 7.39 (d, J = 3.2 Hz, 1 H), 6.17 (s, 1 H), 4.23 - 4.13 (m, 2 H), 4.10 - 4.00 (m, 2 H). 5- Bromo-2-(1,3-dioxolan-2-yl)thiazole

To a solution of 2-(1,3-dioxolan-2-yl)thiazole (4.20 g, 26.72 mmol) in anhydrous THF (40 mL) was added n -BuLi (2.5 M, 13 mL, 32.5 mmol) dropwise at -78°C. Then, the mixture was stirred at -78°C for 30 min and CBr ₄ (26.60 g, 80.15 mmol) was added dropwise. The mixture was warmed to 0°C and stirred for 2 hr. Water (50 mL) was slowly added to the reaction mixture at 0°C. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether to give the title compound (5.30 g, 22.45 mmol, 84% yield) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.69 (s, 1 H), 6.06 (s, 1 H), 4.16 - 4.11 (m, 2 H), 4.10 - 4.05 (m, 2 H). 5- Bromothiazole-2-carbaldehyde

To a solution of 5-bromo-2-(1,3-dioxolan-2-yl)thiazole (6.50 g, 27.53 mmol) in THF (50 mL) was added HCl (1M, 30 mL). The mixture was stirred at 70°C for 16 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaHCO ₃ solution. The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (80 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether to give the title compound (3.80 g, 19.79 mmol, 72% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.87 (s, 1 H), 8.02 (s, 1 H). 5- Bromo -2-(4-( trifluoromethyl )-1 H -imidazol -2- yl ) thiazole

To a solution of sodium acetate (2.82 g, 34.36 mmol) in water (60 mL) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (6.96 g, 25.78 mmol) dropwise at 0°C. After the addition, the mixture was stirred at 100°C for 1 hr. After cooling to room temperature, a solution of 5-bromo-1,3-thiazole-2-carbaldehyde (3.30 g, 17.19 mmol), MeOH (120 mL) and ammonium hydroxide (28%, 40 mL) were added to the solution and the resulting mixture was stirred at room temperature for 16 hr. The volatiles were removed in vacuo. The residue was diluted with water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 25%) in petroleum ether to give the title compound (1.57 g, 5.27 mmol, 31% yield) as a yellow oil.

LC-MS (ESI+): m/z 297.8 (M+H) ⁺ . 5- Bromo -2-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

To a solution of 5-bromo-2-[5-(trifluoromethyl) -3H -imidazol-2-yl]-1,3-thiazole (400 mg, 1.34 mmol) and Cs ₂ CO ₃ (1092.9 mg, 3.35 mmol) in DMF (6 mL) was added iodomethane (380.4 mg, 2.68 mmol) dropwise at 0° C. The mixture was gradually warmed to room temperature and stirred for 16 hr. Water (20 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (280.0 mg, 0.90 mmol, 67% yield) as a yellow solid.

LC-MS (ESI+): m/z 311.9 (M+H) ⁺ . 5-(3-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-1- methyl -4,6- dihydropyrrolo [3,4-c] pyrazol -5( 1H )-yl ) -2-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

To a solution of 5-bromo-2-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)thiazole (81.1 mg, 0.26 mmol) and 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole (84.1 mg, 0.31 mmol) in toluene (2 mL) was added _Pd2 (dba) ₃ (24.0 mg, 0.03 mmol), BINAP (80.0 mg, 0.13 mmol) and sodium tert-butoxide (50.0 mg, 0.52 mmol). The mixture was stirred at 80 °C under Ar for 16 h. To the cooled reaction mixture was added water (15 mL) and the aqueous phase was extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over _Na2SO4 , _filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 503.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.59 (s, 1 H), 7.94 (s, 1 H), 6.94 (s, 1 H), 4.65 (s, 2 H), 4.38 (s, 2 H), 4.01 (s, 3 H), 3.94 (s, 3 H), 3.88 (s, 3 H), 2.73 - 2.61 (m, 1 H), 1.10 - 1.04 (m, 2 H), 0.98 - 0.90 (m, 2 H). Example B20: Synthesis of Compound 11: (4 -Cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid

To a solution of 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (2.00 g, 7.24 mmol) in 5% (v/v) TFA/DCM (20 mL) was added methylboronic acid (2.16 g, 36.22 mmol). The mixture was stirred at room temperature for 18 hr. The volatiles were removed under reduced pressure to give a residue, which was purified by reverse phase column (H ₂ O/ACN 100/0 to 4/1) to give the title compound (850.0 mg, 4.38 mmol, 60% yield) as a white solid.

LC-MS (ESI+): m/z 195.1 (M+H) ⁺ . 1-(4 -cyclopropyl -6- methoxypyrimidin- 5- yl )-3- methyl - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 3-methyl- 1H -pyrazolo[3,4- c ]pyridine (250.0 mg, 1.88 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boranediol (728.2 mg, 3.75 mmol) in dioxane (8 mL) was added copper(II) acetate monohydrate (112.4 mg, 0.56 mmol) and DBU (571.3 mg, 3.75 mmol). The mixture was stirred at 70°C for 16 hr. Water (40 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/1) to give the title compound (80.0 mg, 0.28 mmol, 15% yield) as a yellow oil.

LC-MS (ESI+): m/z 282.1 (M+H) ⁺ . 1-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine

A mixture of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methylpyrazolo[3,4-c]pyridine (70.0 mg, 0.25 mmol) and platinum(IV) oxide (33.9 mg, 0.15 mmol) in EtOH (3 mL) was stirred at room temperature under _H2 for 16 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (50.0 mg, 0.18 mmol, 72% yield) as a yellow oil.

LC-MS (ESI+): m/z 286.2 (M+H) ⁺ . 1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-3- methyl -6-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2 -yl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4-c] pyridine

A mixture of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol), 2-fluoro-5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyridine (103.1 mg, 0.42 mmol) and DIEA (108.6 mg, 0.84 mmol) in DMSO (3 mL) was stirred at 130° C. for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 511.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ = 8.72 (s, 1 H), 8.41 (d, J = 2.0 Hz, 1 H), 7.95 - 7.85 (m, 2 H), 7.08 (d, J = 8.8 Hz, 1 H), 4.58 - 4.45 (m, 2 H), 4.03 - 3.85 (m, 5 H), 3.74 (s, 3 H), 2.72 - 2.58 (m, 2 H), 2.16 (s, 3 H), 1.65 - 1.54 (m, 1 H), 1.14 - 0.98 (m, 4 H). Example B21: Synthesis of Compound 12: 1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-6-(5-(1- ethyl -4-( trifluoromethyl )-1H- imidazol -2- yl ) pyridin -2- yl )-3- methyl -4,5,6,7- tetrahydro -1H -pyrazolo [3,4-c] pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine (50.0 mg, 0.18 mmol) and 5-[3-ethyl-5-(trifluoromethyl)imidazol-2-yl]-2-fluoropyridine (90.0 mg, 0.35 mmol) in DMSO (3 mL) was added DIEA (90.0 mg, 0.70 mmol). The mixture was stirred at 130° C. for 16 hr. Water (20 mL) was added to the cooled reaction mixture and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 525.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.72 (s, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 7.98 (s, 1 H), 7.80 - 7.88 (m, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 4.58 - 4.45 (m, 2 H), 4.12 - 4.02 (m, 2 H), 3.99 - 3.88 (m, 5 H), 2.67 - 2.55 (m, 2 H), 2.16 (s, 3 H), 1.64 - 1.54 (m, 1 H), 1.32 (t, J = 7.2 Hz, 2 H), 1.15 - 1.10 (m, 1 H), 1.05 - 0.97 (m, 3 H). Example B22: Synthesis of compound 13: 2-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)hydrazine-1-carboxylic acid tert-butyl ester

To a solution of 5-bromo-6-cyclopropyl-4-methoxypyrimidine (5.00 g, 21.82 mmol) in toluene (60 mL) were added tert-butyl hydrazinecarboxylate (5.80 g, 43.89 mmol), Pd(OAc) ₂ (500.0 mg, 2.23 mmol)), X-PHOS (1.04 g, 2.18 mmol) and sodium tert-butoxide (4.20 g, 43.70 mmol). The reactants were stirred at 100 °C under Ar for 16 h. Water (100 mL) was added to the cooled reaction mixture and extracted with EtOAc (100 mL×2). The combined organic fractions were washed with brine (100 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (ethyl acetate (0% to 40%) in petroleum ether) to give the title compound (3.20 g, 11.42 mmol, 52% yield) as a white solid.

LC-MS (ESI+): m/z 281.1 (M+H) ⁺ . 4 -Cyclopropyl-5-hydrazino-6-methoxypyrimidine

A solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)hydrazine-1-carboxylate (3.20 g, 11.42 mmol) in HCl/MeOH (4M, 20 mL) was stirred at room temperature for 3 hr. Volatiles were removed to give the title compound as a yellow solid (1.91 g, 10.61 mmol, 93% yield), which was used directly in the next step.

LC-MS (ESI+): m/z 181.1 (M+H) ⁺ . 3- Bromo- N -methoxy- N -methylisonicotinamide

To a solution of 3-bromopyridine-4-carboxylic acid (15.00 g, 74.25 mmol), EDCI (17.10 g, 89.11 mmol), HOBt (12.04 g, 89.11 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.86 g, 111.38 mmol) in DCM (150 mL) was added TEA (30.06 g, 297.03 mmol). The mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with DCM (100 mL) and the organic phase was washed with water (2×100 mL). The combined organic layers were washed with brine (100 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (13.00 g, 53.04 mmol, 71% yield) as a yellow solid.

