Selective JAK2 inhibitors and uses thereof

Abstract

Described herein are compounds that are JAK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of JAK2 activity.

Description

SELECTIVE JAK2 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 681,037, filedon August 8, 2024, and US Provisional Application No.63 / 851,058, filed on July 25, 2025, each of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] The present disclosure relates to compounds that bind to the pseudokinase domain(JH2) of the non-receptor tyrosine kinase Janus kinase 2 (JAK2). Compounds of the present disclosure may selectively bind the JH2 domain of JAK2 over the JH1 domain of JAK2. Compounds of the present disclosure may selectively bind the V617F mutant of JAK2 over wild-type JAK2. Additional aspects of the disclosure include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes useful in the synthesis of the compounds.

[0003] JAK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family ofprotein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including JAK2, are integral to cytokine signaling through the JAK- STAT pathway. Small molecule inhibitors of JAK family kinases have proven effective for the treatment of numerous diseases, including cancer.

[0004] All FDA-approved JAK2 inhibitors are type 1 inhibitors targeting the JH1 domain.However, JAK2 inhibitors that selectively bind the pseudokinase (JH2) domain may present several advantages.

[0005] Mutant JAK2 V617F is widespread in the myeloproliferative neoplasms (MPNs),presenting over half of all cases of essential thrombocythemia and myelofibrosis and presenting lobe of the JH2 domain. Inhibitors of JAK2 JH2 with selectivity for the JAK2 V617F mutant over wild-type JAK2 may be useful for treating various pathologies, such as MPNs, while minimizing effects to the off-target function of wild-type JAK2. SUMMARY OF THE INVENTION

[0006] Compounds described herein are modulators of the JAK family of kinases. Morespecifically, the compounds of the present disclosure are inhibitors of JAK2. In some embodiments, compounds are selective for JAK2 over other JAKs. In some embodiments, compounds are selective for the pseudokinase domain (JH2) of JAK2 over the kinase domain (JH1). In some embodiments, compounds are selective for the V617F mutant of JAK2 overwild-type JAK2. In some embodiments, a compound of the present disclosure may be an allosteric modulator or noncompetitive inhibitor of JAK2. In additional embodiments, a compound described herein may be useful in the treatment of JAK2 mediated diseases or disorders. In some embodiments, the compounds of the present disclosure are useful for the treatment of cancer. In some embodiments, the compounds of the present disclosure are useful for the treatment of myeloproliferative neoplasms (MPNs). In some embodiments, the compounds of the present invention are useful for the treatment of a disease selected from myelofibrosis, polycythemia vera, and essential thrombocythemia.

[0007] In one aspect, described herein is a compound of Formula (I-1):Formula (I-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, - NRaS(O)2Rb, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl,substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N;R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstitutedmonocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0008] In one aspect, described herein is a compound of Formula (I-1):Formula (I-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N;X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substitutedcarbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-;each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0009] In one aspect, described herein is a compound of Formula (I-1-st-1):Formula (I-1-st-1); or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0010] In one aspect, described herein is a compound of Formula (I-1-st-2):Formula (I-1-st-2); or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0011] In one aspect, described herein is a compound of Formula (I-1-st-3):Formula (I-1-st-3); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0012] In one aspect, described herein is a compound of Formula (I-1-st-4):Formula (I-1-st-4); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0013] In one aspect, described herein is a compound of Formula (I-1-st-5):Formula (I-1-st-5); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2;or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0014] Any combination of the groups described above for the various variables iscontemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0015] Also described herein are pharmaceutical compositions comprising a compounddescribed herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

[0016] Described herein are compounds and pharmaceutically acceptable salts, tautomers, orsolvates thereof useful in the treatment of JAK2-mediated disorders. Described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of a JAK2-mediated disorder.

[0017] In some embodiments, the compound described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a JAK2-V617F- mediated disorder.

[0018] In some embodiments, the compound described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a myeloproliferative diseases (MPDs).

[0019] In any of the aforementioned aspects are further embodiments in which the effectiveamount of the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation; and / or (e) administered by nasal administration; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[0020] In any of the aforementioned aspects are further embodiments comprising singleadministrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound isadministered to the mammal multiple times over the span of one day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0021] In any of the embodiments disclosed herein, the mammal is a human.

[0022] In some embodiments, compounds provided herein are orally administered to a human.

[0023] Articles of manufacture, which include packaging material, a compound describedherein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating JAK2, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating JAK2, are provided.

[0024] Other objects, features and advantages of the compounds, methods and compositionsdescribed herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0025] JAK activity has been linked to numerous diseases, including inflammatory diseasesand disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.

[0026] Mutations to JAK2 are associated with myeloproliferative neoplasms (MPNs). Forexample, the JAK2-V617F mutation occurs in 95% of patients with polycythemia vera (PV), 60% of patients with essential thrombocythemia (ET), and 55% of patients with myelofibrosis (MF). Additionally, gain-of-function mutations to JAK2 exon 12 and in the thrombopoietin receptor are often present in JAK2-V617F-negative MPNs.

[0027] There is a continuing need to provide novel inhibitors of Janus kinases having moreeffective or advantageous pharmaceutically relevant properties. For example, compounds with increased selectivity for JAK2 over other JAK kinases, and / or selectivity for particular mutant JAKs. There is a need for novel inhibitors that selectively bind the pseudokinase domain (JH2) over the kinase domain (JH1), as this may introduce unique selectivity and limit off-target effects. There is also a need for inhibitors that selectively bind to mutant JAK2-V617F overwild-type JAK2. JAK2 inhibitors that selectively bind mutant JAK2-V617F over wild-type JAK2 may limit off-target effects and / or facilitate mutant allele burden reduction.

[0028] In some embodiments, the JAK2 inhibitors described herein have selectivity for JAK2over JAK1, JAK3, and / or TYK2. In some embodiments, the JAK2 inhibitors described herein have selectivity for JH2 binding over JH1 binding. In some embodiments, the JAK2 inhibitors described herein have selectivity for mutant JAK2-V617F binding over wild-type JAK2 binding.

[0029] In some embodiments, compounds with selectivity for JH2 binding deliver apharmacological response that favorably treats one or more of the diseases or conditions described herein without the side-effects associated with the inhibition of wild-type JAK2. The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of Janus Kinase 2 (JAK2), to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat certain cancers, and to intermediates and processes useful in the synthesis of the compounds.

[0030] In some embodiments, the JAK2 inhibitors described herein are used in the treatmentof a disease or condition in a mammal. Compounds of the Present Disclosure

[0031] Compounds described herein, including pharmaceutically acceptable salts, tautomers,and solvates thereof, are inhibitors of JAK2. In some embodiments, compounds described herein are selective for JAK2 over other JAKs. In some embodiments, compounds described herein bind selectively / specifically to the pseudokinase domain (JH2) of JAK2. In some embodiments, compounds described herein bind selectively / specifically to the V617F mutant of JAK2. In some embodiments, a compound described herein binds to an allosteric site of JAK2. In additional embodiments, a compound described herein may be useful in the treatment of JAK2-mediated diseases or disorders. In some embodiments, a compound described herein may be useful in the treatment of JAK2-V617F-mediated diseases or disorders.

[0032] In one aspect, the present disclosure provides compounds of Formula (I-a):Formula (I-a), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, - NRaS(O)2Rb, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclicheterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X5is CR25or N; X6is CR26or N; X7is CR27or N; wherein one of X4, X5, X6, and X7is CR1; R21, R22, R23, R24, R25, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl;R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl;each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0033] In one aspect, the present disclosure provides compounds of Formula (I-a):Formula (I-a), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl;L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X5is CR25or N; X6is CR26or N; X7is CR27or N; wherein one of X4, X5, X6, and X7is CR1; R21, R22, R23, R24, R25, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2;Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl;R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstitutedmonocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0034] In some embodiments, the present disclosure provides compounds of Formula (I-a-st-Formula (I-a-st-1).

[0035] In some embodiments, the present disclosure provides compounds of Formula (I-a-st-Formula (I-a-st-2).

[0036] In some embodiments, the present disclosure provides compounds of Formula (I-a-st-3):Formula (I-a-st-3); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0037] In some embodiments, the present disclosure provides compounds of Formula (I-a-st-4):Formula (I-a-st-4); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0038] In some embodiments, the present disclosure provides compounds of Formula (I-a-st-5):Formula (I-a-st-5); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0039] In some embodiments, the present disclosure provides compounds of Formula (I-a-N):Formula (I-a-N).

[0040] In some aspects, the compound of Formula (I-a) is a compound of Formula (I-a-X4):Formula (I-a-X4); wherein X5is CR25or N; X6is CR26or N; X7is CR27or N; R25, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2.

[0041] In some embodiments,X5is CR25,X6is CR26, andX7is CR27;or X5is CR25, X6is N, and X7is CR27; or X5is N, X6is CR26, and X7is CR27; or X5is CR25, X6is CR26, and X7is N; or X5is CR25, X6is N, and X7is N; or X5is N, X6is CR26, and X7is N;orX5is N,X6is N, andX7is CR27.

[0042] In some embodiments,X5is CR25, X6is N, and X7is CR27; or X5is N, X6is CR26, and X7is CR27; or X5is CR25, X6is CR26, and X7is N; or X5is CR25, X6is N, and X7is N; or X5is N, X6is CR26, and X7is N;orX5is N,X6is N, andX7is CR27;or X5is N, X6is N, and X7is N.

[0043] In some embodiments,X5is CR25, X6is N, and X7is CR27; or X5is N, X6is CR26, and X7is CR27; or X5is CR25, X6is CR26, and X7is N; or X5is CR25, X6is N, and X7is N; or X5is N, X6is CR26, and X7is N;orX5is N,X6is N, andX7is CR27.

[0044] In some embodiments,X5is CR25, X6is N, and X7is CR27; or X5is N, X6is CR26, and X7is CR27; or X5is CR25, X6is CR26, and X7is N.

[0045] In some embodiments,X5is CR25,X6is N, andX7is CR27. In some embodiments,X5is N, X6is CR26, and X7is CR27. In some embodiments, X5is CR25, X6is CR26, and X7is N.

[0046] In some embodiments, R25, R26, and R27 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R25, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R25, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R25, R26, and R27are each independently hydrogen, -F, -Cl, -Br, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R25, R26, and R27are each independently hydrogen, -F, or CH3. In some embodiments, R25, R26, and R27are each hydrogen.

[0047] In some embodiments,X5is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X5is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X5is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

[0048] In some embodiments,X5is CH, C-CH3, or CF,X6is N, andX7is CH, C-CH3, or CF.

[0049] In some embodiments,X5is N,X6is CH, C-CH3, or CF, andX7is CH, C-CH3, or CF.

[0050] In some embodiments,X5is CH, C-CH3, or CF,X6is CH, C-CH3, or CF, andX7is N.

[0051] In some aspects, the compound of Formula (I-a) is a compound of Formula (I-a-X6):Formula (I-a-X6); wherein X4is CR24or N; X5is CR25or N; X7is CR27or N; R24, R25, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2.

[0052] In some embodiments,X4is CR24,X5is CR25, andX7is CR27;or X4is CR24, X5is N, and X7is CR27; or X4is N, X5is CR25, and X7is CR27; or X4is CR24, X5is CR25, and X7is N; or X4is CR24, X5is N, and X7is N; or X4is N, X5is CR25, and X7is N;orX4is N,X5is N, andX7is CR27.

[0053] In some embodiments,X4is CR24, X5is N, and X7is CR27; or X4is N, X5is CR25, and X7is CR27; or X4is CR24, X5is CR25, and X7is N; or X4is CR24, X5is N, and X7is N; or X4is N, X5is CR25, and X7is N;orX4is N,X5is N, andX7is CR27;or X4is N, X5is N, and X7is N.

[0054] In some embodiments,X4is CR24, X5is N, and X7is CR27; or X4is N, X5is CR25, and X7is CR27; or X4is CR24, X5is CR25, and X7is N; or X4is CR24, X5is N, and X7is N; or X4is N, X5is CR25, and X7is N;orX4is N,X5is N, andX7is CR27.

[0055] In some embodiments,X4is CR24, X5is N, and X7is CR27; or X4is N, X5is CR25, and X7is CR27; or X4is CR24, X5is CR25, and X7is N.

[0056] In some embodiments,X4is CR24,X5is N, andX7is CR27. In some embodiments,X4is N, X5is CR25, and X7is CR27. In some embodiments, X4is CR24, X5is CR25, and X7is N.

[0057] In some embodiments, R24, R25, and R27 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R25, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R25, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R25, and R27are each independently hydrogen, -F, -Cl, -Br, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R25, and R27are each independently hydrogen, -F, or CH3. In some embodiments, R24, R25, and R27are each hydrogen.

[0058] In some embodiments,X4is CH, C-CH3, or CF, X5is N, and X7is CH, C-CH3, or CF; or X4is N, X5is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X5is CH, C-CH3, or CF, and X7is N.

[0059] In some embodiments,X4is CH, C-CH3, or CF,X5is N, andX7is CH, C-CH3, or CF.

[0060] In some embodiments,X4is N,X5is CH, C-CH3, or CF, andX7is CH, C-CH3, or CF.

[0061] In some embodiments,X4is CH, C-CH3, or CF,X5is CH, C-CH3, or CF, andX7is N.

[0062] In some aspects, described herein is a compound of Formula (I-b):Formula (I-b), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Rxis hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, - NRaS(O)2Rb, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N;X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted orsubstituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2;or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0063] In some aspects, described herein is a compound of Formula (I-b):Formula (I-b), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Rxis hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl,unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13;R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl,unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; andm is 0-4.

[0064] In some embodiments, the present disclosure provides compounds of Formula (I-b-st-1):Formula (I-b-st-1).

[0065] In some embodiments, the present disclosure provides compounds of Formula (I-b-st-2)Formula (I-b-st-2).

[0066] In some embodiments, the present disclosure provides compounds of Formula (I-b-st-3):Formula (I-b-st-3); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0067] In some embodiments, the present disclosure provides compounds of Formula (I-b-st-4):Formula (I-b-st-4); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0068] In some embodiments, the present disclosure provides compounds of Formula (I-b-st-5):Formula (I-b-st-5); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0069] In some embodiments, the present disclosure provides compounds of Formula (I-b-N):Formula (I-b-N).

