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  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present disclosure relates to novel sulfonimidamide compounds and related compounds and their use in treating a disorder responsive to modulation of cytokines such as IL-1 b and IL-18, modulation of NLRP3, or inhibition of the activation of NLRP3 or related components of the inflammatory process.
• cytokines such as IL-1 b and IL-18
• modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
• NLR NOD-like receptor
• NLRP3 pyrin domain-containing protein 3
• NLRP3 is an intracellular receptor protein that senses certain inflammatory signals. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). The NLRP3 - ASC complex then polymerizes to form a large aggregate known as an ASC speck. Polymerized NLRP3-ASC in turn interacts with the cysteine protease caspase- 1 to form a complex termed the inflammasome.
• ASC caspase activation and recruitment domain
• caspase-l which cleaves the proinflammatory cytokines IL- 1 b and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis.
• the ASC speck can also recruit and activate caspase-8, which can process pro-IL-lp and pro-IL-l8 and trigger apoptotic cell death.
• Caspase-l cleaves pro-IL-lp and pro-IL-l8 to their active forms, which are secreted from the cell. Active caspase-l also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-l also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-l also cleaves intracellular IL-1R2 resulting in its degradation and allowing the release of IL-la. In human cells caspase-l may also control the processing and secretion of IL-37. A number of other caspase-l substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase-l -dependent inflammation.
• NLRP3 -dependent ASC specks are released into the extracellular environment where they can activate caspase-l, induce processing of caspase-l substrates and propagate
• Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury.
• PMb signalling induces the secretion of the pro- inflammatory cytokines IL-6 and TNF.
• IL-lp and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Thl7 cells and by gd T cells in the absence of T cell receptor engagement.
• IL-18 and IL-12 also synergize to induce IFN-g production from memory T cells and NK cell driving a Thl response.
• PRRs intracellular pattern recognition receptors
• NLRs nuclear-binding protein receptors
• NLRP1 and NLRC4 are also capable of forming inflammasomes.
• NLRP1 and NLRC4 are also capable of forming inflammasomes.
• NLRP3 -dependent IL- 1 b processing can also be activated by an indirect, non-canonical pathway downstream of caspase- 11
• NLRP3 autoinflammatory syndrome and neonatal -onset multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a critical component of the inflammatory process.
• NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.
• NLRP3 A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using mice with constitutive NLRP3 activation, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes, the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL- 1 b signaling, resulting in cell death and inflammation. [0011] There is a need to provide compounds and pharmaceutical compositions with improved pharmacological and/or physiological and/or physicochemical properties and/or those that provide a useful alternative to known compounds and pharmaceutical compositions.
• the present disclosure provides compounds and pharmaceutical compositions that are useful for inhibiting an inflammasome, such as the NLRP3 inflammasome.
• the compounds and pharmaceutical compositions are also useful in modulating interleukins.
• the disclosed compounds have desirable molecular weights, physico-chemical properties, and lipophilicity, which are features that help with achieving therapeutic efficacy and decreasing unintended liabilities.
• R 1 is (i) or (ii):
• R 1 is a monocyclic pyrazole of formula
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C2-C 6 alkenyl, Cri-Cxcycloalkenyl, C2-C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b ,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 73 , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , --NR 7a C(0)NR 8a , --NR 7a C(0)NR 8a , -NR 7a C
• R 1 is a fused pyrazole of formula
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6-membered heteroaryl; wherein the 3-7-membered heterocyclyl and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and
• R lx is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 73 ,
• R lx and R ly together with the atoms to which they are attached can form a C3-Ciocycloalkyl, 3-7-membered heterocyclyl, or a 5-6-membered aryl or heteroaryl; wherein the C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, and 5-6-membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl,
• 6-membered heteroaryl, and C 6 aryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring;
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R’ a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 21a , and R 22a are independently, at each occurrence
• R 3b , R 4b , R 5b , R 6b , R 713 , R 8b , R 9b , R 10b , R 21b , and R 22b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a ,
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 73 , -C(0)R 7b , a, -NR 7a C(0)NR 8a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 73 , -C(0)R
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7-membered
• heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 93 , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a ,
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl,
• 6-membered heteroaryl and C 6 aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,
• Ci-C 6 haloalkyl C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 21a , R 22a , R 23a , and R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted
• R 3b , R 4b , R 5b , R 6b , R 713 , R 8b , R 9b , R 10b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -NHS(0) 2 CH 3 , Ci-C 8 alkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C2-C 6 alkenyl, C 4 -C 8 cycloalkenyl, C2-C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered
• heterocyclyl 5-membered heteroaryl, ; wherein the Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and
• 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• X 2 is N or CR 2a ;
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ;
• X 6 and X 7 are independently N or CR 2 ' 1 , wherein at least one of X 6 and X 7 is N;
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered hetero
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b ,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 73 , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , -NR 7
• heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 93 , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a ,
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 173 , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and
• each R 2j , R 2k , R 2m , and R 2n is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2 ', R 2k , R 2m , and R 2n together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• H, D are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl),
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 100 is selected from the group consisting of H, D, -Cl, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a ,
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 ,-SR 7a , -OR 7a , -C(0)R 7b ,
• 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl; wherein the 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and -NR 9a S(O) 2 R 10a ; or
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C3-Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and --NR 9
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 ,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 15a , R 16a , R 17a , R 18a , R 19a and R 20a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)2, C3-Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 15b , R 17b , and R 18b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lz is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, and C 6 aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,