LC-MS (ESI+): m/z 244.9 (M+H) ⁺ . 1-(3- bromopyridin-4-yl)ethan-1-one

To a stirred solution of 3-bromo-N-methoxy-N-methylpyridine-4-carboxamide (13.00 g, 53.04 mmol) in anhydrous THF (130 mL) was slowly added methylmagnesium bromide (26.52 mL, 3 M in THF, 79.56 mmol) at 0° C. and the mixture was stirred for 2 hr at 0° C. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (60 mL) at 0° C. and the aqueous phase was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 12%) in petroleum ether to give the title compound (8.70 g, 43.50 mmol, 82% yield) as a colorless oil.

LC-MS (ESI+): m/z 200.9 (M+H) ⁺ . 5-(2-(1-(3 -bromopyridin -4- yl ) ethyl ) hydrazino )-4- cyclopropyl -6- methoxypyrimidine

To a solution of 1-(3-bromopyridin-4-yl)ethan-1-one (3.00 g, 14.98 mmol) in EtOH (50 mL) was added 4-cyclopropyl-5-hydrazino-6-methoxypyrimidine (3.00 g, 16.65 mmol) and NaOAc (3.41 g, 41.62 mmol). The mixture was stirred at 80°C for 2 hr. Water (30 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 25%) in petroleum ether to give the title compound (3.00 g, 8.28 mmol, 55% yield) as a yellow oil.

LC-MS (ESI+): m/z 362.0 (M+H) ⁺ . 1-(4 -cyclopropyl -6- methoxypyrimidin- 5- yl )-3- methyl - 1H - pyrazolo [3,4-c] pyridine

To a solution of 5-(2-(1-(3-bromopyridin-4-yl)ethylidene)hydrazino)-4-cyclopropyl-6-methoxypyrimidine (500.0 mg, 1.38 mmol) in DMSO (6 mL) were added CuI (26.0 mg, 0.14 mmol) and K ₃ PO ₄ (586.0 mg, 2.76 mmol). The mixture was stirred at 100° C. for 16 hr. To the cooled reaction mixture was added water (15 mL) and the aqueous phase was extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (15 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 30%) in petroleum ether to give the title compound (180.0 mg, 0.64 mmol, 46% yield) as a yellow solid.

LC-MS (ESI+): m/z 282.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.69 (s, 1 H), 8.64 (s, 1 H), 8.41 (d, J = 5.6 Hz, 1 H), 7.83 - 7.55 (m, 1 H) , 3.92 (s, 3 H), 2.69 (s, 3 H), 1.59 - 1.52 (m, 1 H), 1.35 - 1.26 (m, 1 H), 1.21 - 1.17 (m, 1 H), 1.02 - 0.99 (m, 1 H), 0.94 - 0.90 (m, 1 H). 1-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] Pyridine

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl- 1H -pyrazolo[3,4- c ]pyridine (180.0 mg, 0.64 mmol) in EtOH (5 mL) was added platinum(IV) oxide (87.0 mg, 0.38 mmol). The reaction was stirred at room temperature under _H2 for 16 hr. The mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound (180.0 mg, 0.63 mmol, 98% yield) as a white solid which was used directly in the next step.

LC-MS (ESI+): m/z 286.1 (M+H) ⁺ . 1-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-6-(5-(1-isopropyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (48.5 mg, 0.17 mmol) and 2-fluoro-5-(1-isopropyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (95.0 mg, 0.35 mmol) in DMSO (3 mL) was added DIEA (90.0 mg, 0.70 mmol). The mixture was stirred at 130° C. for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 539.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.72 (s, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 8.14 (s, 1 H), 7.80 - 7.70 (m, 1 H), 7.09 (d, J = 9.2 Hz, 1 H), 4.57 - 4.42 (m, 2 H), 4.40 - 4.20 (m, 1 H), 3.97 - 3.91 (m, 5 H), 2.72 - 2.60 (m, 2 H), 2.16 (s, 3 H), 1.65 - 1.50 (m, 1 H), 1.39 (d, J = 6.8 Hz, 6 H), 1.14 - 1.10 (m, 1 H), 1.04 - 0.98 (m, 3 H). Example B23: Synthesis of compound 14: 1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-3- methyl -6-(6-(1- methyl -4-( trifluoromethyl ) -1H - imidazole -2- yl ) pyridin -3- yl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol) and 5-bromo-2-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyridine (96.0 mg, 0.31 mmol) in toluene (1 mL) were added Pd(OAc) ₂ (5.0 mg, 0.02 mmol), X-PHOS (200.0 mg, 0.42 mmol) and sodium tert-butoxide (40.0 mg, 0.42 mmol). The mixture was stirred at 100° C. under Ar for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 511.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.71 (s, 1 H), 8.40 (d, J = 2.8 Hz, 1 H), 7.95 - 7.80 (m, 2 H), 7.8 - 7.48 (m , 1 H), 4.33 - 4.22 (m, 2 H), 4.02 (s, 3 H), 3.94 (s, 3 H), 3.85 - 3.70 (m, 2 H), 2.70 - 2.54 (m, 2 H), 2.15 (s, 3 H), 1.56 - 1.52 (m, 1 H), 1.20- 1.10 (m, 1 H), 1.08 - 0.96 (m, 3H). Example B24: Synthesis of Compound 15: 1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-3- methyl -6-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazole -2- yl ) pyrazin -2- yl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol), 2-chloro-5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyrazine (82.8 mg, 0.32 mmol) in DMF (8 mL) was added DIEA (81.4 mg, 0.63 mmol). The mixture was stirred at 100° C. for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 2/1) to give the title compound.

LC-MS (ESI+): m/z 512.4 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d 6) δ = 8.72 (s, 1 H), 8.66 (s, 1 H), 8.51 (s, 1 H), 7.93 (s, 1 H), 4.65 - 4.50 (m, 2 H), 4.10 - 3.97 (m, 2 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 2.70 - 2.60 (m, 2 H), 2.16 (s, 3 H), 1.59 - 1.49 (m, 1 H), 1.12 - 0.98 (m, 4 H). Example B25: Synthesis of Compound 16: 3-(6 -cyclopropyl-4-methoxypyrimidin-5-yl)-1-methyl-5-{5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyrimidin-2-yl}-4,5,6,7-tetrahydropyrazolo[4,3- c ]pyridine

To a solution of 2-chloro-5-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]pyrimidine (55.2 mg, 0.21 mmol) and 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (40.0 mg, 0.14 mmol) in IPA (5 mL) was added DIEA (54.0 mg, 0.42 mmol). The mixture was stirred at 100° C. for 16 hr. To the cooled reaction mixture was added water (100 mL) and the aqueous phase was extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE/EA = 2/1) to give the title compound.

LC-MS (ESI+): m/z 512.3 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.80 - 8.65 (m, 3 H), 7.93 (s, 1 H), 4.74 - 4.61 (m, 2 H), 4.30 - 4.20 (m, 1 H), 4.07 - 4.00 (m, 1 H), 3.94 (s, 3 H), 3.75 (s, 3 H), 2.70 - 2.60 (m, 2 H), 2.17 (s, 3 H), 1.63 - 1.50 (m, 1 H), 1.21 - 1.10 (m, 1 H), 1.04 - 0.95 (m, 3 H). Example B26: Synthesis of Compound 17: 1-(4 -cyclopropyl-6-methoxypyrimidin-5-yl)-6-(3-fluoro-4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol) and 2-(4-bromo-2-fluorophenyl)-3-methyl-5-(trifluoromethyl)imidazole (101.9 mg, 0.32 mmol) in toluene (3 mL) was added Pd(OAc) ₂ (4.7 mg, 0.02 mmol), X-PHOS (200.4 mg, 0.42 mmol) and sodium tert-butoxide (40.4 mg, 0.42 mmol) at room temperature. The mixture was stirred at 100° C. under Ar for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EtOAc=1/1) to give the title compound.