[0070] In some aspects, described herein is a compound of Formula (I-1):Formula (I-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl;L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, - NRaS(O)2Rb, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12);R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstitutedor substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1;q is 0 or 1; and m is 0-4.

[0071] In some aspects, described herein is a compound of Formula (I-1):Formula (I-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl;each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl,substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

[0072] In some embodiments, the present disclosure provides compounds of Formula (I-1-st-1):Formula (I-1-st-1).

[0073] In some embodiments, the present disclosure provides compounds of Formula (I-1-st-2)Formula (I-1-st-2).

[0074] In some embodiments, the present disclosure provides compounds of Formula (I-1-st-3):Formula (I-1-st-3); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0075] In some embodiments, the present disclosure provides compounds of Formula (I-1-st-4):Formula (I-1-st-4); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0076] In some embodiments, the present disclosure provides compounds of Formula (I-1-st-5):Formula (I-1-st-5); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted - (C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0077] In some embodiments, the present disclosure provides compounds of Formula (I-1-N):Formula (I-1-N).

[0078] In some embodiments, Ring A is a monocyclic heteroaryl or a bicyclic heteroaryl.

[0079] In some embodiments,is

[0080] In some embodiments, the compound is a compound of Formula (II-1):Formula (II-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is N, CH, or C-RE; and REis hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2.

[0081] In some embodiments, the present disclosure provides compounds of Formula (II-1-N):Formula (II-1-N).

[0082] In some embodiments, the compound is a compound of Formula (IIa-1):Formula (IIa-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is N, CH, or C-RE; REis hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, -C(O)N(R18)2, N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2.

[0083] In some embodiments, the present disclosure provides compounds of Formula (IIa-1¬N):Formula (IIa-1-N).

[0084] In some embodiments, W is -NH- or -CH2-.

[0085] In some embodiments, R15is C1-C4alkyl or C1-C4deuteroalkyl.

[0086] In some embodiments, R15is -CH3or -CD3.

[0087] In some embodiments, R15is unsubstituted or substituted C3-C6cycloalkyl.

[0088] In some embodiments, R15is cyclopropyl.

[0089] In some embodiments,each REis independently hydrogen, fluoro, chloro, C1-C4alkyl, C2-C4alkynyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C4alkyl and C1-C4deuteroalkyl; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-.

[0090] In some embodiments, p is 1.

[0091] In some embodiments, R11 is hydrogen.

[0092] In some embodiments, R12 is -C(=O)R13.

[0093] In some embodiments,R13is unsubstituted or substitutedC1-C6 alkyl, unsubstituted orsubstituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-memberedmonocyclic heterocycloalkyl.

[0094] In some embodiments,R13is unsubstituted or substituted cyclopropyl.

[0095] In some embodiments,R13is unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl. In some embodiments, R13is unsubstituted or substituted monocyclic 5- membered heteroaryl. In some embodiments, R13is monocyclic 5-membered heteroaryl substituted with 1 to 3 groups independently selected from halogen, C1-C6alkyl, and -CN. In some embodiments, R13is 1-methyl-1H-pyrazol-4-yl. In some embodiments, R13is unsubstituted or substituted monocyclic 6-membered heteroaryl.

[0096] In some embodiments, R12 is an unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl.

[0097] In some embodiments, if R12 is substituted then it is substituted with 1 to 3 groupsindependently selected from halogen, C1-C6alkyl, and -CN.

[0098] In some embodiments, R12 is 1-methyl-1H-pyrazol-4-yl

[0099] In some embodiments, p is 0.

[0100] In some embodiments, q is 1.

[0101] In some embodiments,RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl,unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl.

[0102] In some embodiments,RDis unsubstituted or substituted heteroaryl.

[0103] In some embodiments,RDis.

[0104] In some embodiments,RDis

[0105] In some embodiments,RDis

[0106] In some embodiments, q is 0.

[0107] In some embodiments, m is 0.

[0108] In some embodiments, m is 1.

[0109] In some embodiments, m is 0-2.

[0110] In some embodiments,

[0111] In some embodiments,

[0112] In some embodiments,

[0113] In some embodiments,

[0114] In some embodiments,

[0115] In some embodiments,X1 is CR21, X2 is CR22, and X3 is CR23;or X1is CR21, X2is CR22, and X3is N; or X1is CR21, X2is N, and X3is CR23; or X1is CR21, X2is N, and X3is N; or X1is N, X2is CR22, and X3is CR23; or X1is N, X2is CR22, and X3is N; or X1 is N, X2 is N, and X3 is CR23.

[0116] In some embodiments,X1is CH, C-CH3, or CF, X2is CH, C-CH3, or CF, and X3is CH, C-CH3, or CF; or X1is CH, C-CH3, or CF, X2is CH, C-CH3, or CF, and X3is N.

[0117] In some embodiments,X1is CH, X2is CH, and X3is CH; or X1is CH, X2is CH, and X3is N.

[0118] In some embodiments,X4is CR24, X6is CR26, and X7is CR27; or X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N; orX4is N,X6is N, andX7is CR27.

[0119] In some embodiments,X4is CR24, X6is CR26, and X7is CR27; or X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N.

[0120] In some embodiments,X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N; orX4is N,X6is N, andX7is CR27.

[0121] In some embodiments,X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N.

[0122] In some embodiments,X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X4is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

[0123] In some embodiments,X4is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X4is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

[0124] In some embodiments,X4is CH, X6is N, and X7is CH.

[0125] In some embodiments,X4is CH, X6is CF, and X7is CH.

[0126] In some embodiments,X4is N, X6is CH, and X7is CH.

[0127] In some embodiments,X4is CH, X6is CH, and X7is N.

[0128] In some embodiments, Y is -N(R7)- or -O-.

[0129] In some embodiments, Y is -N(R7)-.

[0130] In some embodiments, R7 is hydrogen orC1-C6 alkyl.

[0131] In some embodiments, R7 isC1-C6 alkyl.

[0132] In some embodiments, R7 is -CH3.

[0133] In some embodiments, R3 is hydrogen, deuterium, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl.

[0134] In some embodiments, R3 is hydrogen, deuterium, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl.

[0135] In some embodiments, R3 is hydrogen, deuterium, halogen,C1-C6 alkyl,C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.

[0136] In some embodiments, R3 is hydrogen, deuterium, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec- butyl, n-pentyl, 2-methylbutan-2-yl, 2,2-dimethylpropyl, 3-methylbutyl, pentan-2-yl, pentan-3- yl, 3-methylbutan-2-yl, 2-methylbutyl, -CH2OCH3,, .

[0137] In some embodiments, R3 is hydrogen, -CH3, -CH2CH3, cyclopentyl, cyclopropyl, or 3-methylbut-2-yl.

[0138] In some embodiments, R3 is hydrogen or deuterium.

[0139] In some embodiments, R3 is -CH3. In some embodiments, R3 is -CH2CH3.

[0140] In some embodiments, R4 is hydrogen, deuterium, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl.

[0141] In some embodiments, R4 is hydrogen, deuterium, halogen,C1-C6 alkyl,C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.

[0142] In some embodiments, R4 is hydrogen or deuterium.

[0143] In some embodiments, R4 is hydrogen.

[0144] In some embodiments, R3 and R4 are taken together with the carbon atom to whichthey are attached to form an unsubstituted or substituted C3-C6cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene.

[0145] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(O)O-*, -OC(O)- *, -C(=S)O-*, -OC(=S)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0146] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(O)O-*, -OC(O)-*, -CRy=CRy-*, -C(O)C(Rz)2- *, -C(Rz)2C(O)-*, -C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, - C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0147] In some embodiments,RAis -C(=O)NRx-* or -C(=O)-; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; where * denotes the attachment point to L.

[0148] In some embodiments,RAis -C(=O)NRx-*; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; where * denotes the attachment point to L.

[0149] In some embodiments,RAis -C(=O)NRx-*; each Rxis independently hydrogen or methyl; where * denotes the attachment point to L.

[0150] In some embodiments,RAis -C(=O)NRx-*; each Rxis independently methyl; where * denotes the attachment point to L.

[0151] In some embodiments,RAis -C(=O)NRx-*; each Rxis independently hydrogen; where * denotes the attachment point to L.

[0152] In some embodiments,L is absent, or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, or C1-C6alkyl; and n is 1.

[0153] In some embodiments, RB unsubstituted or substituted phenyl or unsubstituted orsubstituted pyridinyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORa, -S(O)2Rb, -NRaS(O)2Rb, or -S(O)2N(Ra)2.

[0154] In some embodiments, RB unsubstituted or substituted phenyl or unsubstituted orsubstituted pyridinyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORa, -S(O)2Rb, or -S(O)2N(Ra)2.

[0155] In some embodiments,each Rais independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0156] In some embodiments, R1 is

[0158] In some embodiments,, and * denotes the attachment point to Y.

[0159] In some embodiments,and * denotes the attachment point to Y.

[0160] In some embodiments,, and * denotes the attachment point to Y.

[0161] In some embodiments,is , and * denotes the attachment point to Y.

[0162] In some embodiments,is, and * denotes the attachment point to Y.

[0163] In some embodiments, the compound is a compound selected from Table 1.

[0164] For any and all of the embodiments, substituents are selected from among a subset ofthe listed alternatives. For example, in some embodiments, Y is -N(R7)-. In other embodiments, Y is -CH2-. In other embodiments, Y is -O-. In other embodiments, Y is -S-. In other embodiments, Y is -S(O)-. In other embodiments, Y is -S(O)2-.

[0165] In some embodiments, Ring A is a heterocyclic ring. In some embodiments, Ring A isa monocyclic heterocyclic ring. In some embodiments, Ring A is a bicyclic heterocyclic ring.

[0166] In some embodiments, Ring A is a heteroaryl. In some embodiments, Ring A is amonocyclic heteroaryl or a bicyclic heteroaryl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a bicyclic heteroaryl.

[0167] In some embodiments, Ring A is selected from the group consisting of pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzoxazole, benzisoxazole, furopyridine, furopyrimidine, furopyridazine, furopyrazine, isoxazolopyridine, isoxazolopyridazine, isoxazolopyrimidine, isoxazolopyrazine, oxazolopyridine, oxazolopyridazine, oxazolopyrimidine, oxazolopyrazine, oxazolotriazine, indolyl, azaindolyl, diazaindolyl, indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridine, benzotriazolyl, triazolopyridine, benzothiophenyl, thienopyridine, thienopyridazine, thienopyrimidine, thienopyrazine, benzothiazole, thiazolopyridine, thiazolopyridazine, thiazolopyrimidine, thiazolopyrazine, benzisothiazole, isothiazolopyridine, isothiazolopyridazine, isothiazolopyrimidine, isothiazolopyrazine, purinyl, indolizinyl, imidazolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, triazolopyridinyl, triazolopyridazinyl, triazolopyrimidinyl, triazolopyrazinyl, imidazopyrimidinonyl, quinolizinyl, quinolizinonyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyridazine, pyridopyrimidine, pyridopyrazine, pteridinyl, and naphthyridinonyl.

[0168] In some embodiments, Ring A is selected from the group consisting of pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzoxazole, benzisoxazole, furopyridine, furopyrimidine, furopyridazine,furopyrazine, isoxazolopyridine, isoxazolopyridazine, isoxazolopyrimidine, isoxazolopyrazine, oxazolopyridine, oxazolopyridazine, oxazolopyrimidine, oxazolopyrazine, oxazolotriazine, indolyl, azaindolyl, diazaindolyl, indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridine, benzotriazolyl, triazolopyridine, benzothiophenyl, thienopyridine, thienopyridazine, thienopyrimidine, thienopyrazine, benzothiazole, thiazolopyridine, thiazolopyridazine, thiazolopyrimidine, thiazolopyrazine, benzisothiazole, isothiazolopyridine, isothiazolopyridazine, isothiazolopyrimidine, isothiazolopyrazine, purinyl, indolizinyl, imidazolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, triazolopyridinyl, triazolopyridazinyl, triazolopyrimidinyl, triazolopyrazinyl, imidazopyrimidinonyl, quinolizinyl, quinolizinonyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyridazine, pyridopyrimidine, pyridopyrazine, pteridinyl, and naphthyridinonyl.

[0169] In some embodiments, Ring A is selected from the group consisting of benzofuranyl,benzoxazole, benzisoxazole, furopyridine, furopyrimidine, furopyridazine, furopyrazine, isoxazolopyridine, isoxazolopyridazine, isoxazolopyrimidine, isoxazolopyrazine, oxazolopyridine, oxazolopyridazine, oxazolopyrimidine, oxazolopyrazine, oxazolotriazine, indolyl, azaindolyl, diazaindolyl, indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridine, benzotriazolyl, triazolopyridine, benzothiophenyl, thienopyridine, thienopyridazine, thienopyrimidine, thienopyrazine, benzothiazole, thiazolopyridine, thiazolopyridazine, thiazolopyrimidine, thiazolopyrazine, benzisothiazole, isothiazolopyridine, isothiazolopyridazine, isothiazolopyrimidine, isothiazolopyrazine, purinyl, indolizinyl, imidazolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, triazolopyridinyl, triazolopyridazinyl, triazolopyrimidinyl, triazolopyrazinyl, imidazopyrimidinonyl, quinolizinyl, quinolizinonyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyridazine, pyridopyrimidine, pyridopyrazine, pteridinyl, and naphthyridinonyl.

[0170] In some embodiments, Ring A is selected from the group consisting of pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, triazolopyrimidinyl, naphthyridinonyl, and imidazopyrimidinonyl.

[0171] In some embodiments, Ring A is selected from the group consisting of pyridinyl,imidazolyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, triazolopyrimidinyl, naphthyridinonyl, and imidazopyrimidinonyl.

[0172] In some embodiments, Ring A is selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolizinyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, triazolopyrimidinyl, naphthyridinonyl, and imidazopyrimidinonyl.

[0173] In some embodiments, Ring A is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, triazinyl, indolizinyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, triazolopyrimidinyl, naphthyridinonyl, and imidazopyrimidinonyl.

[0174] In some embodiments, Ring A is a monocyclic heterocyclic ring. In someembodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a 6- membered monocyclic heteroaryl or a 5-membered monocyclic heteroaryl.