LC-MS (ESI+): m/z 528.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1 H), 7.92 (s, 1 H), 7.42 - 7.29 (m, 1 H), 7.05 - 6.90 (m, 1 H), 4.29 - 4.18 (m, 2 H), 3.93 (s, 3 H), 3.82 - 3.69 (m, 2 H), 3.56 (s, 3 H), 2.75 - 2.65 (m, 2 H), 2.15 (s, 3 H), 1.60 - 1.47 (m, 1 H), 1.21 - 0.96 (m, 4 H). Example B27: Synthesis of Compound 18: 1-(6 -cyclopropyl-4-methoxypyrimidin-5-yl)-6-{2-fluoro-4-[3-methyl-5-(trifluoromethyl)imidazol-2-yl]phenyl}-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine

To a solution of 1-(6-cyclopropyl-4-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[3,4- c ]pyridine (50.0 mg, 0.18 mmol) and 2-(4-bromo-3-fluorophenyl)-3-methyl-5-(trifluoromethyl)imidazole (113.2 mg, 0.35 mmol) in toluene (2 mL) was added Pd(OAc) ₂ (3.9 mg, 0.02 mmol), X-PHOS (167.0 mg, 0.35 mmol) and sodium tert-butoxide (33.7 mg, 0.35 mmol) at room temperature. The mixture was stirred at 100° C. under Ar for 16 hr. Water (10 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.69 (s, 1 H), 7.91 (s, 1 H), 7.53 - 7.49 (m, 1 H), 7.43 - 7.40 (m, 1 H), 7.20 - 7.08 (m, 1H), 4.15 - 4.02 (m, 2 H), 3.94 (s, 3 H), 3.77 (s, 3 H), 3.55 - 3.47 (m, 2 H), 2.64 - 2.59 (m, 2 H), 2.17 (s, 3 H) , 1.63 - 1.55 (m, 1 H), 1.17 - 1.05 (m, 1 H), 1.01 - 0.90 (m, 3 H). Example B28: Synthesis of Compound 19:

The synthetic route for compound 19 was similar to that for compound 11 , by replacing 11-1 with (2-isopropylphenyl)boronic acid. The crude product was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 481.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.37 (d, J = 2.0 Hz, 1 H), 7.98 - 7.80 (m, 2 H), 7.59 - 7.51 (m, 2 H), 7.38 - 7.34 (m, 1 H), 7.32 - 7.21 (m, 1 H), 7.06 (d, J = 9.2 Hz, 1 H), 4.54 (s, 2 H), 3.98 - 3.88 (m, 2 H), 3.73 (s, 3 H), 2.75 - 2.68 (m, 1 H), 2.65 - 2.52 (m, 2 H), 2.15 (s, 3 H), 1.09 (d, J = 6.8 Hz, 6 H). Example B29: Synthesis of Compound 20: 2- Chloro -5-(5- methyl -3-( trifluoromethyl ) -1H - pyrazol -1- yl ) pyridine

To a solution of 2-chloro-5-hydrazinopyridine (0.90 g, 6.26 mmol) in HFIP (10 mL) was slowly added TEA (1.90 g, 18.80 mmol) and 1,1,1-trifluoropentane-2,4-dione (965.8 mg, 6.26 mmol) at 0°C. The mixture was stirred at 0°C for 2 hr and at room temperature for 16 hr. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (950.0 mg, 3.63 mmol, 58% yield) as a white solid.

LC-MS (ESI+): m/z 262.0 (M+H) ⁺ . 1-(4 -cyclopropyl -6- methoxypyrimidin -5 -yl )-3- methyl -6-(5-(5- methyl -3-( trifluoromethyl ) -1H - pyrazol -1- yl ) pyridin -2 -yl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol) and 2-chloro-5-(5-methyl-3-(trifluoromethyl) -1H -pyrazol-1-yl)pyridine (82.5 mg, 0.31 mmol) in toluene (2 mL) was added Pd(OAc) ₂ (4.7 mg, 0.02 mmol), X-PHOS (200.4 mg, 0.42 mmol) and sodium tert-butoxide (40.4 mg, 0.42 mmol). The mixture was stirred at 100 °C under Ar for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified twice by preparative TLC (PE/EA = 1/1, DCM/EA = 3/1) to give the title compound.

LC-MS (ESI+): m/z 511.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.71 (s, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 7.80 - 7.70 (m, 1 H), 7.10 (d, J = 9.2 Hz, 1 H), 6.72 (s, 1 H), 4.60 - 4.40 (m, 2 H), 3.99 - 3.87 (m, 5 H), 2.70 - 2.58 (m, 2 H), 2.27 (s, 3 H), 2.15 (s, 3 H), 1.65 - 1.52 (m, 1 H), 1.14 - 0.94 (m, 4 H). Example B30: Synthesis of Compound 21: 2-(1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-3 -methyl -1,4,5,7- tetrahydro - 6H - pyrazolo [3,4- c ] pyridin -6- yl )-5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (50.0 mg, 0.18 mmol) and 2-bromo-5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)thiazole (109.0 mg, 0.35 mmol) in DMSO (3 mL) was added DIEA (90.0 mg, 0.70 mmol). The reactants were stirred at 90°C for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 517.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.71 (s, 1 H), 7.85 (s, 1 H), 7.61 (s, 1 H), 4.50 - 4.40 (s, 2 H), 3.94 (s, 3 H), 3.86 - 3.78 (m, 5 H), 2.75 - 2.60 (m, 2 H), 2.17 (s, 3 H), 1.70 - 1.53 (m, 1 H), 1.20 - 1.07 (m, 1 H), 1.03 - 0.95 (m, 3 H). Example B31: Synthesis of Compound 22: 1-(2- Isopropylphenyl)-3-methyl-4,6-dihydropyrrolo[3,4- c ] pyrazole-5(1 H ) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 3-methyl-4,6-dihydropyrrolo[3,4- c ]pyrazole-5(1 H )-carboxylate (0.20 g, 0.89 mmol), (2-isopropylphenyl)boronic acid (294.0 mg, 1.79 mmol) in DCE (6 mL) were added copper(II) acetate (49.0 mg, 0.27 mmol) and pyridine (142.0 mg, 1.79 mmol). The reactants were stirred at 70° C. for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 5/1) to give the title compound (100.0 mg, 0.29 mmol, 33% yield) as a yellow solid.

LC-MS (ESI+): m/z 342.2 (M+H) ⁺ . 1-(2- Isopropylphenyl)-3-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole

To a solution of tert-butyl 1-(2-isopropylphenyl)-3-methyl-4,6-dihydropyrrolo[3,4- c ]pyrazole-5( 1H )-carboxylate (80.0 mg, 0.23 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C. The reaction was stirred at room temperature for 1 hr. The mixture was concentrated to give the title compound (50.0 mg, 0.21 mmol, 91% yield) as a yellow solid which was used directly in the next step.

LC-MS (ESI+): m/z 242.2 (M+H) ⁺ . 2-(1-(2- isopropylphenyl )-3- methyl -4,6- dihydropyrrolo [3,4-c] pyrazol -5( 1H )-yl ) -5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) thiazole

To a solution of 1-(2-isopropylphenyl)-3-methyl-1,4,5,6-tetrahydropyrrolo[3,4- c ]pyrazole (35.0 mg, 0.14 mmol) and 2-bromo-5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)thiazole (68.0 mg, 0.22 mmol) in DMSO (2 mL) was added DIEA (94.0 mg, 0.73 mmol). The reactants were stirred at 90° C. for 18 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 473.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.85 (s, 1 H), 7.68 (s, 1 H), 7.60 - 7.50 (m, 1 H), 7.49 - 7.40 (m, 1 H), 7.39 - 7.30 (m, 2 H), 4.70 - 4.50 (m, 4 H), 3.83 (s, 3 H), 3.11 - 3.04 (m, 1 H), 2.26 (s, 3 H), 1.15 (d, J = 7.2 Hz, 6 H). Example B32: Synthesis of Compound 23: 2- Bromo -5-(4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridine

To a solution of sodium acetate (7.94 g, 96.77 mmol) in water (120 mL) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (19.59 g, 72.58 mmol) dropwise at 0°C. The mixture was then stirred at 100°C for 1 h. After cooling to room temperature, a mixture of 6-bromonicotinaldehyde (9.05 g, 48.66 mmol), MeOH (240 mL) and ammonium hydroxide (28%, 80 mL) was added to the solution and the resulting mixture was stirred at room temperature for 16 hr. Volatiles were removed in vacuo. The residue was diluted with water (150 mL), and the aqueous phase was extracted with EtOAc (150 mL×3). The combined organic fractions were washed with brine (100 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (9.00 g, 30.81 mmol, 63% yield) as a yellow solid.

LC-MS (ESI+): m/z 291.9 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 13.50 (br.s, 1 H), 8.94 (d, J = 2.4 Hz, 1 H), 8.25 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 H), 8.05 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H). 2- Bromo -5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridine

To a solution of 2-bromo-5-(4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (5.02 g, 17.18 mmol) and Cs ₂ CO ₃ (13.94 g, 42.79 mmol) in DMF (60 mL) was added iodomethane (4.86 g, 34.23 mmol) dropwise at 0°C. The mixture was gradually warmed to room temperature and stirred at room temperature for 16 hr. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 20%) in petroleum ether to give the title compound (2.9 g, 9.50 mmol, 55% yield) as a yellow solid.

LC-MS (ESI+): m/z 305.9 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.75 (d, J = 2.4 Hz, 1 H), 8.11 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 8.04 (s, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 3.83 (s, 3 H). 1-(4 -Cyclopropyl-6-methoxypyrimidin-5-yl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro- 6H - pyrazolo[3,4- c ] pyridine-6-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3-(trifluoromethyl)-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridine-6-carboxylate (700.0 mg, 2.40 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (699.0 mg, 3.60 mmol) in dioxane (10 mL) were added copper(II) acetate (131.0 mg, 0.72 mmol) and DBU (731.0 mg, 4.80 mmol). The mixture was stirred at 30°C for 16 hr. Water (20 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether and re-purified with preparative TLC (PE/EA = 5/1) to give the title compound (100 mg, 0.23 mmol, 10% yield) as a colorless oil.

LC-MS (ESI+): m/z 440.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.62 (s, 1 H), 4.38 - 4.24 (m, 2 H), 3.98 (s, 3 H), 3.83 - 3.73 (m, 1 H), 3.70 - 3.55 (m, 1 H), 2.85 - 2.70 (m, 2 H), 1.47 (s, 9 H), 1.41 - 1.23 (m, 2 H), 1.21 - 1.05 (m, 1 H), 1.05 - 0.90 (m, 2 H). 1-(4 -Cyclopropyl-6-methoxypyrimidin-5-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine

To a solution of tert-butyl 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridine-6-carboxylate (100 mg, 0.23 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C. The mixture was stirred at room temperature for 2 hr. The mixture was concentrated to give the title compound (75.0 mg, 0.22 mmol, 96% yield) as a colorless oil, which was used directly in the next step.

LC-MS (ESI+): m/z 340.1 (M+H) ⁺ . 1-(4 -cyclopropyl -6- methoxypyrimidin- 5 -yl )-6-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2 -yl )-3-( trifluoromethyl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (65.0 mg, 0.19 mmol) and 2-bromo-5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (88.0 mg, 0.29 mmol) in toluene (2 mL) was added sodium tert-butoxide (36.5 mg, 0.38 mmol), _Pd2 (dba) ₃ (18.0 mg, 0.02 mmol) and BINAP (62.0 mg, 0.10 mmol). The mixture was stirred at 90 °C under Ar for 16 hr. To the cooled reaction mixture was added water (15 mL) and the aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 5/1) to give the title compound.

LC-MS (ESI+): m/z 565.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.80 (s, 1 H), 8.44 (d, J = 2.0 Hz, 1 H), 7.95 - 7.80 (m, 2 H), 7.13 (d, J = 8.8 Hz, 1 H), 4.75 - 4.54 (m, 2 H), 4.10 - 3.94 (m, 5 H), 3.75 (s, 3 H), 2.90 - 2.73 (m, 2 H), 1.53 - 1.40 (m, 1 H), 1.25 - 1.13 (m, 1 H), 1.13 - 1.00 (m, 3 H). Example B33: Synthesis of Compound 24: 6 -Cyclopropyl -5-(3 -methyl -6-(5-(1- methyl -4-( trifluoromethyl ) -1H - imidazol - 2- yl ) pyridin -2 -yl )-4,5,6,7 - tetrahydro - 1H - pyrazolo [3,4- c ] pyridin -1- yl ) pyrimidin -4- ol

A solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-6-(5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (240.0 mg, 0.47 mmol) in HCl/MeOH (10 mL, 4M) was stirred at 100° C. for 16 hr. After cooling to room temperature, the volatiles were removed in vacuo. DCM (50 mL) was added to the residue and washed with saturated aqueous NaHCO ₃ solution (30 mL×3). _The organic layer was dried over _Na2SO4 , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/MeOH = 20/1) to give the title compound (100 mg, 0.20 mmol, 42% yield) as a yellow solid.

LC-MS (ESI+): m/z 497.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.76 (br.s, 1 H), 8.41 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 7.95 - 7.83 (m , 2 H), 7.05 (d, J = 8.8 Hz, 1 H), 4.62 - 4.43 (m, 2 H), 3.99 - 3.85 (m, 2 H), 3.74 (s, 3 H), 2.65 - 2. 55 (m, 2 H), 2.13 (s, 3 H), 1.53 - 1.46 (m, 1 H), 1.01 - 0.84 (m, 4H). 1-(4 -cyclopropyl -6-( difluoromethoxy ) pyrimidin -5- yl )-3- methyl -6-(5-(1- methyl -4-( trifluoromethyl )- 1H - imidazol -2- yl ) pyridin -2 -yl )-4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 6-cyclopropyl-5-(3-methyl-6-(5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-1-yl)pyrimidin-4-ol (40.0 mg, 0.08 mmol), sodium 2-chloro-2,2- _{difluoroacetate} (18.0 mg, 0.12 mmol) in ACN (0.8 mL) was added _Na2CO3 (17.0 mg, 0.16 mmol). The mixture was stirred at 90°C for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/MeOH = 15/1) to give the title compound.

LC-MS(ESI+) : m/z 547.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.85 (s, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 8.01 - 7.65 (m, 3 H), 7.08 (d, J = 8.8 Hz, 1 H), 4.71 - 4.47 (m, 2 H), 4.01 - 3.89 (m, 2 H), 3.74 (s, 3 H), 2.73 - 2.55 (m, 2 H), 2.18 (s, 3 H), 1.64 - 1.51 (m, 1 H), 1.21 - 1.01 (m, 4 H). Example B34: Synthesis of Compound 25: 6- Chloro -2- fluoro -3-(4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridine

To a solution of sodium acetate (925.0 mg, 11.28 mmol) in water (12 mL) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (2283.0 mg, 8.46 mmol) dropwise at 0°C. Then, the mixture was stirred at 100°C for 1 hr. After cooling to room temperature, a mixture of 6-chloro-2-fluoronicotine aldehyde (903.0 mg, 5.66 mmol), MeOH (24 mL) and ammonium hydroxide (28%, 8 mL) was added to the solution and the resulting mixture was stirred at room temperature for 16 hr. Volatiles were removed in vacuo. Water (50 mL) was added to the residue and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (855 mg, 3.22 mmol, 57% yield) as a yellow solid.

LC-MS (ESI+): m/z 266.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 13.19 (br.s, 1 H), 8.60 - 8.50 (m, , 1 H), 8.00 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H). 6- Chloro -2 -fluoro -3-(1- methyl -4-( trifluoromethyl )-1 H -imidazol -2- yl ) pyridine

To a solution of 6-chloro-2-fluoro-3-(4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (500.0 mg, 1.88 mmol) and Cs ₂ CO ₃ (1533.0 mg, 4.70 mmol) in DMF (6 mL) was added iodomethane (534 mg, 3.76 mmol) dropwise at 0° C. The mixture was gradually warmed to room temperature and stirred at room temperature for 16 hr. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (300.0 mg, 1.07 mmol, 57% yield) as a yellow solid.

LC-MS(ESI+) : m/z 280.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d 6) δ = 8.35 - 8.20 (m, 1 H), 8.08 (s, 1 H), 7.80 -7.65 (m, 1 H), 3.68 (s, 3 H). 1-(4 -Cyclopropyl -6- methoxypyrimidin -5- yl )-6-(6- fluoro -5-(1- methyl -4-( trifluoromethyl )-1 H -imidazol -2- yl ) pyridin -2 -yl )-3- methyl -4,5,6,7- tetrahydro -1 H -pyrazolo [3,4- c ] pyridine

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (60.0 mg, 0.21 mmol) and 6-chloro-2-fluoro-3-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (88.0 mg, 0.31 mmol) in toluene (2 mL) under Ar were added Pd(OAc) ₂ (4.0 mg, 0.02 mmol), X-PHOS (200 mg, 0.42 mmol) and sodium tert-butoxide (40 mg, 0.42 mmol). The mixture was stirred at 100 °C for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na2SO4, filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified twice by preparative TLC (PE/EA = 1/1, DCM/EA = 3/1) to give the title compound.

LC-MS(ESI+) : m/z 529.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d 6) δ = 8.72 (s, 1 H), 7.94 (s, 1 H), 7.90 - 7.78 (m, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 4.69 - 4.40 (m, 2 H), 3.99 - 3.85 (m, 5 H), 3.58 (s, 3 H), 2.71 - 2.59 (m, 2 H), 2.16 (s, 3 H), 1.61 - 1.48 (m, 1 H), 1.21 - 0.85 (m, 4 H). Example B35: Synthesis of Compound 26: 2-(4-(1- methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) phenyl ) acetonitrile

To a solution of 2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl) -1H -imidazole (3.00 g, 9.83 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.88 g, 14.75 mmol) in dioxane (30 mL) and H ₂ O (5 mL) were added Pd(dppf)Cl ₂ (732.0 mg, 1.0 mmol) and K ₂ CO ₃ (2.72 g, 19.66 mmol). The mixture was stirred at 100 °C under N ₂ for 16 hr. To the cooled reaction mixture was added water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 30%) in petroleum ether to give the title compound (1.20 g, 4.52 mmol, 46% yield) as a yellow solid.

LC-MS (ESI+): m/z 266.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.67 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.40 - 7.30 (m, 1 H), 3.83 (s, 2 H), 3.78 (s, 3 H). Dimethyl pyridine-3,4-dicarboxylate

To a solution of pyridine-3,4-dicarboxylic acid (20.00 g, 119.67 mmol) in SOCl ₂ (200 mL) was added DMF (2 mL) at 0°C. The mixture was stirred at 80°C for 6 hr. The volatiles were removed in vacuo. The residue was dissolved in MeOH (100 mL) and the mixture was stirred at room temperature for 16 hr. The solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and it was washed with saturated aqueous NaHCO ₃ solution (100 mL). The organic layer was washed with brine (80 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give the title compound (21.00 g, 107.60 mmol, 90% yield) as a brown oil, which was used directly in the next step.

LC-MS (ESI+): m/z 196.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.03 (s, 1 H), 8.92 (d, J = 4.8 Hz, 1 H), 7.80 - 7.65 (m, 1 H), 3.88 (s, 6 H). 3,4- Bis(methoxycarbonyl)pyridine 1-oxide

To a solution of dimethyl pyridine-3,4-dicarboxylate (11.00 g, 56.36 mmol) in DCM (120 mL) was added m-CPBA (17.16 g, 84.54 mmol, 85%) portionwise at 0°C over 5 min. The reaction was then stirred at room temperature for 5 hr. The mixture was diluted with DCM (200 mL) and washed sequentially with saturated aqueous sodium sulfite solution (100 mL), followed by saturated aqueous sodium carbonate solution (200 mL). The organic fraction was washed with brine (150 mL), dried over _Na2SO4 , filtered through a Celite® _pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 50%) in petroleum ether to give the title compound (11.5 g, 54.46 mmol, 97% yield) as a yellow solid.