[0175] In some embodiments, Ring A is a pyridine, pyrimidine, pyridazine, pyrazine ortriazine ring. In some embodiments, Ring A is a pyridine ring. In some embodiments, Ring A is a pyrimidine ring. In some embodiments, Ring A is a pyridazine ring. In some embodiments, Ring A is a pyrazine ring. In some embodiments, Ring A is a triazine ring.

[0176] In some embodiments,, , In some embodiments,is.

[0177] In some embodiments, Ring A is a bicyclic heterocyclic ring.,

[0180] In some embodiments,wherein: each REis independently hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1- C6fluoroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, - S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-.

[0181] In some embodiments,wherein: each REis independently hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, - S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-.

[0182] In some embodiments,wherein: Z is N or CH; and each REis independently hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1- C6fluoroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, - S(O)2R19, and -S(O)2N(R18)2.

[0183] In some embodiments,wherein: Z is N or CH; and REis hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6- membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, - NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selectedfrom the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6- membered heterocycloalkyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2.

[0184] In some embodiments,wherein: Z is N or CH.

[0185] In some embodiments,.

[0187] In some embodiments, Ring A is a carbocyclic ring. In some embodiments, Ring A is amonocyclic or bicyclic carbocyclic ring. In some embodiments, Ring A is a cycloalkyl ring or an aryl ring. In some embodiments, Ring A is a cycloalkyl ring. In some embodiments, Ring A is a monocyclic cycloalkyl ring. In some embodiments, Ring A is a C3-C6cycloalkyl ring. In some embodiments, Ring A is a bicyclic cycloalkyl ring. In some embodiments, Ring A is an aryl ring. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is naphthyl.

[0188] In some embodiments,RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl,unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl.

[0189] In some embodiments,RDis unsubstituted or substituted carbocyclyl or unsubstitutedor substituted heterocyclyl. In some embodiments, RDis unsubstituted or substituted carbocyclyl. In some embodiments, unsubstituted or substituted heterocyclyl. In some embodiments, RDis unsubstituted or substituted 4 to 10-membered heterocyclyl. In some embodiments, RDis unsubstituted or substituted 5-membered heterocyclyl. In some embodiments, RDis heteroaryl. In some embodiments, RDis 5-membered heteroaryl. In some embodiments, RDis 6-membered heteroaryl. In some embodiments, RDis substituted or unsubstituted imidazolyl. In some embodiments, RDis substituted or unsubstituted imidazolyl. In some embodiments, RDis substituted or unsubstituted triazolyl. In some embodiments, RDis substituted or unsubstituted oxadiazolyl.

[0190] In some embodiments, ifRDis substituted then it is substituted with 1 or more groupsindependently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, - NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0191] In some embodiments, ifRDis substituted then it is substituted with 1 or more groupsindependently selected from halogen, unsubstituted or substituted C1-C3alkyl, unsubstituted or substituted C1-C3deuteroalkyl, unsubstituted or substituted C1-C3fluoroalkyl, unsubstituted or substituted C2-C3alkenyl, unsubstituted or substituted C2-C3alkynyl, unsubstituted or substituted C1-C3heteroalkyl, unsubstituted or substituted C3-C4carbocyclyl, unsubstituted or substituted 4 to 5-membered heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0192] In some embodiments, ifRDis substituted then it is substituted with 1 or more groupsindependently selected from -F, -Cl, C1-C3alkyl, C1-C3deuteroalkyl, and C1-C3fluoroalkyl,

[0193] In some embodiments, ifRDis substituted then it is substituted with 1 or more groupsindependently selected from -CH3.some embodiments, RDis. In some embodiments, RDis. In some embodiments, RDis. In some embodiments, RDis.

[0196] In some embodiments,W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; each R17is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl.

[0197] In some embodiments, W is -NR16-, -C(R17)2- or -O-; R16 is hydrogen or C1-C4 alkyl;and each R17is independently hydrogen or C1-C4alkyl.

[0198] In some embodiments, R15 and R16 are taken together with the N atom to which theyare attached to form a substituted or unsubstituted N-containing heterocycloalkyl.

[0199] In some embodiments, W is -NR16-; R16 is hydrogen or C1-C4 alkyl. In someembodiments, W is -NR16-; R16is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. In some embodiments, W is -NR16-; R16is hydrogen, methyl, or ethyl. Insome embodiments, W is -NH- or -N(CH3)-. In some embodiments, W is -NH-. In some embodiments, W is -N(CH3)-.

[0200] In some embodiments, W is -NH-, -N(CH3)-, -O-, or -CH2-. In some embodiments, Wis -NH- or -CH2-. In some embodiments, W is -O-. In some embodiments, W is -CH2-.

[0201] In some embodiments, R15 is hydrogen, unsubstituted or substitutedC1-C6 alkyl,unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl. In some embodiments, R15is hydrogen, unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4alkoxy, unsubstituted or substituted C3-C4cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl.

[0202] In some embodiments, R15 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4fluoroalkyl. In some embodiments, R15is C1-C4alkyl. In some embodiments, R15is C1-C4deuteroalkyl. In some embodiments, R15is -CH3or -CD3. In some embodiments, R15is -CH3. In some embodiments, R15is -CD3.

[0203] In some embodiments, R15 is unsubstituted or substitutedC1-C6 alkyl, unsubstituted orsubstituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl. In some embodiments, R15is unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4alkoxy, unsubstituted or substituted C3-C4cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl. In some embodiments, R15is C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl.

[0204] In some embodiments, W is -NH- or -CH2-; and R15 is -CH3 or -CD3.

[0205] In some embodiments, the compound is a compound of Formula (III-1):Formula (III-1).

[0206] In some embodiments, the compound is a compound of Formula (IIIa-1):Formula (IIIa-1).

[0207] In some embodiments, the compound is a compound of Formula (III-1-N):Formula (III-1-N).

[0208] In some embodiments, the compound is a compound of Formula (IIIa-1-N):Formula (IIIa-1-N).

[0209] In some embodiments, the compound is a compound of Formula (IV-1):Formula (IV-1).

[0210] In some embodiments, the compound is a compound of Formula (IVa-1):Formula (IVa-1).

[0211] In some embodiments, the compound is a compound of Formula (IV-1-N):Formula (IV-1-N).

[0212] In some embodiments, the compound is a compound of Formula (IVa-1-N):Formula (IVa-1-N).

[0213] In some embodiments, each RE is independently hydrogen, halogen,C1-C6 alkyl,C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6- membered heterocycloalkyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and - S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-. In some embodiments, each REis independently hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6- membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, - NR18C(O)R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, unsubstituted orsubstituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2.

[0214] In some embodiments, each RE is independently hydrogen, halogen,C1-C6 alkyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, and 3- to 6-membered heterocycloalkyl; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-. In some embodiments, each REis independently hydrogen, halogen, C1-C6alkyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, - N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C6alkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, and 3- to 6-membered heterocycloalkyl.

[0215] In some embodiments, each RE is independently hydrogen, fluoro, chloro, C1-C4 alkyl,C2-C4alkynyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C4alkyl and C1-C4deuteroalkyl; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-. In some embodiments, each REis independently hydrogen, fluoro, chloro, C1-C4alkyl, C2-C4alkynyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C4alkyl and C1-C4deuteroalkyl.

[0216] In some embodiments, two RE attached to the same aliphatic carbon atom are takentogether with the carbon atom to which they are attached to form -C(O)-.

[0217] In some embodiments,R11is hydrogen orC1-C6 alkyl. In some embodiments,R11ishydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl. In some embodiments, R11is hydrogen or C1-C4alkyl. In some embodiments, R11is C1-C4alkyl. In some embodiments, R11is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. In some embodiments, R11is hydrogen.

[0218] In some embodiments, R12 is -C(=O)R13, -C(=O)NR13R14, or -C(=O)OR13. In someembodiments, R12is -C(=O)R13. In some embodiments, R12is -C(=O)NR13R14. In some embodiments, R12is -C(=O)OR13.

[0219] In some embodiments,R13is hydrogen, unsubstituted or substitutedC1-C6 alkyl,unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocycliccarbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substitutedmonocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R13is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C10monocyclic or bicyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclicheterocycloalkyl. In some embodiments, R13is unsubstituted or substituted C1-C6alkyl,unsubstituted or substitutedC3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl. In some embodiments, R13is unsubstituted orsubstitutedC1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted orsubstituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with 1 or more groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.

[0220] In some embodiments,R13is unsubstituted or substituted monocyclic carbocyclyl,unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclicheterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl.

[0221] In some embodiments,R13is unsubstituted or substituted bicyclic carbocyclyl,unsubstituted or substituted bicyclic heterocyclyl.

[0222] In some embodiments,R13is unsubstituted or substituted spirocyclic carbocyclyl,unsubstituted or substituted spirocyclic heterocyclyl.

[0223] In some embodiments,R13is unsubstituted or substituted spirocyclic carbocyclyl.

[0224] In some embodiments,R13is unsubstituted spirocyclic carbocyclyl.

[0225] In some embodiments,R13is

[0226] In some embodiments,R13is spirocyclic C5-C10 carbocyclyl optionally substituted with-F.

[0227] In some embodiments,R13is unsubstituted or substituted C3-C4 cycloalkyl. In someembodiments, R13is unsubstituted or substituted cyclopropyl. In some embodiments, R13is cyclopropyl substituted with one or more fluorines.

[0228] In some embodiments,R13is unsubstituted or substituted aryl.

[0229] In some embodiments,R13is unsubstituted or substituted heteroaryl. In someembodiments, R13is unsubstituted or substituted pyrazolyl.

[0230] In some embodiments, R14 is hydrogen,C1-C6 alkyl,C1-C6 deuteroalkyl, orC1-C6fluoroalkyl. In some embodiments, R14is hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl. In some embodiments, R14is hydrogen. In some embodiments, R14is hydrogen or C1-C4alkyl. In some embodiments, R14is C1-C4alkyl. In some embodiments, R14is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. In some embodiments, R14is hydrogen.

[0231] In some embodiments,R13and R14 are taken together with the intervening atoms towhich they are attached to form an unsubstituted or substituted heterocyclyl. In someembodiments, R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl. In some embodiments, R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted spirocyclic heterocyclyl.

[0232] In some embodiments, R12 is an unsubstituted or substituted heterocyclyl orunsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2. In some embodiments, R12is an unsubstituted or substituted heterocyclyl or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 to 3 groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1- C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, - CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0233] In some embodiments, R12 is an unsubstituted or substituted carbocyclyl. In someembodiments, R12is an unsubstituted or substituted monocyclic or an unsubstituted or substituted bicyclic carbocyclyl.

[0234] In some embodiments, R12 is unsubstituted or substituted cycloalkyl or unsubstituted orsubstituted aryl. In some embodiments, R12is unsubstituted or substituted monocyclic cycloalkyl, unsubstituted or substituted bicyclic monocyclic cycloalkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl.

[0235] In some embodiments, R12 is unsubstituted or substituted cycloalkyl. In someembodiments, R12is unsubstituted or substituted monocyclic cycloalkyl. In some embodiments, R12is unsubstituted or substituted C3-C6cycloalkyl. In some embodiments, R12is unsubstituted or substituted bicyclic cycloalkyl.

[0236] In some embodiments, R12 is unsubstituted or substituted aryl. In some embodiments,R12is unsubstituted or substituted phenyl. In some embodiments, R12is unsubstituted or substituted naphthyl.

[0237] In some embodiments, R12 is an unsubstituted or substituted heterocyclyl. In someembodiments, R12is an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, R12is an unsubstituted or substituted bicyclic heterocyclyl.

[0238] In some embodiments, R12 is an unsubstituted or substituted heteroaryl. In someembodiments, R12is an unsubstituted or substituted monocyclic heteroaryl or an unsubstituted or substituted bicyclic heteroaryl. In some embodiments, R12is an unsubstituted or substituted monocyclic heteroaryl. In some embodiments, R12is an unsubstituted or substituted bicyclic heteroaryl.

[0239] In some embodiments, R12 is an unsubstituted or substituted monocyclic heteroaryl. Insome embodiments, R12is an unsubstituted or substituted monocyclic 5-membered heteroaryl. In some embodiments, R12is an unsubstituted or substituted monocyclic 6-membered heteroaryl.

[0240] In some embodiments, R12 is an unsubstituted or substituted pyrrolyl, unsubstituted orsubstituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted furyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted furazanyl, unsubstituted or substituted thienyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted triazinyl. In some embodiments, R12is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted furyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted furazanyl, unsubstituted or substituted thienyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted triazinyl. In some embodiments, R12is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl. In some embodiments, R12is an unsubstituted or substituted pyridinyl. In some embodiments, R12is an unsubstituted or substituted pyrimidinyl.

[0241] In some embodiments, R12 is an unsubstituted or substitutedC1-C6 alkyl, unsubstitutedor substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl. In some embodiments, R12is an unsubstituted or substituted C1-C6alkyl, or unsubstituted or substituted C1-C6heteroalkyl. In some embodiments, R12is an unsubstituted or substituted C1-C4alkyl, or unsubstituted or substituted C1-C4heteroalkyl. In some embodiments, R12is an unsubstituted or substituted C1-C4alkyl. In some embodiments, R12is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. In some embodiments, R12is methyl.

[0242] In some embodiments, if R12 is substituted then it is substituted with 1 or more groupsindependently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, unsubstituted or substituted C3-C6monocycliccycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl, -CN,-OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2. In some embodiments, if R12is substituted then it is substituted with 1 to 3 groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, unsubstituted or substituted C3-C6monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclicheterocycloalkyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, - NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2. In some embodiments, if R12is substituted then it is substituted with 1 to 3 groups independently selected from halogen, C1-C6alkyl, and -CN.

[0243] In some embodiments, R12 is 5-fluoropyridin-2-yl, 6-cyanopyridin-2-yl, 2,6-dimethylpyrimidin-4-yl, 5-(morpholinomethyl)pyridin-2-yl, or 4-((4-(methylsulfonyl)piperidin- 1-yl)methyl)phenyl. In some embodiments, R12is 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-2- yl, 6-cyanopyridin-2-yl, or 2,6-dimethylpyrimidin-4-yl. In some embodiments, R12is 5- fluoropyridin-2-yl, 6-cyanopyridin-2-yl, or 2,6-dimethylpyrimidin-4-yl. In some embodiments, R12is 5-fluoropyridin-2-yl. In some embodiments, R12is 6-cyanopyridin-2-yl. In some embodiments, R12is 2,6-dimethylpyrimidin-4-yl. In some embodiments, R12is 5- (morpholinomethyl)pyridin-2-yl. In some embodiments, R12is 4-((4-(methylsulfonyl)piperidin- 1-yl)methyl)phenyl.In some embodiments, R12is .[,

[0255] In some embodiments,X1 is CR21, X2 is CR22, and X3 is CR23;or X1is CR21, X2is CR22, and X3is N; or X1is CR21, X2is N, and X3is CR23; or X1is CR21, X2is N, and X3is N; or X1is N, X2is CR22, and X3is CR23; or X1is N, X2is CR22, and X3is N;or X1 is N, X2 is N, and X3 is CR23.