LC-MS (ESI+): m/z 212.0 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.35 (d, J = 1.6 Hz, 1 H), 8.30 - 8.20 (m, 1 H), 7.70 (d, J = 6.8 Hz, 1 H), 3.96 (s, 3 H), 3.93 (s, 3 H). Dimethyl 2- chloropyridine-3,4-dicarboxylate

A solution of 3,4-bis(methoxycarbonyl)pyridine 1-oxide (10.00 g, 47.36 mmol) in POCl ₃ (100 mL) was stirred at 110°C for 6 hr. After cooling to room temperature, the volatiles were removed in vacuo. The residue was diluted with DCM (30 mL) and slowly quenched with water (100 mL) at 0°C. Then, a saturated aqueous NaHCO ₃ solution was added to adjust pH = 7. The aqueous phase was extracted with DCM (80 mL×3). The combined organic layers were washed with brine (100 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 5%) in petroleum ether to give the title compound (3.9 g, 16.98 mmol, 36% yield) as a yellow solid.

LC-MS (ESI+): m/z 230.0 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.59 (d, J = 4.8 Hz, 1 H), 7.79 (d, J = 5.2 Hz, 1 H), 4.01 (s, 3 H), 3.95 (s, 3 H). (2- Chloropyridine-3,4-diyl)dimethanol

To a solution of dimethyl 2-chloropyridine-3,4-dicarboxylate (6.4 g, 27.87 mmol) in EtOH (60 mL) was added _NaBH4 (6.33 g, 167.22 mmol) portionwise at 0 °C. The mixture was stirred at room temperature for 2 hr. Formic acid was added to adjust pH = 5, and volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate (30% to 67%) in petroleum ether to give the title compound (2.3 g, 13.25 mmol, 48% yield) as a yellow solid.

LC-MS(ESI+): m/z 174.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.31 (d, J = 4.8 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 5.63 - 5.45 (m, 1 H), 5.25 - 5.10 (m, 1 H), 4.75 (d, J = 5.2 Hz, 2 H), 4.59 (d, J = 5.2 Hz, 2 H). 2- Chloro-3,4-bis(chloromethyl)pyridine

To a solution of (2-chloropyridine-3,4-diyl)dimethanol (2.30 g, 13.25 mmol) in DCM (20 mL) was added SOCl ₂ (20 mL). The mixture was stirred at 35 °C under N ₂ for 2 hr. The volatiles were removed in vacuo. A saturated aqueous sodium carbonate solution was added to the residue to adjust pH = 8. The resulting solution was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 10%) in petroleum ether to give the title compound (1.00 g, 4.75 mmol, 36% yield) as a yellow solid.

LC-MS (ESI+): m/z 210.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.47 (d, J = 4.8 Hz, 1 H), 7.61 (d, J = 4.8 Hz, 1 H), 4.98 (s, 2 H), 4.96 (s, 2 H). 1- Chloro-6-(4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)phenyl)-6,7-dihydro-5 H -cyclopenta[ c ]pyridine-6-carbonitrile

To a solution of 2-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)acetonitrile (700.0 mg, 2.64 mmol) and 2-chloro-3,4-bis(chloromethyl)pyridine (834.0 mg, 3.96 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF) (5.28 mL, 5.28 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 2 hr. Water (40 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 30%) in petroleum ether to give the title compound (310 mg, 0.77 mmol, 29% yield) as a yellow solid.

LC-MS (ESI+): m/z 403.0 (M+H) ⁺ . 1-(2- Isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine-6-carbonitrile

To a solution of 1-chloro-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine-6-carbonitrile (350.0 mg, 0.87 mmol) in dioxane (10 mL) and _H2O (2 mL) was added 2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.15 g, 8.70 mmol), Pd(dppf) _Cl2 (66.0 mg, 0.09 mmol) and _K2CO3 (240.0 mg, 1.74 mmol). The reaction was stirred at 100 °C for 16 _hr . To the cooled reaction mixture was added water (30 mL) and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with ethyl acetate (0% to 100%) in petroleum ether) to give the title compound (120.0 mg, 0.25 mmol, 29% yield) as a brown solid.

LC-MS (ESI+): m/z 488.2 (M+H) ⁺ . 1-(2- Isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine-6-carboxylic acid

To a solution of 1-(2-isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H- imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine-6-carbonitrile (105.0 mg, 0.22 mmol) in EtOH (1 mL) and H ₂ O (1 mL) was added KOH (62.0 mg, 1.10 mmol). The reaction was stirred at 110° C. for 16 hr. The volatiles were removed in vacuo. Water (10 mL) was added to the residue and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/MeOH = 10/1) to give the title compound (34.0 mg, 0.07 mmol, 32% yield) as a brown solid.

LC-MS (ESI+): m/z 507.1 (M+H) ⁺ . 1-(2- isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine

To a solution of 1-(2-isopropylpyridin-3-yl)-6-(4-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)phenyl)-6,7-dihydro- 5H -cyclopenta[ c ]pyridine-6-carboxylic acid (30.0 mg, 0.06 mmol) in DMSO (30 mL) and H ₂ O (10 mL) was added LiCl (12.7 mg, 0.30 mmol). The reactants were stirred at 140° C. for 24 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (DCM/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 463.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.66 - 8.55 (m, 1 H), 8.49 (d, J = 5.2 Hz, 1 H), 7.91 (s, 1 H), 7.75 - 7.53 (m , 3 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 4.8 Hz, 1 H), 7.35 - 7.22 (m, 1 H), 3.88 - 3.70 (m, 4 H), 3.56 - 3.45 (m, 1 H), 3.22 - 2.85 ( m, 4 H), 1.08 (d, J = 6.4 Hz, 6H). Example B36: Synthesis of intermediate 27-4: Ethyl 5- amino-1-(propan-2-yl)pyrazole-4-carboxylate

A mixture _of ethyl ( 2E )-2-cyano-3-ethoxyprop-2-enoate (7.65 g, 45.21 mmol), propan-2-yldiazane hydrochloride (5.00 g, 45.21 mmol) and _K2CO3 (6.25 g, 45.21 mmol) in ethanol/methanol (50 mL/5 mL) was stirred at 80°C for 18 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 60%) in petroleum ether to give the title compound (6.60 g, 33.47 mmol, 74% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.64 (s, 1 H), 5.04 (br.s, 2 H), 4.35 - 4.24 (m, 2 H), 4.21 - 4.08 (m, 1 H), 1.46 (d, J = 6.4 Hz, 6 H), 1.33(t, J = 7.0 Hz, 3 H). 4- Methyl-2-(propan-2-yl)pyrazol-3-amine

To a solution of ethyl 5-amino-1-(propan-2-yl)pyrazole-4-carboxylate (6.40 g, 32.45 mmol) in dioxane (70 mL) was added lithium aluminum tetrahydride (4.93 g, 129.82 mmol) portionwise at 0°C. The reaction mixture was stirred at 100°C for 4 hr. Water (4.9 mL), 10% sodium hydroxide solution (4.9 mL) and water (14.7 mL) were added sequentially to the reaction mixture at 0°C. After stirring at room temperature for 0.5 hr, _Na2SO4 was _added to the mixture. The suspension was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with MeOH (0% to 30%) in DCM to give the title compound (4.00 g, 28.74 mmol, 89% yield) as a yellow oil.

LC-MS (ESI+): m/z 140.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.20 (d, J =2.8 Hz, 1 H), 4.45 - 4.33 (m, 1 H), 3.21 (br.s, 2 H), 1.93 (d, J =2.0 Hz, 3 H) 1.55 - 1.40 (m, 6 H). 5- Hydrazino-1-isopropyl-4-methyl- 1H- pyrazole

To a solution of 4-methyl-2-(propan-2-yl)pyrazol-3-amine (2.00 g, 14.37 mmol) in 6N HCl (25 mL) was added dropwise a solution of NaNO ₂ (10.99 g, 14.37 mmol) in H ₂ O (15 mL) at -10°C. After stirring for 1 hr at -10°C, a solution of SnCl ₂ (5.45 g, 28.74 mmol) in 6N HCl (25 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for another 1 hr. The mixture was filtered through a Celite® pad and the filtrate was purified by reverse phase column (H ₂ O/ACN 100:0) to give the title compound (1.5 g, 9.73 mmol, 67.7% yield) as a white solid.

LC-MS (ESI+): m/z 155.3 (M+H) ⁺ . Example B37: Synthesis of Compound 27:

The synthetic route for compound 27 was similar to that for compound 13 by replacing intermediate 13-3 with 27-4 and intermediate H with intermediate C , respectively. The crude product was purified by preparative TLC (PE/EA = 1/1) to give the title compound.

LC-MS (ESI+): m/z 485.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.38 (d, J = 2.0 Hz, 1 H), 7.95 - 7.80 (m, 2 H), 7.49 (s, 1 H), 7.12 (d, J = 9.2 Hz, 1 H), 4.76 - 4.45 (m, 2 H), 4.02 - 3.96 (m, 2 H), 3.95 - 3.83 (m, 1 H), 3.73 (s, 3 H), 2.72 - 2.55 (m, 2 H), 2.16 (s, 3 H), 1.87 (s, 3 H), 1.30 (d, J = 6.8 Hz, 6 H). Example B38: Synthesis of Compound 28: 3- Chloro -1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl ) -1H - pyrazolo [3,4- c ] pyridine

To a solution of 3-chloro- 1H -pyrazolo[3,4- c ]pyridine (500.0 mg, 3.26 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1260.9 mg, 6.50 mmol) in dioxane (10 mL) were added copper(II) acetate monohydrate (194.0 mg, 0.97 mmol) and DBU (990.0 mg, 6.50 mmol). The mixture was stirred at room temperature for 16 hr. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 25%) in petroleum ether to give the title compound (260.0 mg, 0.86 mmol, 26% yield) as a white solid.

LC-MS (ESI+): m/z 302.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1 H), 8.81 (s, 1 H), 8.49 (d, J = 5.6 Hz, 1 H), 7.95 - 7.80 (m, 1 H), 3.90 (s, 3 H), 1.63 - 1.50 (m, 1 H), 1.23 - 0.75 (m, 4 H). 3- Chloro-1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine

A mixture of 3-chloro-1-(4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H -pyrazolo[3,4- c ]pyridine (260.0 mg, 0.86 mmol) and platinum(IV) oxide (117.0 mg, 0.51 mmol) in EtOH (6 mL) was stirred at room temperature under _H2 for 16 hr. The mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/MeOH = 20/1) to give the title compound (200.0 mg, 0.65 mmol, 76% yield) as a white solid.

LC-MS (ESI+) : m/z 306.0 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.70 (s, 1 H), 3.92 (s, 3 H), 3.65 - 3.50 (m, 2 H), 3.00 - 2.88 (m, 2 H), 2.48 - 2.40 (m, 2 H), 1.56 - 1.50 (m, 1 H), 1.14 - 0.99 (m, 4 H). 3- Chloro -1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-6-(5-(1- methyl -4-( trifluoromethyl )-1 H -imidazol -2- yl ) pyridin -2 -yl )-4,5,6,7 - tetrahydro -1 H -pyrazolo [3,4- c ] pyridine

To a solution of 3-chloro-1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (70.0 mg, 0.23 mmol) in toluene (2 mL) was added 2-bromo-5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (140.0 mg, 0.46 mmol), Pd(OAc) ₂ (5 mg, 0.02 mmol), X-Phos (218.0 mg, 0.46 mmol) and tert-BuONa (44.0 mg, 0.46 mmol). The reaction was then stirred at 100 °C for 16 hr. To the cooled reaction mixture was added water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EA = 3/1) to give the title compound.

LC-MS(ESI+) : m/z 531.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.76 (s, 1 H), 8.43 (d, J = 2.4 Hz, 1 H), 7.95 - 7.83 (m, 2 H), 7.11 (d, J = 8.8 Hz, 1 H), 4.70 - 4.50 (m, 2 H), 4.02 - 3.97 (m, 2 H), 3.96 (s, 3 H), 3.74 (s, 3 H), 2.64 (s, 2 H), 1.65 - 1.50 (m, 1H), 1.23 - 0.98 (m, 4 H). Example B39: Synthesis of Compound 29:

The synthetic route for intermediate 29-1 is similar to that for intermediate 11-3 by replacing intermediate 13-3 with 27-4 .

The synthetic route for intermediate 29-2 is similar to that for intermediate C by replacing 6-fluoronicotinaldehyde with 5-chloropyrazine-2-carboxaldehyde and converting MeI with EtI, respectively. 6-(5-(1- ethyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyrazin -2- yl )-1-(1- isopropyl -4- methyl - 1H - pyrazol- 5- yl )-3- methyl -4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(1-isopropyl-4-methyl- 1H -pyrazol-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (70.0 mg, 0.27 mmol), 2-chloro-5-(1-ethyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyrazine (112.0 mg, 0.40 mmol) in DMF (6 mL) was added TEA (81 mg, 0.81 mmol). The mixture was stirred at 100° C. for 16 hr. To the cooled reaction mixture was added water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE/EA = 3/1) to give the title compound.

LC-MS (ESI+): m/z 500.3 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.66 - 8.60 (m, 1 H), 8.56 (d, J = 1.2 Hz, 1 H), 8.00 (d, J = 1.2 Hz, 1 H), 7.49 (s, 1 H), 4.60 - 4.50 (m, 2 H), 4.44 (q, J = 7.0 Hz, 2 H), 4.16 - 4.00 (m, 1 H), 3.99 - 3.90 (m, 2 H), 2.72 - 2.60 (m, 2 H), 2.17 (s, 3 H), 1.87 (s, 3 H), 1.36 - 1.29 (m, 9 H). Example B40: Synthesis of Compound 30: 6-(3- Fluoro -4-(1- methyl - 4- ( trifluoromethyl ) -1H - imidazol -2- yl ) phenyl )-1-(1- isopropyl -4- methyl - 1H - pyrazol- 5- yl )-3- methyl -4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(1-isopropyl-4-methyl- 1H -pyrazol-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (40.0 mg, 0.15 mmol) and 2-(4-bromo-2-fluorophenyl)-1-methyl-4-(trifluoromethyl) -1H -imidazole (75.0 mg, 0.23 mmol) in toluene (3 mL) was added Pd(OAc) ₂ (3.5 mg, 0.02 mmol), X-Phos (147.0 mg, 0.31 mmol) and sodium tert-butoxide (30.0 mg, 0.31 mmol). The mixture was stirred at 100°C for 16 hr. To the cooled reaction mixture was added water (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EtOAc=2/1) to give the title compound.

LC-MS (ESI+): m/z 502.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.92 (s, 1 H), 7.49 (s, 1 H), 7.40 - 7.26 (m, 1 H), 6.99 - 6.95 (m, 1 H), 6.91 - 6.85 (m, 1 H), 4.26 - 4.19 (m, 2 H), 3.99 - 3.93 (m, 1 H), 3.82 - 3.65 (m, 2 H), 3.55 (s, 3 H), 2.67 - 2.61 (m, 2 H), 2.17 (s, 3 H), 1.85 (s, 3 H), 1.31 - 1.23 (m, 6 H). Example B41: Synthesis of intermediate 31-2: 4-(5-(1- methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)isoxazole

To a solution of 2-bromo-5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridine (3.21 g, 10.49 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (3.00 g, 15.38 mmol) in DMSO (30 mL) and H ₂ O (8 mL) were added Pd(dppf)Cl ₂ (768.0 mg, 1.05 mmol) and potassium fluoride (1.20 g, 20.65 mmol). The mixture was stirred at 110° C. under N ₂ for 16 hr. To the cooled reaction mixture was added water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 100%) in petroleum ether to give the title compound (1.60 g, 5.44 mmol, 52% yield) as a brown solid.

LC-MS (ESI-): m/z 293.1 (MH) ^- . 2-(5-(1 -methyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) pyridin -2- yl ) acetonitrile

To a solution of 4-(5-(1-methyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyridin-2-yl)isoxazole (1.60 g, 5.44 mmol) in MeOH (12 mL) and H ₂ O (4 mL) was added potassium fluoride (790.0 mg, 13.60 mmol). The mixture was stirred at 90° C. for 6 hr. To the cooled reaction mixture was added water (20 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (15 mL), dried _{over Na2SO4} , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate (0% to 30%) in petroleum ether to give the title compound (1.06 g, 3.98 mmol, 73% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.92 - 8.05 (m, 1 H), 8.21 - 8.18 (m, 1 H), 8.02 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 4.33 (s, 2 H), 3.83 (s, 3 H). Example B42: Synthesis of Compound 31:

The synthetic route for compound 31 was similar to that for compound 26 by replacing intermediate 26-1 with intermediate 31-2 and intermediate A with intermediate D , respectively. The crude product was purified by preparative TLC (DCM/EA = 3/1) to give the title compound.

LC-MS (ESI+): m/z 493.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.86 - 8.78 (m, 1 H), 8.68 - 8.60 (m, 1 H), 8.54 - 8.46 (m, 1 H), 8.15 - 8.05 (m, 1 H), 8.02 - 7.95 (m, 1 H), 7.54 - 7.46 (m, 1 H), 7.39 - 7.34 (m, 1 H), 4.00 - 3.94 (m, 1 H), 3.87 - 3.78 (m, 6 H), 3.54 - 3.36 (m, 2 H), 3.15 - 2.96 (m, 2 H), 1.70 - 1.51 (m, 1H), 1.11 - 0.87 (m, 4 H). Example B43: Synthesis of compound 32: 1-(4 -cyclopropyl -6- methoxypyrimidin -5- yl )-6-(5-(1- ethyl -4-( trifluoromethyl ) -1H - imidazol -2- yl ) Pyrazin -2- yl )-3- methyl -4,5,6,7- tetrahydro - 1H - pyrazolo [3,4- c ] pyridine

To a solution of 1-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine (70.0 mg, 0.25 mmol), 2-chloro-5-(1-ethyl-4-(trifluoromethyl) -1H -imidazol-2-yl)pyrazine (145.0 mg, 0.52 mmol) in DMF (6 mL) was added TEA (106.4 mg, 1.051 mmol). The mixture was stirred at 100°C for 16 hr. To the cooled reaction mixture was added water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM/EA = 2/1) to give the title compound.

LC-MS (ESI+): m/z 526.1 (M+H) ⁺ .

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or variations thereof should be understood by those skilled in the art and are intended to be included within the spirit and scope of this application and the scope of the accompanying patent applications. All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety for all purposes.