[0256] In some embodiments, X1 is CR21, X2 is CR22, and X3 is CR23; or X1 is CR21, X2 isCR22, and X3is N.

[0257] In some embodiments, X1 is CR21, X2 is CR22, and X3 is CR23. In some embodiments,X1is CR21, X2is CR22, and X3is N. In some embodiments, X1is CR21, X2is N, and X3is CR23. In some embodiments, X1is CR21, X2is N, and X3is N. In some embodiments, X1is N, X2is CR22, and X3is CR23. In some embodiments, X1is N, X2is CR22, and X3is N. In someembodiments, X1 is N, X2 is N, and X3 is CR23.

[0258] In some embodiments, R21, R22, and R23 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R21, R22, and R23are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R21, R22, and R23are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R21, R22, and R23are each independently hydrogen, -F, -Cl, -Br, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R21, R22, and R23are each independently hydrogen, -F, or CH3. In some embodiments, R21, R22, and R23are each hydrogen. In some embodiments, R21, R22, and R23are each hydrogen, halogen, -OMe, N-piperidinyl, 2,6-dimethylphenyl, -C(O)NHCH3, or -C(O)OCH3. In some embodiments, R21, R22, and R23are each hydrogen, -OMe, N-piperidinyl, 2,6-dimethylphenyl, -C(O)NHCH3, or -C(O)OCH3.

[0259] In some embodiments, X1 is CH, C-CH3, or CF, X2 is CH, C-CH3, or CF, and X3 isCH, C-CH3, or CF; or X1is CH, C-CH3, or CF, X2is CH, C-CH3, or CF, and X3is N. In some embodiments, X1is CH, C-CH3, or CF, X2is CH, C-CH3, or CF, and X3is CH, C-CH3, or CF. In some embodiments, X1is CH, C-CH3, or CF, X2is CH, C-CH3, or CF, and X3is N.

[0260] In some embodiments,X4is CR24,X6is CR26, andX7is CR27;or X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N;orX4is N,X6is N, andX7is CR27.

[0261] In some embodiments,X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N;orX4is N,X6is N, andX7is CR27;or X4is N, X6is N, and X7is N.

[0262] In some embodiments,X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N;orX4is N,X6is N, andX7is CR27.

[0263] In some embodiments,X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N.

[0264] In some embodiments,X4is CR24, X6is CR26, and X7is CR27;or X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N;orX4is N,X6is N, andX7is CR27.

[0265] In some embodiments,X4is CR24,X6is N, andX7is CR27. In some embodiments,X4is N, X6is CR26, and X7is CR27. In some embodiments, X4is CR24, X6is CR26, and X7is N.

[0266] In some embodiments, R24, R26, and R27 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R26, and R27are each independently hydrogen, -F, -Cl, -Br, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R26, and R27are each independently hydrogen, -F, or CH3. In some embodiments, R24, R26, and R27are each hydrogen.

[0267] In some embodiments,X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X4is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

[0268] In some embodiments,X4is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X4is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

[0269] In some embodiments,X4is CH, C-CH3, or CF,X6is N, andX7is CH, C-CH3, or CF.

[0270] In some embodiments,X4is N,X6is CH, C-CH3, or CF, andX7is CH, C-CH3, or CF.

[0271] In some embodiments,X4is CH, C-CH3, or CF,X6is CH, C-CH3, or CF, andX7is N.

[0272] In some embodiments, R24, R25, R26, and R27 are each independently hydrogen,halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R25, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, -CN, -OH, -OR19, or -N(R18)2. In some embodiments, R24, R25, R26, and R27are each independently hydrogen, halogen, C1-C3alkyl, C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R25, R26, and R27are each independently hydrogen, -F, -Cl, -Br, C1-C3alkyl,C1-C3fluoroalkyl, or -CN. In some embodiments, R24, R25, R26, and R27are each independently hydrogen, -F, or CH3. In some embodiments, R24, R25, R26, and R27are each hydrogen.

[0273] In some embodiments, Y is -N(R7)-, -O-, or -S-. In some embodiments, Y is -N(R7)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, Y is -N(R7)-, or -O-. In some embodiments, Y is - N(R7)-. In some embodiments, Y is -O-. In some embodiments, Y is -S-. In some embodiments, R7is hydrogen or C1-C6alkyl. In some embodiments, R7is C1-C6alkyl. In some embodiments, R7is C1-C4alkyl. In some embodiments, R7is hydrogen, methyl, ethyl, n-propyl, i-propyl, n- butyl, sec-butyl, i-butyl, or t-butyl. In some embodiments, R7is -CH3. In some embodiments, R7is hydrogen, cyclopropyl, or -CH3. In some embodiments, R7is cyclopropyl. In some embodiments, R7is hydrogen, C3-C6cycloalkyl, or C1-C6alkyl.

[0274] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or - S(O)2N(R18)2.

[0275] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl.

[0276] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl.

[0277] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,halogen, unsubstituted C1-C6alkyl, unsubstituted C1-C6deuteroalkyl, unsubstituted C1-C6fluoroalkyl, unsubstituted C1-C6heteroalkyl, unsubstituted C3-C6cycloalkyl, unsubstituted monocyclic heterocycloalkyl, unsubstituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted -(C1- C3alkylene)-heterocyclyl.

[0278] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, - NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; or R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, (C1-C3alkoxy)C1-C3alkyl, or C3-C6cycloalkyl; or R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3- C6cycloalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C5alkyl, C1-C5deuteroalkyl, C1-C5heteroalkyl, or C3-C5cycloalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4heteroalkyl, or C3-C4cycloalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, or substituted or unsubstituted 4- to 6- membered heterocycloalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl.

[0279] In some embodiments, R3 and R4 are each independently hydrogen, deuterium,C1-C6alkyl, or C1-C6deuteroalkyl; or R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C6alkyl, or C1-C6deuteroalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C3alkyl, C1-C3deuteroalkyl, or C1- C3heteroalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, C1-C3alkyl, or C1-C3deuteroalkyl. In some embodiments, R3and R4are each independently hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, 2-methylbutan-2-yl, 2,2- dimethylpropyl, 3-methylbutyl, pentan-2-yl, pentan-3-yl, 3-methylbutan-2-yl, 2-methylbutyl, - CH2OCH3,. In some embodiments, R3and R4are each independently hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, 3-methylbut-2-yl, or -CH2OCH3. In some embodiments, R3and R4are each independently hydrogen, deuterium, cyclopropyl, methyl, ethyl, or -CH2OCH3. In some embodiments, R3andR4 are each independently hydrogen, deuterium, -CH3, or -CH2CH3. In some embodiments, R3and R4are each independently hydrogen, deuterium, or -CH3. In some embodiments, R3and R4are each independently hydrogen or deuterium. In some embodiments, R3and R4are each independently hydrogen or -CH3. In some embodiments, R3and R4are each independently hydrogen, -CH3, -CH2CH3, cyclopentyl, cyclopropyl, or 3-methylbut-2-yl.

[0280] In some embodiments, R3 and R4 are taken together with the carbon atom to whichthey are attached to form an unsubstituted or substituted C3-C6cycloalkylene or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C4cycloalkylene or an unsubstituted or substituted 3- to 4-membered heterocycloalkylene. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered heterocycloalkylene. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 4-membered heterocycloalkylene. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form an oxetane ring. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form a cyclopropane ring.

[0281] In some embodiments, R3 and R4 are taken together with the carbon atom to whichthey are attached to form -C(O)-.

[0282] In some embodiments, R3 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, - SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0283] In some embodiments, R3 is hydrogen, deuterium, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl.

[0284] In some embodiments, R3 is hydrogen, deuterium, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl.

[0285] In some embodiments, R3 is hydrogen, deuterium, unsubstitutedC1-C6 alkyl,unsubstituted C1-C6deuteroalkyl, unsubstituted C1-C6fluoroalkyl, unsubstituted C1-C6heteroalkyl, unsubstituted C3-C6cycloalkyl, unsubstituted monocyclic heterocycloalkyl, unsubstituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted -(C1-C3alkylene)-heterocyclyl.

[0286] In some embodiments, R3 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or - S(O)2N(R18)2. In some embodiments, R3is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments, R3is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, (C1-C3alkoxy)C1-C3alkyl, or C3-C6cycloalkyl. In some embodiments, R3is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments, R3is hydrogen, deuterium, C1-C5 alkyl, C1-C5 deuteroalkyl, C1-C5 heteroalkyl, or C3-C5 cycloalkyl. In some embodiments, R3is hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4heteroalkyl, or C3-C4cycloalkyl. In some embodiments, R3is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.

[0287] In some embodiments, R3 is hydrogen, deuterium, substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, or substituted or unsubstituted 4- to 6-membered heterocycloalkyl. In some embodiments, R3is hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl.

[0288] In some embodiments, R3 is hydrogen, deuterium,C1-C6 alkyl, orC1-C6 deuteroalkyl.In some embodiments, R3is hydrogen, deuterium, C1-C6alkyl, or C1-C6deuteroalkyl. In someembodiments, R3is hydrogen, deuterium, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3heteroalkyl. In some embodiments, R3is hydrogen, deuterium, C1-C3alkyl, or C1-C3deuteroalkyl. In some embodiments, R3is hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, 2- methylbutan-2-yl, 2,2-dimethylpropyl, 3-methylbutyl, pentan-2-yl, pentan-3-yl, 3-methylbutan- 2-yl, 2-methylbutyl, -CH2OCH3,, . In some embodiments, R3is hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, 3-methylbut-2-yl, or -CH2OCH3. In some embodiments, R3is hydrogen, deuterium, cyclopropyl, methyl, ethyl, or -CH2OCH3. In some embodiments, R3is hydrogen, deuterium, -CH3, or - CH2CH3. In some embodiments, R3 is hydrogen, deuterium, or -CH3. In some embodiments, R3is hydrogen or deuterium. In some embodiments, R3is hydrogen or -CH3. R3is hydrogen, -CH3, -CH2CH3, cyclopentyl, cyclopropyl, or 3-methylbut-2-yl. In some embodiments, R3is hydrogen, deuterium, -CH3, -CH2CH3, or cyclopropyl. In some embodiments, R3is hydrogen.

[0289] In some embodiments, R4 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, - SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0290] In some embodiments, R4 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C3alkylene)- heterocyclyl.

[0291] In some embodiments, R4 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl.

[0292] In some embodiments, R4 is hydrogen, deuterium, halogen, unsubstitutedC1-C6 alkyl,unsubstituted C1-C6deuteroalkyl, unsubstituted C1-C6fluoroalkyl, unsubstituted C1-C6heteroalkyl, unsubstituted C3-C6cycloalkyl, unsubstituted monocyclic heterocycloalkyl, unsubstituted -(C1-C3alkylene)-carbocyclyl, or unsubstituted -(C1-C3alkylene)-heterocyclyl.

[0293] In some embodiments, R4 is hydrogen, deuterium, halogen, unsubstituted or substitutedC1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or - S(O)2N(R18)2. In some embodiments, R4is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, (C1-C3alkoxy)C1-C3alkyl, or C3-C6cycloalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C5alkyl, C1-C5deuteroalkyl, C1-C5heteroalkyl, or C3-C5cycloalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4heteroalkyl, or C3-C4cycloalkyl.

[0294] In some embodiments, R4 is hydrogen, deuterium, substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, or substituted or unsubstituted 4- to 6-membered heterocycloalkyl. In some embodiments, R4is hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl.

[0295] In some embodiments, R4 is hydrogen, deuterium,C1-C6 alkyl, orC1-C6 deuteroalkyl.In some embodiments, R4is hydrogen, deuterium, C1-C6alkyl, or C1-C6deuteroalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3heteroalkyl. In some embodiments, R4is hydrogen, deuterium, C1-C3alkyl, or C1-C3deuteroalkyl. In some embodiments, R4is hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, 2- methylbutan-2-yl, 2,2-dimethylpropyl, 3-methylbutyl, pentan-2-yl, pentan-3-yl, 3-methylbutan- 2-yl, 2-methylbutyl, -CH2OCH3,, . In some embodiments, R4is hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, 3-methylbut-2-yl, or -CH2OCH3. In some embodiments, R4is hydrogen, deuterium, cyclopropyl, methyl, ethyl, or -CH2OCH3. In some embodiments, R4is hydrogen, deuterium, -CH3, or - CH2CH3. In some embodiments, R4 is hydrogen, deuterium, or -CH3. In some embodiments, R4is hydrogen or deuterium. In some embodiments, R4is hydrogen or -CH3. R4is hydrogen, -CH3, -CH2CH3, cyclopentyl, cyclopropyl, or 3-methylbut-2-yl. In some embodiments, R4is hydrogen, deuterium, -CH3, -CH2CH3, or cyclopropyl. In some embodiments, R4is hydrogen.

[0296] In some embodiments,R1is RA-L-RB; or R1is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)- heterocyclyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0297] In some embodiments,R1is RA-L-RB; or R1is unsubstituted or substituted C3-C6alkyl, unsubstituted or substituted C3-C6deuteroalkyl, unsubstituted or substituted C3-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)- heterocyclyl, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0298] In some embodiments, R1 is unsubstituted or substitutedC1-C6 alkyl, unsubstituted orsubstituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0299] In some embodiments, R1 is unsubstituted or substituted C2-C6 alkyl, unsubstituted orsubstituted C2-C6deuteroalkyl, unsubstituted or substituted C2-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C2-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0300] In some embodiments, R1 is unsubstituted or substituted carbocyclyl, unsubstituted orsubstituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0301] In some embodiments, R1 is unsubstituted or substituted C3-C6 alkyl, unsubstituted orsubstituted C3-C6deuteroalkyl, unsubstituted or substituted C3-C6fluoroalkyl, unsubstituted or substituted C3-C6alkenyl, unsubstituted or substituted C3-C6alkynyl, unsubstituted or substituted C3-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -C(O)R18, -C(O)OR18, - C(O)N(R18)2, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2.