Claims (95)

A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, Formula (I) wherein, Ring A is an aryl group or a heteroaryl group; Ring B is a phenyl group, a phenyl homoelectron array or a heteroaryl group; Ring C is an optionally substituted 5- to 6-membered heteroaryl group; Ring D is an optionally substituted 5- to 6-membered heterocycloalkyl group or an optionally substituted 5- to 6-membered cycloalkyl group; each ^RA is independently selected ^from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC( ₌ O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra , -S(= ^O)2Ra _, -S(=O) ^2NRcRd , -S(=O)(= ^NRb ) ^{Rb , -NRcR d} , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more ^RA1 as the case may be; or two ^RAs together with the intervening atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of them is independently substituted with one or more ^RA1 as the ^case may be; each ^RA1 is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd , _-SF5 , -SH, ^-SRa , -S(=O) ^Ra -S(=O) _2R ^a , -S(=O) _2NR ^c R ^d , -S(=O)(=NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) _2R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein _each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, 4, or 5; each ^RB is independently selected from halogen, -CN, _-NO2 , -OH, ^-ORa , -OC(=O) ^Ra , -OC(=O) ^ORb , -OC(=O) ^NRcRd _, ^-SF5 , -SH _, ^-SRa , -S(=O) ^{Ra ,} -S(=O) _2Ra , -S ⁽ = ^O )2NRcRd ^, -S(=O)(= ^NRb ) ^Rb , ^-NRcRd , ^-NRb C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R ^B1 as appropriate; _n is 0, 1, 2, 3 or 4; each R ^B1 is independently selected from halogen, -CN, -NO ₂ , -OH, -OR ^a , -OC(═O)R ^a , -OC(═O)OR ^b , -OC(═O)NR ^c R ^d , -SF ₅ , -SH, -SR ^a , -S(═O)R ^a , -S(═O) ₂ R ^a , -S(═O) ₂ NR ^c R ^d , -S(═O)(═NR ^b )R ^b , -NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -NR ^b S(=O) ₂ R ^a , -N=S(=O)(R ^b ) ₂ , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , -P(=O)(R ^b ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R; _R is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is independently substituted with one or more ^R ; each ^Ra is independently _C1 - _C6 alkyl, C1-C6 haloalkyl, ^C1 _{- C6} hydroxyalkyl, _{C1 -} C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _{C2 - C6} The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C The present invention preferably comprises a _{C 1} -C ₆ alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, a C ₁ -C ₆ alkylene (cycloalkyl), a C ₁ -C ₆ alkylene (heterocycloalkyl), a C _{1 -C 6 alkylene (aryl) or a C 1} -C ₆ alkylene (heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted with one or more R as the case may be; R ^c and R ^d are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C 6 C ₁ -C ₆ alkylene (cycloalkyl), C 1 -C 6 alkylene (heterocycloalkyl), C ₁ -C ₆ alkylene (aryl) or C ₁ -C ₆ alkylene (heteroaryl), wherein _each alkyl, alkylene, _alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently substituted with one or more R as the case may be; or R ^c and R _d together with the atoms to which they are attached form a heterocycloalkyl group optionally substituted with one or more R as the case may be; and each ^R is independently halogen, -CN, -OH, -SF ₅ , -SH, -S(═O) C ₁ -C ₃ alkyl, -S(═O) ₂ C ₁ -C ₃ alkyl, -S(═O) _{2 NH2} , -S(=O) _2NHC1 - _C3alkyl , -S(=O) _{2N ( C1} - _C3alkyl ) ₂ , _-S (=O)(= _NC1 -C3alkyl)(C1-C3alkyl _{), -NH2 , -NHC1 -} C3alkyl, -N( _C1 -C3alkyl) ₂ , -N=S(=O)( _{C1 - C3alkyl} ) ₂ , -C(=O) _C1 -C3alkyl, _-C (=O)OH, -C(=O) _{OC1 -} C3alkyl, _-C (=O) _NH2 , -C(=O) _{NHC1 -C3alkyl} , -C(=O)N( _C1 -C3alkyl) ₂ , -P(=O)( _C1 - _C3alkyl ) ₂ , _{C1 - C3alkyl} , _C1 -C C _{1 -C 3 alkoxy, C 1 -C 3 halogenated} alkyl, C ₁ -C ₃ halogenated alkoxy, C 1 -C ₃ hydroxyalkyl, C ₁ -C ₃ aminoalkyl, C ₁ -C ₃ heteroalkyl or C ₃ -C ₆ cycloalkyl; or two R on the same atom form a pendant oxy group. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring A is a phenyl group or a 5- to 6-membered monocyclic heteroaryl group. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the ring A is phenyl or a 5- to 6-membered monocyclic heteroaryl group. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein for , , , , , , or , wherein X ¹ is N or CR ^x ; ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyl alkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R; X ² is N or CR ² ; X ³ is N, NR ^1N , CR ¹ , S or O; X ⁴ is N, NR ^2N , CR ² , S or O; X ⁵ is N or C; each of R ¹ and R ² is independently hydrogen, halogen, -CN, OH, -SF ₅ , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C 1 -C 6 hydroxyl alkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C 6 heteroalkyl. wherein each of the alkyl, _{the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; each of R 1N and R 2N is independently hydrogen, C 1-6 alkyl} ^, _{C 1-6} halogenated alkyl, C _1-6 hydroxyalkyl, C 1-C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or the heteroalkyl is optionally substituted with one or more R; each of R 4 and R ^4' is independently selected from hydrogen, halogen, -CN, -OR a , -SR a , -NR c R d , C _1-6 alkyl, C 1-6 halogenated alkyl, C _1-6 hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or the heteroalkyl is optionally substituted with one or more R; each of R ⁴ and R ^4' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁴ and R ^4' together form a pendoxy group; or R ⁴ and R ^4' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; each of R ⁵ and R ^5' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C _{1-6 -C6} haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or ^R5 and R5 ^' together form a pendoxy group; or ^R5 and R5 ^' together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of ^R6 and R6 ^' is independently selected from hydrogen, halogen, -CN, ^{-ORa , -SRa} , ^-NRcRd , _C1-6 alkyl, _{C1-6 -C6} haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or ^R6 and R6 ^' together form a pendooxy group; or ^R6 and R6 ^' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein for , , , , , , , , , , , or . A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIA): Formula (IIA). The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIB): Formula (IIB). A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIC): Formula (IIC). A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IID) Formula (IID). A compound according to any one of claims 1 to 4 or 7 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IID'): Formula (IID'), wherein, ^Z1 is N or CR ^Z1 ; ^Z2 is N or CR ^Z2 ; ^Z3 is N or CR ^Z3 ; ^Z4 is N or CR ^Z4 ; ^Z5 is N or CR ^Z4 ; each of R ^Z1 , R ^Z2 , R ^Z3 , R ^Z4 and R ^Z5 is independently hydrogen or ^RA , provided that when ^Z1 is CR ^Z1 and ^Z5 is CR ^Z5 , at least one of R ^Z1 and R ^Z5 is selected from ^RA ; ^R1 is halogen, -CN, OH, _-SF5 , -SH, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or ^{R 4'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; R ⁵ and R ^5' are each independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^5' together form a pendoxy group; or R ⁵ and R ^{R 5'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendoxy group; or R ⁶ and R ^6' together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R groups. A compound according to any one of claims 1 to 4 or 7 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IID''): Formula (IID''), Ring A is a 5-membered heteroaryl group; ^Y1 is N or ^CRY1 ; ^Y2 is N or ^CRY2 ; ^Y3 is N or ^CRY3 ; ^Y4 is N or ^CRY4 ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; ^R1 is hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1- _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _{C1 -C6 heteroalkyl} , _C2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or ^{R 4'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; R ⁵ and R ^5' are each independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^5' together form a pendoxy group; or R ⁵ and R ^{R 5'} together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R ^6' together form a pendoxy group; or R ⁶ and R ^6' together with the carbon to which it is attached forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R groups. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIE): Formula (IIE), ^Y1 is N or ^CRY1 ; ^Y2 is N or ^CRY2 ; ^Y3 is N or ^CRY3 ; ^Y4 is N or ^CRY4 ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, C wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; X ¹ is N or ^CRX ; ^RX is hydrogen, halogen, C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C 1-C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R; each of R ⁴ and R ^4' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C 1-C 6 aminoalkyl or C ₁ -C ₆ heteroalkyl. ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R ⁴ and R ^4' together form a pendoxy group; or R ⁴ and R ^4' together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R ⁶ and R ^6' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or ^R6 and R6 ^' together form a pendooxy group; or ^R6 and R6 ^' together with the carbon to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more R. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIF): Formula (IIF), ^Y1 is N or CR ^Y1 ; ^Y2 is N or CR ^Y2 ; ^Y3 is N or CR ^Y3 ; ^Y4 is N or CR ^Y4 ; ^X2 is N or CR ² ; each of ^RY1 , ^RY2 , ^RY3 and ^RY4 is independently hydrogen or ^RB ; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl, _C1 - _C6 heteroalkyl, _C2-6 alkenyl, C ^R4 and R4 ^' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd, _C1-6 alkyl, C1- _C6 halogenated ^alkyl , C1 _-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-6 ^alkenyl , C2-6 ^alkynyl , cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, _cycloalkyl or heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, ^-NRcRd , C1-6 alkyl, _C1 - _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _- C6 heteroalkyl, _C2-6 alkenyl, C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^; or R ^{4 '} and R ^4' are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; each of R ⁵ and R ^5' is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁵ and R ^R and R ^{5 '} together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of R and R ^{6 '} is independently selected from hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^c R ^d , C _1-6 alkyl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - _{C 6} aminoalkyl, C ₁ -C ₆ heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R ⁶ and R or R ⁶ and R ^{6' together} with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R. The compound of any one of claims 2 to 4, 12 or 11 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 2 to 4, 12 or 11, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen. The compound of any one of claims 2 to 4, 6 to 11 or 13 to 15 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 2 to 4, 6 to 11 or 13 to 16 or a pharmaceutically acceptable salt thereof, wherein R ^5' is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (IIG): Formula (IIG), ^Z1 is N or ^CRZ1 ; ^Z2 is N or ^CRZ2 ; ^Z3 is N or ^CRZ3 ; ^Z4 is N or ^CRZ4 ; ^Z5 is N or ^CRZ4 ; each of ^RZ1 , ^RZ2 , ^RZ3 , ^RZ4 and ^RZ5 is independently hydrogen or ^RA , provided that at least one of ^RZ1 and ^RZ5 is present and selected from ^RA ; ^X3 is N, ^NR1N , ^CR1 , S or O; ^X4 is N, ^NR2N , ^CR2 , S or O; ^X5 is N or C; each of ^R1 and ^R2 is independently hydrogen, halogen, -CN, OH, _-SF5 , -SH, _C1-6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 hydroxyalkyl, C1-C6 wherein _each of the alkyl, the _heteroalkyl , the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; each of ^R1N and ^R2N is independently hydrogen, _C1-6 alkyl, _{C1 - C6 halogenated} alkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 aminoalkyl or C1- _C6 heteroalkyl, wherein each of the alkyl or the heteroalkyl is optionally substituted with one or more R; ^X1 is N or ^CRX ; ^RX is hydrogen, halogen, _C1-6 alkyl, _C1 - _{C6 halogenated} alkyl, _{C1 - C6} ^R4 and R4 ^' are each independently selected from hydrogen, halogen, _-CN , -ORa, -SRa, -NRcRd, C1-6 alkyl, C1- _C6 halogenated alkyl, C1 _{- C6} hydroxyalkyl, _C1 -C6 aminoalkyl, _C1 -C6 heteroalkyl, C2-6 alkenyl, ^{C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or R4 and R4' are each independently selected from hydrogen, halogen, -CN, -ORa, -SRa, -NRcRd , C1-6 alkyl} , _{C1 - C6} halogenated alkyl, C1 _{- C6} hydroxyalkyl, C1 _{- C6} aminoalkyl, C1 _{- C6} heteroalkyl, C2-6 alkenyl, _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with ^one or more R; ^R4 and ^{R4' together} with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R; and each of ^R6 and R6 ^' is independently selected from hydrogen, halogen, ^-CN , _-ORa , ^-SRa , ^-NRcRd , C1-6 alkyl, ^C1 _{- C6} haloalkyl, C1 _{- C6} hydroxyalkyl, C1- _{C6 aminoalkyl, C1-C6 heteroalkyl , C2-6 alkenyl} , _C2-6 alkynyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, the heteroalkyl, the cycloalkyl or the heterocycloalkyl is optionally substituted with one or more R; or ^R6 and R or R ⁶ and R ^{6' together} with the carbon to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more R. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein for or . The compound of claim 18 or 19 or a pharmaceutically acceptable salt thereof, wherein X ³ is N, NR ^1N or CR ¹ . The compound of any one of claims 18 to 20 or a pharmaceutically acceptable salt thereof, wherein R ^1N is hydrogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 4, 7 or 9 to 20 or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen, C _1-6 alkyl or C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound or pharmaceutically acceptable salt thereof of any one of claims 18 to 22, wherein X ⁴ is N, NR ^2N or CR ² . The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 23, wherein each of R ^Z1 , R ^Z2 , R ^Z3 and R ^Z4 is hydrogen. The compound of any one of claims 10 or 18 to 24, or a pharmaceutically acceptable salt thereof, wherein Z ¹ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein ^Z1 is CR ^Z1 . The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R ^Z1 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more ^RA1 . The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein Z ² is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein ^Z2 is ^CRZ2 . The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R ^Z2 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more ^RA1 . The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein Z ³ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein Z ³ is CR ^{Z 3} . The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R ^Z3 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more ^RA1 . The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein Z ⁴ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein ^Z4 is ^CRZ4 . The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R ^Z4 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more ^RA1 . The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein Z ⁵ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 10 or 18 to 24, wherein ^Z5 is ^CRZ5 . The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R ^Z5 is ^RA , wherein ^RA is selected from halogen, -OR ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl and cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more ^RA1 . The compound or pharmaceutically acceptable salt thereof of any one of claims 12 and 18 to 39, wherein X ¹ is CR ^X . The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein ^RX is hydrogen, halogen, _C1-6 alkyl or _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 4, 6 or 8 to 40, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 4, 6 or 8 to 42, or a pharmaceutically acceptable salt thereof, wherein R ^4' is selected from hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 4 or 6 to 43 or a pharmaceutically acceptable salt thereof, wherein ^R6 is selected from hydrogen, halogen, _C1-6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 4 or 6 to 44 or a pharmaceutically acceptable salt thereof, wherein R ^6' is hydrogen, halogen, C _1-6 alkyl and C ₁ -C ₆ halogenated alkyl, wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 11 to 17 or 22 to 45, or a pharmaceutically acceptable salt thereof, wherein each of R ^Y1 , R ^Y2 , R ^Y3 and R ^Y4 is hydrogen. The compound of any one of claims 11 to 17 or 22 to 45, or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 11 to 17 or 22 to 46, wherein ^Y1 is CR ^Y1 . The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein ^RY1 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . The compound of any one of claims 11 to 17, 22 to 45 or 47 to 49 or a pharmaceutically acceptable salt thereof, wherein Y ² is N. The compound of any one of claims 11 to 17, 22 to 45 or 47 to 49 or a pharmaceutically acceptable salt thereof, wherein ^Y2 is CR ^Y2 . The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein ^RY2 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . The compound of any one of claims 11 to 17, 22 to 45 or 47 to 52, or a pharmaceutically acceptable salt thereof, wherein Y ³ is N. The compound of any one of claims 11 to 17, 22 to 45 or 47 to 52 or a pharmaceutically acceptable salt thereof, wherein Y ³ is CR ^Y3 . The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein ^RY3 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . The compound of any one of claims 11 to 17, 22 to 45 or 47 to 55, or a pharmaceutically acceptable salt thereof, wherein Y ⁴ is N. The compound of any one of claims 11 to 17, 22 to 45 or 47 to 55 or a pharmaceutically acceptable salt thereof, wherein Y ⁴ is CR ^Y4 . The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein ^RY4 is ^RB , wherein ^RB is selected from halogen, _C1 - _C6 alkyl and _C1 - _C6 halogenated alkyl, wherein the alkyl is optionally substituted with one or more ^RB1 . The compound of any one of claims 1 to 9, 11 to 17, 22 to 24 or 40 to 58 or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl. The compound of any one of claims 1 to 9, 11 to 17, 22 to 24 or 40 to 58 or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered monocyclic heteroaryl group. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, thiophene or thiazole. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein for , , , , , , , , , , , , , , , , , or . The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein Select from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein Selected from , , , and . The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein Select from: , , , , , , , and . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9 or 14 to 65, wherein Ring B is phenyl. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9 or 14 to 65, wherein ring B is a phenyl homoelectron array. The compound of claim 67 or its pharmaceutically acceptable salt, wherein the phenyl group is a cubane. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or 14 to 65, wherein Ring B is a 5- to 6-membered monocyclic heteroaryl group. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, thiophene or thiazole. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein Select from: , , , and . The compound of any one of claims 1 to 71 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a heteroaryl group, wherein the heteroaryl group is optionally substituted with one or more R ^B1 groups. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, O, S and P. The compound of claim 73 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is an optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl group. The compound of any one of claims 1 to 75 or a pharmaceutically acceptable salt thereof, wherein R ^B1 is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ halogenated alkyl; wherein the alkyl is optionally substituted with one or more R. The compound of any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is selected from: , , , , , , , , , , , , , , , , , , , , , and . A compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. A method for regulating ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. A method for inhibiting ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to the subject a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. A method for inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1) in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. A method for treating a disease or condition associated with ubiquitin-specific protease 1 (USPl) in an individual, the method comprising administering to the individual a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. A method for treating a disease or condition associated with ubiquitin-specific protease 1 (USP1) regulation in an individual, the method comprising administering to the individual a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. The method of claim 83 or 84, wherein the disease or condition is cancer. A method for treating cancer in an individual, comprising administering to the individual in need thereof an effective amount of a compound of any one of claims 1 to 78 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79. The method of claim 85 or 86, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. The method of claim 85 or 86, wherein the cancer is ovarian cancer. The method of claim 85 or 86, wherein the cancer is breast cancer. The method of claim 89, wherein the cancer is ovarian cancer or breast cancer. The method of any one of claims 85 to 90, wherein the cancer comprises cancer cells having elevated levels of RAD18. The method of any one of claims 85 to 91, wherein the cancer is a cancer with a defect in a DNA damage repair pathway. The method of any one of claims 85 to 92, wherein the cancer is PARP inhibitor-resistant or refractory cancer. The method of any one of claims 85 to 93, wherein the cancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. The method of claim 94, wherein the cancer is a BRAC1 -deficient cancer.