[0302] In some embodiments, R1 is unsubstituted or substitutedC1-C6 alkyl, unsubstituted orsubstituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted - (C1-C6alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl.

[0303] In some embodiments, R1 is unsubstituted or substituted carbocyclyl, unsubstituted orsubstituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl.

[0304] In some embodiments, R1 is unsubstituted or substituted C2-C6 alkyl, unsubstituted orsubstituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted - (C1-C6alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl.

[0305] In some embodiments, R1 is unsubstituted or substituted C3-C6 alkyl, unsubstituted orsubstituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted - (C1-C6alkylene)-carbocyclyl, or unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl.

[0306] In some embodiments, R1 is unsubstituted or substituted heterocyclyl or unsubstitutedor substituted -(C1-C6alkylene)-heterocyclyl.

[0307] In some embodiments, R1 is unsubstituted or substituted monocyclic carbocyclyl,unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R1is unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted fused bicyclic carbocyclyl, unsubstituted or substituted spirocyclic bicyclic carbocyclyl, unsubstituted or substituted bridged bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted fused bicyclic heterocyclyl, unsubstituted or substituted spirocyclic bicyclic heterocyclyl, or unsubstituted or substituted bridged bicyclic heterocyclyl.

[0308] In some embodiments, R1 is unsubstituted or substituted C3-C6 cycloalkyl,unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -(C1-C3alkylene)-(C3-C6cycloalkyl), or unsubstituted or substituted -(C1-C3alkylene)-(3- to 6-membered heterocycloalkyl).

[0309] In some embodiments, R1 is unsubstituted or substitutedC1-C6 alkyl, unsubstituted orsubstituted tetrahydropyranyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted orsubstituted piperidinyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydropyranyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydrofuranyl, or unsubstituted or substituted - (CH2)-piperidinyl.

[0310] In some embodiments, R1 is unsubstituted or substituted C2-C6 alkyl, unsubstituted orsubstituted tetrahydropyranyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydropyranyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydrofuranyl, or unsubstituted or substituted - (CH2)-piperidinyl.

[0311] In some embodiments, R1 is unsubstituted or substituted C3-C6 alkyl, unsubstituted orsubstituted tetrahydropyranyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydropyranyl, unsubstituted or substituted -(C1-C2alkylene)-tetrahydrofuranyl, or unsubstituted or substituted - (CH2)-piperidinyl.

[0315] In some embodiments, R1 isor

[0316] In some embodiments, R1 is unsubstituted or substituted bicyclic cycloalkyl. In someembodiments, R1is unsubstituted or substituted fused bicyclic cycloalkyl, unsubstituted or substituted bicyclic spirocyclic cycloalkyl, or unsubstituted or substituted bridged bicyclic cycloalkyl. In some embodiments, R1is unsubstituted or substituted spirocyclic bicyclic cycloalkyl.

[0317] In some embodiments, R1 is an unsubstituted or substituted heterocyclyl. In someembodiments, R1is an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, R1is an unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, R1is an unsubstituted or substituted fused bicyclic heterocyclyl, unsubstituted or substituted spirocyclic bicyclic heterocyclyl, or unsubstituted or substituted bridged bicyclic heterocyclyl.

[0318] In some embodiments, R1 is an unsubstituted or substituted carbocyclyl orunsubstituted or substituted heterocyclyl, wherein if R1is substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, - S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl;each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl.

[0319] In some embodiments, R1 is an unsubstituted or substituted heterocyclyl,wherein if R1is substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, - S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl.

[0320] In some embodiments, R1 is an unsubstituted or substituted heterocyclyl,wherein if R1is substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C3alkyl, unsubstituted or substituted C1-C3deuteroalkyl, unsubstituted or substituted C1-C3fluoroalkyl, unsubstituted or substituted C1-C3heteroalkyl, unsubstituted or substituted C3-C4carbocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, -CH3, CH2CH3, CH2F, CHF2, CF3, CH2D, or CHD2; and each Rbis independently -CH3, CH2CH3, CH2F, CHF2, CF3, CH2D, or CHD2.

[0321] In some embodiments, R1 is an unsubstituted or substituted spirocyclic carbocyclyl orunsubstituted or substituted spirocyclic heterocyclyl,

[0322] In some embodiments, R1 is an unsubstituted or substituted spirocyclic carbocyclyl orunsubstituted or substituted spirocyclic heterocyclyl, wherein if R1is substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, - S(O)N(Ra)2, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl.

[0323] In some embodiments, R1 is an unsubstituted or substituted spirocyclic bicyclicheterocyclyl.

[0324] In some embodiments, R1 is an unsubstituted or substituted fused bicyclic heterocyclyl.

[0325] In some embodiments, R1 is an unsubstituted or substituted bridged bicyclicheterocyclyl.

[0326] In some embodiments, R1 is an unsubstituted or substituted tricyclic heterocyclyl.

[0327] In some embodiments, R1 is a 5-membered heterocyclyl. In some embodiments, R1 is a6-membered heterocyclyl. In some embodiments, R1is a 7-membered heterocyclyl. In some embodiments, R1is an 8-membered heterocyclyl. In some embodiments, R1is a 9-membered heterocyclyl. In some embodiments, R1is a 10-membered heterocyclyl.

[0328] In some embodiments, R1 is -RA-L-RB.

[0329] In some embodiments,RAis unsubstituted or substituted carbocyclylene or unsubstituted or substituted heterocyclylene; L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, -N(R6)C(O), -S(O)-, -S(O)2-, or - S(O)2N(R6)-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2.

[0330] In some embodiments,RAis unsubstituted or substituted spirocyclic carbocyclylene or unsubstituted or substituted spirocyclic heterocyclylene.

[0331] In some embodiments,.

[0332] In some embodiments, RB is unsubstituted or substituted C3-C6 cycloalkyl,unsubstituted or substituted 4- to 6-membered heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-membered heteroaryl, or unsubstituted or substituted 6- membered heteroaryl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -SRa, -S(O)Rb, -S(O)2Rb, or -S(O)2N(Ra)2.

[0333] In some embodiments, RB unsubstituted or substituted phenyl or unsubstituted orsubstituted 6-membered heteroaryl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -S(O)2Rb, or -S(O)2N(Ra)2.

[0334] In some embodiments, RB unsubstituted or substituted phenyl or unsubstituted orsubstituted pyridinyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)2, -NRaC(O)Rb, -S(O)2Rb, or -S(O)2N(Ra)2.

[0335] In some embodiments, each Ra is independently hydrogen, substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0336] In some embodiments, each Ra is independently hydrogen,C1-C6 alkyl,C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8- membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0337] In some embodiments,each Rais independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0338] In some embodiments, each Ra is independently hydrogen,C1-C6 alkyl,C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N- containing heterocyclyl; each Rbis independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0339] In some embodiments, each Ra is independently hydrogen, C1-C4 alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C3-C6cycloalkyl, monocyclic 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0340] In some embodiments, two Ra on the same N atom are taken together with the N atomto which they are attached to form a substituted or unsubstituted N-containing heterocyclyl.

[0341] In some embodiments,each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl.

[0342] In some embodiments,each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0343] In some embodiments,each Rbis independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0344] In some embodiments, each Rb is independently C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4fluoroalkyl, C3-C6cycloalkyl, monocyclic 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

[0345] In some embodiments, RB is unsubstituted or substituted carbocyclyl or unsubstitutedor substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, or -S(O)2N(Ra)2.

[0346] In some embodiments, RB is an unsubstituted or substituted carbocyclyl. In someembodiments, RBis an unsubstituted or substituted monocyclic or an unsubstituted or substituted bicyclic carbocyclyl.

[0347] In some embodiments, RB is unsubstituted or substituted cycloalkyl or unsubstituted orsubstituted aryl. In some embodiments, RBis unsubstituted or substituted monocyclic cycloalkyl, unsubstituted or substituted bicyclic cycloalkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl.

[0348] In some embodiments, RB is unsubstituted or substituted cycloalkyl. In someembodiments, RBis unsubstituted or substituted monocyclic cycloalkyl. In some embodiments, RBis unsubstituted or substituted C3-C6cycloalkyl.

[0349] In some embodiments, RB is unsubstituted or substituted bicyclic cycloalkyl. In someembodiments, RBis unsubstituted or substituted fused bicyclic cycloalkyl, unsubstituted or substituted bicyclic spirocyclic cycloalkyl, or unsubstituted or substituted bridged bicyclic cycloalkyl. In some embodiments, RBis unsubstituted or substituted spirocyclic bicyclic cycloalkyl.

[0350] In some embodiments, RB is unsubstituted or substituted aryl. In some embodiments,RBis unsubstituted or substituted phenyl. In some embodiments, RBis unsubstituted or substituted naphthyl.

[0351] In some embodiments, RB is an unsubstituted or substituted heterocyclyl. In someembodiments, RBis an unsubstituted or substituted monocyclic heterocyclyl. In some embodiments, RBis an unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, RBis an unsubstituted or substituted fused bicyclic heterocyclyl, unsubstituted or substituted spirocyclic bicyclic heterocyclyl, or unsubstituted or substituted bridged bicyclic heterocyclyl. In some embodiments, RBis an unsubstituted or substituted spirocyclic bicyclic heterocyclyl.

[0352] In some embodiments, RB is an unsubstituted or substituted heteroaryl. In someembodiments, RBis an unsubstituted or substituted monocyclic heteroaryl or an unsubstituted or substituted bicyclic heteroaryl. In some embodiments, RBis an unsubstituted or substituted monocyclic heteroaryl. In some embodiments, RBis an unsubstituted or substituted bicyclic heteroaryl.

[0353] In some embodiments, RB is an unsubstituted or substituted monocyclic heteroaryl. Insome embodiments, RBis an unsubstituted or substituted monocyclic 5-membered heteroaryl. In some embodiments, RBis an unsubstituted or substituted monocyclic 6-membered heteroaryl.

[0354] In some embodiments, RB is an unsubstituted or substituted pyrrolyl, unsubstituted orsubstituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted furyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted furazanyl, unsubstituted or substituted thienyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted triazinyl. In some embodiments, RBis an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl. In some embodiments, RBis an unsubstituted or substituted pyridinyl. In some embodiments, RBis an unsubstituted or substituted pyrimidinyl.,[0

[0360] In some embodiments,

[0361] In some embodiments, RA is unsubstituted or substituted carbocyclylene orunsubstituted or substituted heterocyclylene. In some embodiments, RAis unsubstituted or substituted cycloalkylene or unsubstituted or substituted heterocycloalkylene. In some embodiments, RAis C3-C6monocyclic cycloalkylene, bicyclic cycloalkylene, 4- to 6-membered monocyclic heterocycloalkylene, or bicyclic heterocycloalkylene. In some embodiments, RAis C3-C6monocyclic cycloalkylene, fused bicyclic cycloalkylene, spirocyclic bicyclic cycloalkylene, bridged bicyclic cycloalkylene, 4- to 6-membered monocyclic heterocycloalkylene, fused bicyclic heterocycloalkylene, spirocyclic bicyclic heterocycloalkylene, or bridged bicyclic heterocycloalkylene. In some embodiments, RAis C3- C6monocyclic cycloalkylene or 4- to 6-membered monocyclic heterocycloalkylene.

[0362] In some embodiments, RA is unsubstituted or substituted cycloalkylene. In someembodiments, RAis C3-C6monocyclic cycloalkylene or bicyclic cycloalkylene. In some embodiments, RAis C3-C6monocyclic cycloalkylene, fused bicyclic cycloalkylene, spirocyclic bicyclic cycloalkylene, or bridged bicyclic cycloalkylene. In some embodiments, RAis C3-C6monocyclic cycloalkylene. In some embodiments, RAis an unsubstituted or substituted cyclobutylene. In some embodiments, RAis an unsubstituted or substituted cyclopentylene. In some embodiments, RAis an unsubstituted or substituted cyclohexylene. In some embodiments, RAis an unsubstituted or substituted bicyclic cycloalkylene. In some embodiments, RAis fused bicyclic cycloalkylene, spirocyclic bicyclic cycloalkylene, or bridged bicyclic cycloalkylene. In some embodiments, RAis fused bicyclic cycloalkylene. In some embodiments, RAis spirocyclic bicyclic cycloalkylene. In some embodiments, RAbridged bicyclic cycloalkylene.

[0363] In some embodiments, RA is unsubstituted or substituted heterocycloalkylene. In someembodiments, RAis 4- to 6-membered monocyclic heterocycloalkylene or bicyclic heterocycloalkylene. In some embodiments, RAis 4- to 6-membered monocyclic heterocycloalkylene, fused bicyclic heterocycloalkylene, spirocyclic bicyclic heterocycloalkylene, or bridged bicyclic heterocycloalkylene. In some embodiments, RAis 4- to 6-membered monocyclic heterocycloalkylene. In some embodiments, RAis an unsubstituted or substituted azetidinylene. In some embodiments, RAis an unsubstituted or substituted pyrrolidinylene. In some embodiments, RAis an unsubstituted or substituted piperidinylene. In some embodiments, RAis an unsubstituted or substituted bicyclic heterocycloalkylene. In some embodiments, RAis fused bicyclic heterocycloalkylene, spirocyclic bicyclic heterocycloalkylene, or bridged bicyclic heterocycloalkylene. In some embodiments, RAis fusedbicyclic heterocycloalkylene. In some embodiments, RAis spirocyclic bicyclic heterocycloalkylene. In some embodiments, RAbridged bicyclic heterocycloalkylene.

[0366] In some embodiments,.

[0367] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl.

[0368] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene.

[0369] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(O)O-*, -OC(O)- *, -C(=S)O-*, -OC(=S)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0370] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0371] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0372] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -S(O)2NRx-*, -NRxS(O)2-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene;where * denotes the attachment point to L.

[0373] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0374] In some embodiments,RAis -C(=O)NRx-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0375] In some embodiments,RAis -C(=O)NRx-*, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

[0376] In some embodiments,RAis unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene.

[0377] In some embodiments, RA is unsubstituted or substituted heterocyclylene. In someembodiments, RAis unsubstituted heterocyclylene. In some embodiments, RAis azetidine-1,3- diyl, pyrrolidine-1,3-diyl, or piperidin-1,4-diyl.

[0378] In some embodiments, RA is unsubstituted or substituted carbocyclylene. In someembodiments, RAis unsubstituted carbocyclene. In some embodiments, RAis cyclobutane-1,3- diyl, cyclopentane-1,3-diyl, or cyclohexane-1,4-diyl.

[0379] In some embodiments, RA is a heteroaryl ring. In some embodiments, RA is a 5-membered heteroaryl ring. In some embodiments, RAis oxazole-diyl, 1,2,4-triazole-diyl, 1,2,4- oxadiazole-diyl, imidazole-diyl, 1,2,3-triazole-diyl, thiazole-diyl, or tetrazole-diyl. In some embodiments, RAis oxazole-diyl, 1,2,4-triazole-diyl, or 1,2,4-oxadiazole-diyl.

[0380] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, or -C(=O)-.

[0381] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(O)O-*, -OC(O)- *, -C(=S)O-*, -OC(=S)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, -C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, or -C(=O)-; where * denotes the attachment point to L.

[0382] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, or -C(=O)-; where * denotes the attachment point to L.

[0383] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, or -C(=O)-; where * denotes the attachment point to L.

[0384] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -S(O)2NRx-*, -NRxS(O)2-*, or -C(=O)-; where * denotes the attachment point to L.

[0385] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, or -C(=O)-; where * denotes the attachment point to L.

[0386] In some embodiments,RAis -C(=O)NRx-* or -NRxC(=O)-*; where * denotes the attachment point to L.

[0387] In some embodiments,RAis -C(=O)NRx-* or -C(=O)-; where * denotes the attachment point to L.

[0388] In some embodiments,RAis -C(=O)NRx-*; where * denotes the attachment point to L.

[0389] In some embodiments,each Rxis independently hydrogen, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl;or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C5 cycloalkyl, or a 3- to 5-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C5cycloalkyl or a 3- to 5-membered heterocycloalkyl.

[0390] In some embodiments, -CRy=CRy-*, is -C(F)=CRy-*. In some embodiments, -CRy=CRy-*, is -C(F)=C(H)-*. In some embodiments, -CRy=CRy-*, is . In someembodiments, -CRy=CRy-*, is . In some embodiments, -CRy=CRy-*, is . In some embodiments, -CRy=CRy-*, is -CRy=C(F)-*. In some embodiments, -C(H)=C(F)-*, is -

[0391] In some embodiments, -C(O)C(Rz)2-* is -C(O)CH2-*, -C(O)CHF-*, or -C(O)CF2-*. Insome embodiments, -C(O)C(Rz)2-* is -C(O)CH2-* or -C(O)CF2-*. In some embodiments, - C(O)C(Rz)2-* is -C(O)CH2-*. In some embodiments, -C(O)C(Rz)2-* is -C(O)CF2-*.

[0392] In some embodiments, -C(Rz)2C(O)-* is -CH2C(O)-*, -CHFC(O)-*, or -CF2C(O)-*. Insome embodiments, -C(Rz)2C(O)-* is -CH2C(O)-* or -CF2C(O)-*. In some embodiments, - C(Rz)2C(O)-* is -CH2C(O)-*. In some embodiments, -C(Rz)2C(O)-* is -CF2C(O)-*.

[0393] In some embodiments, -C(Rw)2NRx-* is -CH2NRx-*, -CH(CF3)NRx-*, orInsome embodiments, -C(Rw)2NRx-* is -CH2NRx-*. In some embodiments, -C(Rw)2NRx-* is - CH(CF3)NRx-*. In some embodiments, -

[0394] In some embodiments,L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, -N(R6)C(O), -S(O)-, -S(O)2-, or - S(O)2N(R6)-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; n is 1 or 2.

[0395] In some embodiments,L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, or -N(R6)C(O)-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; n is 1 or 2.

[0396] In some embodiments,L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, or -N(R6)C(O)-; each R5is independently hydrogen, deuterium, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; n is 1 or 2.

[0397] In some embodiments,L is absent, -(C(R5)2)n-, -C(O)-, -O-, or -N(R6)-; each R5is independently hydrogen, deuterium, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl;n is 1 or 2.

[0398] In some embodiments,L is absent, -(C(R5)2)n-, or -C(O)-; each R5is independently hydrogen, deuterium, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C5cycloalkyl, or a 3- to 5-membered heterocycloalkyl; n is 1 or 2.

[0399] In some embodiments,L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C5 cycloalkyl, or a 3- to 5-membered heterocycloalkyl; n is 1 or 2.

[0400] In some embodiments,L is absent or -C(R5)2-; each R5is independently hydrogen, deuterium, -OH, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C5 cycloalkyl, or a 3- to 5-membered heterocycloalkyl. odiments, L is absent, -CH2-, -CHD-, -CD2-, -CH(CH3)-, -C(CH3)2-,some embodiments, L is -CH2-, -CHD-, -CD2-, -CH(CH3)-, -C(CH3)2-, some embodiments, L is absent, -CH2-, -CHD-, -CD2-, -CH(CH3)-, - In some embodiments, L is -CH2-, -CHD-, -CD2-, -CH(CH3)-, -C(CH3)2-,. mbodiments, L is absent, -CH2-, -CHD-, -CD2-, -CH(CH3)-, or -C(CH3)2-. In some embodiments, L is -CH2-, -CHD-, -CD2-, -CH(CH3)-, or -C(CH3)2-.

[0402] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, or -C(=O)-, where * denotes the attachment point to L, and L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; and n is 1 or 2; or RAis unsubstituted or substituted carbocyclylene or unsubstituted or substituted heterocyclylene, and L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, -N(R6)C(O), -S(O)-, - S(O)2-, or -S(O)2N(R6)-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and n is 1 or 2.

[0403] In some embodiments,RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, or -C(=O)-, where * denotes the attachment point to L, and L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; and n is 1 or 2.

[0404] In some embodiments,RAis unsubstituted or substituted carbocyclylene or unsubstituted or substituted heterocyclylene, and L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, -N(R6)C(O), -S(O)-, - S(O)2-, or -S(O)2N(R6)-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and n is 1 or 2.

[0405] In some embodiments, L is absent.

[0406] In some embodiments, L is -(C(R5)2)n-, wherein each R5 is independently hydrogen,deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, L is - (C(R5)2)n-, wherein two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl. In some embodiments, L is -CH2-. In some embodiments, L is -CD2-. In some embodiments, L is -C(CH3)2-. In some embodiments, L is - CH(CH3)-. In some embodiments, L is. In some embodiments, L is. In some embodiments,.

[0407] In some embodiments, L is -O-.

[0408] In some embodiments, L is -N(R6)-, wherein R6 is hydrogen,C1-C6 alkyl,C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, L is -N(R6)-, wherein R6is hydrogen, C1-C3alkyl, C1-C3deuteroalkyl, or C1-C3fluoroalkyl. In some embodiments, L is -NH-. In some embodiments, L is -N(CH3)-.

[0409] In some embodiments, L is -C(O)N(R6)- or -N(R6)C(O)-. In some embodiments, L is -C(O)NH- or -NHC(O)-. In some embodiments, L is -C(O)NH-. In some embodiments, L is - C(O)NH-.

[0410] In some embodiments L is -S(O)-, -S(O)2-, or -S(O)2N(R6)-. In some embodiments L is-S(O)2-.

[0411] In some embodiments,RAis unsubstituted or substituted cycloalkylene or unsubstituted or substituted heterocycloalkylene; L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, -C(O)N(R6)-, or -N(R6)C(O)-; each R5is independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R6is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; n is 1 or 2; and RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -SRa, -S(O)Rb, -S(O)2Rb, or -S(O)2N(Ra)2.

[0412] In some embodiments,RAis C3-C6monocyclic cycloalkylene, bicyclic cycloalkylene, 4- to 6-membered monocyclic heterocycloalkylene, or bicyclic heterocycloalkylene; L is absent, -(C(R5)2)n-, -C(O)-, -O-, -N(R6)-, or -C(O)N(R6)-; each R5is independently hydrogen, deuterium, or C1-C6alkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a cyclopropyl or cyclobutyl; R6is hydrogen or C1-C6alkyl; and n is 1 or 2.

[0413] In some embodiments,RAis C3-C6monocyclic cycloalkylene or 4- to 6-membered monocyclic heterocycloalkylene; L is absent, or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, or C1-C6alkyl; and n is 1.

[0414] In some embodiments,.

[0418] In some embodiments,

[0421] In some embodiments, each RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted orsubstituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or - S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, - OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2.

[0422] In some embodiments, RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, - SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2.

[0423] In some embodiments, RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, -CN, -C(O)R18, -C(O)OR18, or -C(O)N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, -CN, -C(O)R18, - C(O)OR18, and -C(O)N(R18)2.

[0424] In some embodiments, RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, -CN, -C(O)R18, -C(O)OR18, or -C(O)N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, -CN, - C(O)R18, -C(O)OR18, and -C(O)N(R18)2.

[0425] In some embodiments, RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C1-C4heteroalkyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4deuteroalkyl, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C1-C4heteroalkyl, unsubstituted or substituted 3 to 6 membered carbocyclyl, unsubstituted or substituted 3 to 6 membered heterocyclyl, and -CN.

[0426] In some embodiments, RE is independently hydrogen, halogen, unsubstituted orsubstituted C1-C3alkyl, unsubstituted or substituted C1-C3deuteroalkyl, unsubstituted or substituted C1-C3fluoroalkyl, unsubstituted or substituted C2-C3alkynyl, unsubstituted or substituted C1-C3heteroalkyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C3alkyl, unsubstituted or substituted C1-C3deuteroalkyl, unsubstituted or substituted C1-C3fluoroalkyl, unsubstituted or substituted C1-C3heteroalkyl, unsubstituted or substituted 3 to 5 membered carbocyclyl, unsubstituted or substituted 3 to 5 membered heterocyclyl, and -CN.

[0427] In some embodiments, RE is independently hydrogen, halogen, C1-C3 alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C2-C3alkynyl, C1-C3heteroalkyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C3alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C1-C3heteroalkyl, 3 to 5 membered carbocyclyl, 3 to 5 membered heterocyclyl, and -CN.

[0428] In some embodiments, RE is independently hydrogen, halogen, C1-C3 alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C2-C3alkynyl, C1-C3heteroalkyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C3alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C1-C3heteroalkyl, 3 to 5 membered carbocyclyl, 3 to 5 membered heterocyclyl, and -CN.

[0429] In some embodiments, RE is independently hydrogen, halogen, C1-C3 alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C2-C3alkynyl, C1-C3heteroalkyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C3alkyl, C1-C3deuteroalkyl, C1-C3fluoroalkyl, C1-C3heteroalkyl, 3 to 5 membered carbocyclyl, 3 to 5 membered heterocyclyl, and -CN.

[0430] In some embodiments, RE is independently hydrogen, -F, -Cl, -CH3, -CH2CH3,isopropyl, n-propyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CD3, -CHD2, -CH2D, ethynyl, propynyl, cyano, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, cyclopropyl, or cyclobutyl.

[0431] In some embodiments, RE is independently hydrogen, -F, -Cl, -CH3, difluoromethyl, -CD3, ethynyl, propynyl, cyano, -C(O)NHCH3, cyclopropyl, or cyclobutyl.

[0432] In some embodiments, two RE attached to the same aliphatic carbon atom are takentogether with the carbon atom to which they are attached to form -C(O)-.

[0433] In some embodiments, each R18 is independently hydrogen, substituted orunsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0434] In some embodiments, each R18 is independently hydrogen, substituted orunsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4fluoroalkyl, substituted or unsubstituted C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0435] In some embodiments, each R18 is independently hydrogen, substituted orunsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3fluoroalkyl, substituted or unsubstituted C1-C3heteroalkyl, or substituted or unsubstituted C3-C4cycloalkyl.

[0436] In some embodiments, each R18 is independently hydrogen, C1-C3 alkyl, C1-C3fluoroalkyl, C1-C3heteroalkyl, or C3-C4cycloalkyl.

[0437] In some embodiments, two R18 on the same N atom are taken together with the N atomto which they are attached to form a substituted or unsubstituted N-containing heterocyclyl.

[0438] In some embodiments, two R18 on the same N atom are taken together with the N atomto which they are attached to form a 5-membered N-containing heterocyclyl.

[0439] In some embodiments, two R18 on the same N atom are taken together with the N atomto which they are attached to form a 6-membered N-containing heterocyclyl.

[0440] In some embodiments, each R19 is independently substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0441] In some embodiments, each R19 is independently substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4fluoroalkyl, substituted or unsubstituted C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0442] In some embodiments, each R19 is independently substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C1-C3fluoroalkyl, or substituted or unsubstituted C1-C3heteroalkyl.

[0443] In some embodiments, each R19 is independently C1-C3 alkyl, C1-C3 fluoroalkyl, or C1-C3heteroalkyl.

[0444] In some embodiments, each R19 is independently substituted or unsubstitutedmonocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

[0445] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments,p is 1.

[0446] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments,q is 1.

[0447] In some embodiments, m is 0-4. In some embodiments, m is 0-3. In someembodiments, m is 0-2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. 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.

[0448] Exemplary compounds described herein include the compounds described in thefollowing Table:Table 1:*Absolute configuration not assigned

[0449] In some embodiments, provided herein is a pharmaceutically acceptable salt of acompound that is described in Table 1.

[0450] In some embodiments, the compound disclosed herein is a compound selected from thegroup consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Further Forms of Compounds

[0451] In one aspect, compounds described herein are in the form of pharmaceuticallyacceptable salts. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0452] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier ordiluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0453] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically activeagent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capabilitycan be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0454] In some embodiments, pharmaceutically acceptable salts are obtained by reacting acompound described herein with an acid. In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0455] In some embodiments, pharmaceutically acceptable salts are obtained by reacting acompound described herein with a base. In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, thecompounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0456] It should be understood that a reference to a pharmaceutically acceptable salt includesthe solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0457] The methods and formulations described herein include the use of N-oxides (ifappropriate), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0458] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings)of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0459] In another embodiment, the compounds described herein are labeled isotopically (e.g.with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0460] Compounds described herein include isotopically-labeled compounds, which areidentical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl,123I,124I,125I,131I,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0461] In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound described herein exists in the R configuration. In some embodiments, the compound described herein exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0462] Individual stereoisomers are obtained, if desired, by methods such as, stereoselectivesynthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0463] In some embodiments, compounds described herein are prepared as prodrugs. A“prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0464] Prodrugs of the compounds described herein include, but are not limited to, esters,ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1- 38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[0465] Prodrug forms of the herein described compounds, wherein the prodrug is metabolizedin vivo to produce a compound described herein as set forth herein are included within the scopeof the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.

[0466] In some embodiments, any one of the hydroxyl group(s), amino group(s) and / orcarboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0467] In additional or further embodiments, the compounds described herein are metabolizedupon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0468] A “metabolite” of a compound disclosed herein is a derivative of that compound that isformed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductivereactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0469] In some instances, heterocyclic rings may exist in tautomeric forms. In such situations,it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below. For example, pyridones could exist in the following tautomeric forms:are encapsulated within the group, “substituted pyridines.” Similarly, pyrazoles, triazoles, pyrimidines, and the like are known to tautomerize; for the purpose of this disclosure, all tautomeric forms (including charged and zwitterionic tautomers) are considered within the scope of the present disclosure. General Synthesis of the Compounds of the Present Disclosure

[0470] Compounds of Formula (I) described herein are synthesized using standard synthetictechniques or using methods known in the art in combination with methods described herein.

[0471] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLCare employed.

[0472] Compounds are prepared using standard organic chemistry techniques such as thosedescribed in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0473] In some embodiments, compounds are prepared as described in the Examples.Certain Terminology

[0474] Unless otherwise stated, the following terms used in this application have thedefinitions given below. The use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0475] As used herein, C1-Cx includes C1-C2, C1-C3 . . . C1-Cx. By way of example only, agroup designated as “C1-C6” indicates that there are one to six carbon atoms in the moiety, i.e.groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.

[0476] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branchedor straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0477] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentionedmonovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0478] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0479] The term “alkylamine” refers to the –N(alkyl)xHy group, where x is 0 and y is 2, orwhere x is 1 and y is 1, or where x is 2 and y is 0.

[0480] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by ahydroxyl. In some embodiments, a hydroxyalkyl is a C1-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.

[0481] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by anamino. In some embodiments, aminoalkyl is a C1-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and the like.

[0482] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbondouble bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and –CH2CH=CH2.

[0483] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbonrefers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, 3 - 2CH3, -CH2

[0484] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms ofthe alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

[0485] carbocyclic aryl (“aryl,” e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0486] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atomsforming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls. In some embodiments, the carbocycle is a fused bicyclic ring. In some embodiments, the carbocycle is a bridged bicyclic ring. In some embodiments the carbocycle is a spirocyclic ring.

[0487] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atomsforming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0488] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are fused, spirocyclic, or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups includegroups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a C3- C4cycloalkyl.

[0489] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo oriodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0490] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms arereplaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

[0491] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known asheteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. In some embodiments, the heterocycle is a fused bicyclic ring. In some embodiments, the heterocycle is a bridged bicyclic ring. In some embodiments the heterocycle is a spirocyclic ring. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1- onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)- onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, pyridonyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached wheresuch is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N- attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5- yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2- one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0492] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group thatincludes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl.

[0493] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least oneheteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2- onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0494] The term “bond” or “single bond” refers to a chemical bond between two atoms, or twomoieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0495] The term “moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0496] The term “optionally substituted” or “substituted” means that the referenced group isoptionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -NHC(=O)Oalkyl, -N(alkyl)C(=O)Oalkyl, -S(=O)2NH2, - S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, - CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1- C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and - S(=O)2C1-C4alkyl. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, - C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -NHC(=O)O(C1-C4alkyl), -N(C1- C4alkyl)C(=O)O(C1-C4alkyl), -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1- C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, -S(=O)2CH3, and -S(=O)2CH2CH3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic)includes oxo (=O). In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NHC(=O)OCH3, -CH3, -CH2CH3, -CHF2, - CF3, -OCH3, -OCHF2, -OCF3, -S(=O)2CH3, and -S(=O)2CH2CH3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0497] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substitutedheteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR18, -CO2R18, -C(=O)N(R18)2, -N(R18)2, -NR18C(=O)R19, -SR18, -S(=O)R19, -SO2R19, or -SO2N(R18)2; each R18 is independentlyselected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2- C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or twoR18 groups are taken together with the N atom to which they are attached to form a N-containingheterocycle; each R19is independently selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

[0498] The term “acceptable” with respect to a formulation, composition or ingredient, as usedherein, means having no persistent detrimental effect on the general health of the subject being treated.

[0499] The term “modulate” as used herein, means to interact with a target either directly orindirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0500] The term “modulator” as used herein, refers to a molecule that interacts with a targeteither directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

[0501] The terms “administer,” “administering,” “administration,” and the like, as used herein,refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0502] The terms “co-administration” or the like, as used herein, are meant to encompassadministration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0503] The terms “effective amount” or “therapeutically effective amount,” as used herein,refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0504] The terms “enhance” or “enhancing,” as used herein, means to increase or prolongeither in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0505] The term “pharmaceutical combination” as used herein, means a product that resultsfrom the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0506] The terms “article of manufacture” and “kit” are used as synonyms.

[0507] The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0508] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abatingor ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. Pharmaceutical Compositions

[0509] In another aspect, the present disclosure provides pharmaceutical compositionscomprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0510] In some embodiments, the compounds described herein are administered either aloneor in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops,intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.

[0511] In some embodiments, pharmaceutical compositions suitable for oral administrationare presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0512] Pharmaceutical compositions may be administered topically, that is by non-systemicadministration. This includes the application of a compound of the present disclosure externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0513] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0514] It should be understood that in addition to the ingredients particularly mentionedabove, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. JAK2 in Myeloproliferative Disorders

[0515] JAK2 activity has been linked to cancer. In particular, mutations to JAK2 areassociated with myeloproliferative neoplasms (MPNs). For example, the JAK2-V617F mutation occurs in 95% of patients with polycythaemia vera (PV), 60% of patients with essential thombocythaemia (ET), and 55% of patients with myelofibrosis (MF). Additionally, gain-of- function mutations to JAK2 exon 12 and in the thrombopoietin receptor are often present in JAK2-V617F-negative MPNs.

[0516] There is a continuing need to provide novel inhibitors of Janus kinases having moreeffective or advantageous pharmaceutically relevant properties. For example, compounds with increased selectivity for JAK2 over other JAK kinases, and / or selectivity for particular mutant JAKs. There is a need for novel inhibitors that selectively bind the pseudokinase domain (JH2) over the kinase domain (JH1), as this may introduce unique selectivity and limit off-targeteffects. There is also a need for inhibitors that selectively bind to mutant JAK2-V617F over wild-type JAK2. JAK2 inhibitors that selectively bind mutant JAK2-V617F over wild-type JAK2 may limit off-target effects and / or facilitate mutant allele burden reduction.

[0517] In one aspect, described herein is a method of treating a JAK2-mediated disorder in apatient in need thereof, comprising administering a selective small molecule antagonist of JAK2 to a patient in need thereof. In another aspect, described herein is a method of inhibiting an activity of JAK2 kinase in a patient in need thereof, comprising contacting the JAK2 kinase with a selective small molecule antagonist of JAK2. In some embodiments, the selective small molecule JAK2 antagonist binds to or interacts with JAK2 and does not substantially bind to or interact with any other JAK family member. In some embodiments, the selective small molecule JAK2 antagonist is at least 5-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more selective for JAK2 than for any other JAK family member. In some embodiments, the other JAK family members comprise JAK1, JAK3, TYK2, or a combination thereof. In some such embodiments, the selective small molecule JAK2 antagonist binds to or interacts with the JAK2- JH2 domain of JAK2 and does not substantially bind to or interact with the JAK2-JH1 domain of JAK2. In some such embodiments, the selective small molecule JAK2 antagonist is at least 2- fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold or more selective for the JAK2-JH2 domain of JAK2 than for the JAK2-JH1 domain of JAK2. In some embodiments, the selective small molecule JAK2 antagonist is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0518] In some embodiments, described herein is a method of inhibiting an activity of theV617F variant of JAK2 kinase, comprising contacting the kinase with a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0519] In some embodiments, the JAK2 inhibitors described herein are used in the treatmentof a disease or condition in a mammal.

[0520] Described herein are compounds described herein, or a pharmaceutically acceptablesalt, tautomer, or solvate thereof useful in the treatment of JAK2-mediated disorders. Described herein are compounds described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of a JAK2-mediated disorder.

[0521] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a JAK2-V617F- mediated disorder.

[0522] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of cancer. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, themethod comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skin cancer, and brain cancer.

[0523] In some embodiments, the cancer is hematological cancer.

[0524] In some embodiments, the cancer is selected from leukemia, lymphoma, multiplemyeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, B- cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non- Hodgkin's lymphoma, a myeloproliferative neoplasm), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0525] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a myeloproliferative disorders (MPDs).

[0526] In some embodiments, described herein is a method of treating a myeloproliferativedisorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, post polycythemia vera myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

[0527] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of myelodysplastic syndrome. In some embodiments, described herein is a method of treating myelodysplastic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0528] In some embodiments, described herein is a method of treating skeletal andchondrocyte disorders in a patient in need thereof, the method comprising administering to thepatient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the skeletal and chondrocyte disorder is achrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia, Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, or craniosynostosis syndrome.

[0529] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a myeloproliferative neoplasms (MPNs). In some embodiments, the myeloproliferative neoplasm is polycythemia vera. In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia. In some embodiments, the myeloproliferative neoplasm is myelofibrosis. In some embodiments, the myelofibrosis is myelofibrosis with myeloid metaplasia (MMM). In some embodiments, the myelofibrosis is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative neoplasm is hypereosinophilic syndrome (HES). In some embodiments, the myeloproliferative neoplasm is 8p11 myeloproliferative syndrome.

[0530] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of leukemia. In some embodiments, the leukemia is chronic myelogenous leukemia (CML). In some embodiments, the leukemia is acute myelogenous leukemia. In some embodiments, the leukemia is chronic myelomonocytic leukemia (CMML). In some embodiments, the leukemia is myeloid leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML). In some embodiments, the leukemia is lymphocytic leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is hairy cell leukemia. In some embodiments, the leukemia is chronic neutrophilic leukemia (CNL). In some embodiments, the leukemia is juvenile myelomonocytic leukemia. In some embodiments, the leukemia is chronic basophilic leukemia. In some embodiments, the leukemia is chronic eosinophilic leukemia. In some embodiments, the leukemia is adult T cell leukemia. In some embodiments, the leukemia is acute megakaryocytic leukemia. In some embodiments, the leukemia is T-cell acute lymphoblastic leukemia. In some embodiments, the leukemia is B-cell acute lymphoblastic leukemia. In some embodiments, the leukemia is T-cell large granular lymphocytic leukemia (T- LGL). In some embodiments, the leukemia is T-cell prolymphocytic leukemia (T-PLL).

[0531] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of systemic mast cell disease (SMCD).

[0532] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of post-essential thrombocythemia myelofibrosis (Post-ET MF).

[0533] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of post-polycythemia vera (Post-PV).

[0534] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of 8p11 myeloproliferative syndrome.

[0535] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of myelodysplastic syndrome (MDS). In some embodiments, the myelodysplastic syndrome (MDS) is red-blood- cell-transfusion-dependent myelodysplastic syndrome (MDS). In some embodiments, the myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder that is characterized by ineffective hematopoiesis on one or more of the major myeloid cell lineages. In some embodiments, the myelodysplastic syndrome (MDS) is clonal hematopoiesis. In some embodiments, the myelodysplastic syndrome (MDS) is refractory cytopenia with unilineage dysplasia (RCUD). In some embodiments, the myelodysplastic syndrome (MDS) is refractory anemia with ring sideroblasts (RARS). In some embodiments, the myelodysplastic syndrome (MDS) is refractory anemia with ring sideroblasts associated with thrombocytosis (RARS-T). In some embodiments, the myelodysplastic syndrome (MDS) is refractory cytopenia with multilineage dysplasia. In some embodiments, the myelodysplastic syndrome (MDS) is refractory anemia with excess blasts-1 (RAEB-1). In some embodiments, the myelodysplastic syndrome (MDS) is refractory anemia with excess blasts-2 (RAEB-2). In some embodiments, the myelodysplastic syndrome (MDS) is myelodysplastic syndrome, unclassified (MDS-U). In some embodiments, the myelodysplastic syndrome (MDS) is myelodysplastic syndrome associated with isolated del(5q). In some embodiments, the myelodysplastic syndrome (MDS) is refractory to erythropoiesis-stimulating agents.

[0536] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome).

[0537] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of leukemic manifestations of lymphomas.

[0538] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of multiple myeloma.

[0539] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of hypereosinophilic syndrome (HES).

[0540] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of myelofibrosis with myeloid metaplasia (MMM).

[0541] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of systemic mastocytosis (SM).

[0542] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of graft versus host disease (GVHD).

[0543] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of unclassified myeloproliferative diseases (UMPD or MPD-NC).

[0544] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of lymphoma. In some embodiments the lymphoma is lymphocytic lymphoma (also called chronic lymphocytic leukemia). In some embodiments the lymphoma is follicular lymphoma. In some embodiments the lymphoma is large cell lymphoma. In some embodiments the lymphoma is Burkitt's lymphoma. In some embodiments the lymphoma is marginal zone lymphoma. In some embodiments the lymphoma is lymphoblastic lymphoma (also called acute lymphoblastic lymphoma). In some embodiments the lymphoma is B-cell lymphoma. In some embodiments the lymphoma is cutaneous T-cell lymphoma. In some embodiments the lymphoma is Hodgkin’s lymphoma. In some embodiments the lymphoma is non-Hodgkin’s lymphoma. In some embodiments the lymphoma is hairy cell lymphoma. In some embodiments the lymphoma is chronic myelogenic lymphoma. In some embodiments the lymphoma is AIDS-related lymphoma. In some embodiments the lymphoma is T-lymphoblastic lymphoma. In some embodiments the lymphoma is B-lymphoblastic lymphoma. In some embodiments the lymphoma is Waldenstrom's Macroglubulinemia.

[0545] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the inhibition of tumor metastases.

[0546] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of cancer. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma). In some embodiments, the cancer is breast cancer (e.g., hormone R positive, triple negative). In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is cancer of the small intestine. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is cancer of the anus. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is gastric cancer (e.g., gastrointestinal stromal tumors). In some embodiments, the cancer is head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth, squamous head and neck cancers). In some embodiments, the cancer is kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor). In some embodiments, the cancer is liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic), liver angiosarcoma, hepatoblastoma). In some embodiments, the cancer is lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma). In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is vulvar cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gall bladder cancer. In some embodiments, the cancer is pancreatic cancer (e.g. exocrine pancreatic carcinoma). In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is parathyroid cancer. In some embodiments, the cancer is neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell cancer, neuroendocrine carcinoma). In some embodiments, the cancer is skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer). In some embodiments, the cancer is brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuro- ectodermal tumors, pineal tumors). In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is rhabdosarcoma. In some embodiments, the cancer is lymphosarcoma. In some embodiments, the cancer is osteosarcoma.

[0547] In some embodiments, the cancer is tumors of the eye. In some embodiments, thecancer is leiomyosarcoma. In some embodiments, the cancer is urothelial carcinoma (e.g. ureter, urethra, bladder, urachus).

[0548] In some embodiments, the compounds described herein, or a pharmaceuticallyacceptable salt, tautomer, or solvate thereof, are useful in the treatment of a cellular proliferative disease. In some embodiments, the cellular proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cellular proliferative disease is a tumor and / or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth.

[0549] In some embodiments, the cellular proliferative disease has mutant JAK2. In someembodiments, the cellular proliferative disease is a myeloproliferative disorder. In some embodiments, the cancer has mutant JAK2. In some embodiments, the hematopoietic cancer has mutant JAK2. In some embodiments, the myeloproliferative disorder has mutant JAK2.

[0550] In some embodiments, the cellular proliferative disease displays overexpression oramplification of JAK2, or somatic mutation of JAK2.

[0551] In some embodiments, the cancer is selected from adenoma; actinic keratosis; adrenalgland; basal cell carcinoma; brain; a carcinoma of the brain; breast (including sporadic breast cancers and sufferers of Cowden disease); bronchus; carcinoma; colon; colon carcinoma; colorectal adenoma; endometrial; esophagus; gastric; gastrointestinal; glioblastoma; glioma; head; hepatocellular; intrahepatic bile duct; kidney; larynx; liver; lung; melanoma; multiple myeloma; a mammary carcinoma; a neoplasia; a neoplasia of epithelial character; neck; ovarian (including clear cell ovarian cancer); oral cavity and pharynx; pancreas; prostate; renal pelvis; rectum; sarcoma; thyroid; small intestine; squamous cell carcinoma; stomach; urinary bladder; uterine corpus; uterine cervical; vaginal; villous colon adenoma.

[0552] In some embodiments, the cancer is breast cancer (including sporadic breast cancersand Cowden disease). In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is ER+ / HER2- breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease.

[0553] In some embodiments, the cancer is adenoma; carcinoma; sarcoma; glioma;glioblastoma; melanoma; multiple myeloma; or lymphoma. In some embodiments, the cancer is a colorectal adenoma or avillous colon adenoma. In some embodiments, the cancer is colon carcinoma; a carcinoma of the brain; a mammary carcinoma; basal cell carcinoma; or a squamous cell carcinoma. In some embodiments, the cancer is a neoplasia or a neoplasia of epithelial character. In some embodiments, the cancer is non-Hodgkin lym...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I-1):Formula (I-1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is -RA-L-RB; RAis -C(=O)NRx-*, -NRxC(=O)-*, -C(=S)NRx-*, -NRxC(=S)-*, -C(=NRx)NRx-*, - NRxC(=NRx)-*, -C(O)O-*, -OC(O)-*, -C(=S)O-*, -OC(=S)-*, -NRxC(=O)NRx-*, -NRxC(=O)O-*, -OC(=O)NRx-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Ryis independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each Rzis independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two Rzon the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; each Rwis independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl;or two Rwon the same carbon atom are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl or a 3- to 6-membered heterocycloalkyl; L is absent or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, -OH, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or two R5on the same carbon atom or on adjacent carbon atoms are taken together with the intervening carbon atom to which they are attached to form a C3-C6cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1 or 2; RBis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -ORb, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, - NRaC(O)Rb, -NRaC(O)ORa, -SRa, -S(O)Rb, -P(O)(Rb)2, -S(O)2Rb, -S(O)N(Ra)2, - NRaS(O)2Rb, or -S(O)2N(Ra)2; each Rais independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6deuteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same P atom are taken together with the P atom to which they are attached to form a substituted or unsubstituted P-containing heterocyclyl; R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; R4is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or R3and R4are taken together with the carbon atom to which they are attached to form - C(O)-, an unsubstituted or substituted C3-C6cycloalkylene, or an unsubstituted or substituted 3- to 6-membered heterocycloalkylene; Y is -N(R7)-, -O-, -S-, -S(O)-, or -S(O)2-, wherein: R7is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; X1is CR21or N; X2is CR22or N; X3is CR23or N; X4is CR24or N; X6is CR26or N; X7is CR27or N; R21, R22, R23, R24, R26, and R27are each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, - S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; Ring A is a carbocyclic ring or a heterocyclic ring; RCis -N(R11)(R12); R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R12is -C(O)R13, -C(O)NR13R14, or -C(O)OR13; R13is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocyclyl, unsubstituted or substituted bicyclic carbocyclyl, unsubstituted or substituted monocyclic heterocyclyl, or unsubstituted or substituted bicyclic heterocyclyl; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or R13and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted heterocyclyl; or R11and R14are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl; or R12is an unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2- C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted carbocyclyl, wherein if R12is substituted then it is substituted with 1 or more groups independently selected from halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted -(C1-C6alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C6alkylene)-heterocyclyl, -CN, -OH, -OR19, -C(O)R18, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, -S(O)2R19, or -S(O)2N(R18)2; RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl;each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl; or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl; or RDis unsubstituted or substituted carbocyclyl or unsubstituted or substituted heterocyclyl; each REis independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; wherein if REis attached to a N atom, then it is selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, -CN, -OH, -OR19, -C(O)R18, - C(O)OR18, -C(O)N(R18)2, -S(O)R19, -S(O)2R19, and -S(O)2N(R18)2; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-; each R18is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R18on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each R19is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl,substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; p is 0 or 1; q is 0 or 1; and m is 0-4.

2. The compound of claim 1, wherein the compound is a compound of Formula (I-1-st-3):Formula (I-1-st-3); wherein R3is hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted monocyclic heterocycloalkyl, unsubstituted or substituted -(C1-C3alkylene)-carbocyclyl, unsubstituted or substituted -(C1-C3alkylene)-heterocyclyl, -CN, -OH, -OR19, - C(O)R18, -C(O)OR18, -C(O)N(R18)2, -N(R18)2, -NR18C(O)R19, -SR18, -S(O)R19, - S(O)2R19, or -S(O)2N(R18)2; or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, tautomer, orsolvate thereof, wherein Ring A is a monocyclic heteroaryl or a bicyclic heteroaryl.

4. The compound of claim 1, wherein the compound is a compound of Formula (II-1):, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Z is N, CH, or C-RE; and REis hydrogen, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR19, -C(O)OR18, -C(O)N(R18)2, - N(R18)2, -NR18C(O)R19, or -S(O)2N(R18)2.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein: W is -NH- or -CH2-.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein: R15is C1-C4alkyl, C1-C4deuteroalkyl, or unsubstituted or substituted C3-C6cycloalkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein: R15is -CH3or -CD3.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein: R15is cyclopropyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein: each REis independently hydrogen, fluoro, chloro, C1-C4alkyl, C2-C4alkynyl, or -CN; wherein if REis attached to a N atom, then it is selected from the group consisting of C1-C4alkyl and C1-C4deuteroalkyl; or two REattached to the same aliphatic carbon atom are taken together with the carbon atom to which they are attached to form -C(O)-.

10. The compound of any one of claims 1-9, wherein p is 1.

11. The compound of claim 10, or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein R11is hydrogen.

12. The compound of claim 10 or 11, or a pharmaceutically acceptable salt, tautomer, orsolvate thereof, wherein R12is -C(=O)R13.

13. The compound of claim 12, or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein R13is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C6 monocyclic cycloalkyl, or unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl.

14. The compound of claim 12 or claim 13, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein R13is unsubstituted or substituted cyclopropyl.

15. The compound of claim 12, or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein R13is unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl.

16. The compound of claim 15 or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein if R13is substituted then it is substituted with 1 to 3 groups independently selected from halogen, C1-C6alkyl, and -CN.

17. The compound of claim 15 or claim 16, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein R13is 1-methyl-1H-pyrazol-4-yl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein q is 1.

19. The compound of claim 18, or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein: RDis -C(=O)-W-R15; W is -NR16-, -C(R17)2- or -O-; R16is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; each R17is independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycloalkyl; R15is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, unsubstituted or substituted C3-C6cycloalkyl, or unsubstituted or substituted monocyclic heterocycloalkyl;or R15and R16are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl.

20. The compound of claim 18, or a pharmaceutically acceptable salt, tautomer, or solvatethereof, wherein:

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein m is 0.

22. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein:

23. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer,or solvate thereof, wherein:.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: X1 is CR21, X2 is CR22, and X3 is CR23;or X1is CR21, X2is CR22, and X3is N; or X1is CR21, X2is N, and X3is CR23; or X1is CR21, X2is N, and X3is N; or X1is N, X2is CR22, and X3is CR23; or X1is N, X2is CR22, and X3is N; or X1 is N, X2 is N, and X3 is CR23.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: X1is CH, X2is CH, and X3is CH.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: X4is CR24, X6is CR26, and X7is CR27; or X4is CR24, X6is N, and X7is CR27; or X4is N, X6is CR26, and X7is CR27; or X4is CR24, X6is CR26, and X7is N; or X4is CR24, X6is N, and X7is N; or X4is N, X6is CR26, and X7is N; orX4is N,X6is N, andX7is CR27.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is N, and X7is CH, C-CH3, or CF; or X4is N, X6is CH, C-CH3, or CF, and X7is CH, C-CH3, or CF; or X4is CH, C-CH3, or CF, X6is CH, C-CH3, or CF, and X7is N.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: X4is CH, X6is N, and X7is CH; or X4is CH, X6is CF, and X7is CH; or X4is N, X6is CH, and X7is CH; or X4is CH, X6is CH, and X7is N.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: Y is -N(R7)-; and R7is hydrogen or C1-C6alkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R7is C1-C6alkyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R3is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.

32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R3is hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl, n-pentyl, 2-methylbutan-2-yl, 2,2-dimethylpropyl, 3-methylbutyl, pentan-2-yl, pentan-3-yl, 3-methylbutan-2-yl, 2-methylbutyl, -CH2OCH3,.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R3is -CH3or -CH2CH3.

34. The compound of any one of claims 1 or 3-33, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R4is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.

35. The compound of any one of claims 1 or 3-34, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein R4is hydrogen.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein:*, -C(=S)O-*, -OC(=S)-*, -CRy=CRy-*, -C(O)C(Rz)2-*, -C(Rz)2C(O)-*, - C(Rw)2NRx-*, -NRxC(Rw)2-*, -S(O)2NRx-*, -NRxS(O)2-*, -S(=O)(=NRx)NRx-*, - NRxS(=O)(=NRx)-*, -P(=O)RxN(Rx)-*, -N(Rx)P(=O)(Rx)-*, -C(=O)-, unsubstituted or substituted carbocyclylene, or unsubstituted or substituted heterocyclylene; where * denotes the attachment point to L.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein:each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; where * denotes the attachment point to L.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: RAis -C(=O)NRx-*; each Rxis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; where * denotes the attachment point to L.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: L is absent, or -(C(R5)2)n-; each R5is independently hydrogen, deuterium, or C1-C6alkyl; andn is 1.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein RBunsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl; wherein if RBis substituted then it is substituted by 1 or more groups independently selected from halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, - CN, -OH, -ORb, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORa, - S(O)2Rb, or -S(O)2N(Ra)2.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein: each Rais independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or two Raon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocyclyl; each Rbis independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C7cycloalkyl, monocyclic 3- to 8-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl.

42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt,tautomer, or solvate thereof, wherein:,, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

44. A pharmaceutical composition comprising the compound of any one of claims 1-44, or apharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

45. A method of inhibiting an activity of the V617F variant of JAK2 kinase, comprisingcontacting the kinase with a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

46. A method of treating a JAK2-mediated disorder in a patient in need thereof, comprisingadministering to a patient a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

47. A method of treating a JAK2-V617F-mediated disorder in a patient in need thereof,comprising administering to a patient a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

48. A method of treating cancer in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

49. The method of claim 48, wherein the cancer is selected from bladder cancer, breastcancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skin cancer, and brain cancer.

50. The method of claim 49, wherein the cancer is a hematological cancer.

51. The method of claim 50, wherein the cancer is selected from leukemia, lymphoma,multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, a myeloproliferative neoplasm), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

52. A method of treating a myeloproliferative disorder in a patient in need thereof, themethod comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

53. The method of claim 52, wherein the myeloproliferative disorder is selected frompolycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, post polycythemia vera myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

54. A method of treating myelodysplastic syndrome in a patient in need thereof, the methodcomprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

55. A method of treating skeletal and chondrocyte disorders in a patient in need thereof, themethod comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

56. The method of claim 55, wherein the skeletal and chondrocyte disorder isachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia, Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, or craniosynostosis syndrome.

57. A method of treating fibrotic diseases in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

58. The method of claim 57, wherein the fibrotic disease is liver cirrhosis,glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, or wound healing.

59. A method of treating a hypophosphatemia disorder in a patient in need thereof, themethod comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof.

60. The method of claim 59, wherein the hypophosphatemia disorder is X-linkedhypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteromalacia.

61. The method of any one of claims 45-60, further comprising administration of at least onecompound selected from ruxolitinib, pacritinib, momelotinib, and fedratinib.

62. The method of any one of claims 45-61, wherein the patient undergoing treatment haspreviously undergone treatment with at least one compound selected from ruxolitinib, pacritinib, momelotinib, and fedratinib.

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