• Ci-C 6 haloalkyl C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R 3a , R 4a , R 7a , R 8a , R lla , R 12a , R 13a , R 14a , R 21a , R 22a , R 23a , and R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered
• heterocyclyl 5-membered heteroaryl
• Ci-C 6 alkyl C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl
• 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a ,
• X 2 is N or CR 2a ;
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ;
• X 6 and X 7 are independently N or CR 2 ' 1 , wherein at least one of X 6 and X 7 is N;
• R lz is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ciocycloalkyl or a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; or
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• each R 2j , R 2k , R 2m , and R 2n is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2 ', R 2k , R 2m , and R 2n together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• each R 2g and R 2h is independently H, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, C 6 aryl, or 5-membered heteroaryl, wherein the 3-7-membered heterocyclyl and
• 5-membered heteroaryl are attached to the nitrogen at a carbon on the 3-7-membered
• 3-7-membered heterocyclyl, C 6 aryl, or 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -0R 21a ,-C(0)R 21b , -P(0)R 21b R 22b , -S(0) 2 R 21b ,-S(0)R 21b , -NR 21a R 22a , -NR 21a C(0)R 22a , -NR 21a C(0)0R 22a , -NR 21a C(0)NR 22a , -NR 21a S(0) 2 R 22a , C 3 -C 10 cycloalkyl,
• R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
• C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 15b , R 17b , R 18b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl),
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, CT-Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lz is H, D, halogen
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a
• 3-7-membered heterocydyl wherein the C 3 -Ci 0 cycloalkyl and 3-7-membered heterocydyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 13a , -C(0)R 13b , -P(0)R 13b R 14b , -S(0) 2 R 13b , -S(0)R 13b , -NR 13a R 14a , -NR 13a C(0)R 14a , -NR 13a C(0)0R 14a , -NR 13a C(0)NR 14a , and
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ciocycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C3-Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• R 3a , R 4a , R 7a , R 8a , R lla , R 12a , R 13a , R 14a , R 15a , R 16a , R 17a , and R 18a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocycly
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 15b , R 17b , and R 18b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• compositions comprising one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides methods of treating disorders including the step of administering an effective amount of one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, to thereby treat the disorder in a subject in need thereof.
• compounds of the present disclosure e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, to thereby treat the disorder in a subject in need thereof.
• the present disclosure provides a methods of treating disorders including the step of administering an effective amount of one or more pharmaceutical compositions of the present disclosure to thereby treat the disorder in a subject in need thereof.
• the present disclosure provides one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, or one or more pharmaceutical compositions of the present disclosure for use in the treatment of a disorder in a subject in need thereof.
• compounds of the present disclosure e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, or one or more pharmaceutical compositions of the present disclosure for use in the treatment of a disorder in a subject in need thereof.
• the present disclosure provides for the use of one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, for the treatment of a disorder in a subject in need thereof.
• compounds of the present disclosure e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, for the treatment of a disorder in a subject in need thereof.
• compositions of the present disclosure for the treatment of a disorder in a subject in need thereof.
• the present disclosure provides for the use of one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, in the manufacture of a medicament for the treatment of a disorder.
• compounds of Formula (I) any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, in the manufacture of a medicament for the treatment of a disorder.
• compositions of the present disclosure in the manufacture of a medicament for the treatment of a disorder.
• the disorder is responsive to inflammasome inhibition.
• the disorder is responsive to inhibition of activation of the NLRP3 inflammasome.
• the disorder is a disorder of the immune system, the liver, the lung, the skin, the cardiovascular system, the renal system, the gastrointestinal tract, the respiratory system, the endocrine system, the central nervous system, or is a cancer or other malignancy, or is caused by or associated with a pathogen.
• the present disclosure provides methods of modulating the activity of a biological target comprising the step of exposing the biological target to one or more compounds of the present disclosure, e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof.
• compounds of the present disclosure e.g., compounds of Formula (I), any variations thereof detailed herein, one or more of Compound Nos. 1-210 in Table 1, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof.
• the present disclosure provides methods of modulating the activity of a biological target comprising the step of exposing the biological target to one or more pharmaceutical compositions of the present disclosure.
• the biological target may be selected from a group consisting of the NLRP3 inflammasome, IL-6, IL-lp, IL-17, IL-18, IL-la, IL-37, IL-22, IL-33 and Thl7 cells.
• compounds of the present disclosure may optionally be substituted with one or more substituents, such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the present disclosure.
• substituents such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the present disclosure.
• substituted refers to the replacement of a hydrogen atom in a given structure with a specified substituent.
• Combinations of substituents envisioned by the present disclosure are typically those that result in the formation of stable or chemically feasible compounds.
• the articles“a” and“an” as used in this disclosure may refer to one or more than one (i.e., to at least one) of the grammatical object of the article.
• “an element” may mean one element or more than one element.
• A“patient” or“subject” may encompass both mammals and non-mammals.
• mammals may include, but are not limited to, any member of the class Mammalia humans; non-human primates such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; companion animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs; and the like.
• farm animals such as cattle, horses, sheep, goats, and swine
• companion animals such as rabbits, dogs, and cats
• laboratory animals including rodents, such as rats, mice and guinea pigs; and the like.
• non-mammals include, but are not limited to, birds, fish, and the like.
• “Patient” or“subject” may include both human and animals.
• the patient or subject is a human
• inhibitor may refer to a molecule such as a compound, a drug, enzyme, or a hormone that blocks or otherwise interferes with a particular biologic activity.
• an “effective amount” or“therapeutically effective amount” when used in connection with one or more compounds or pharmaceutical compositions may refer to a sufficient amount of the one or more compounds or pharmaceutical compositions to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disorder, or any other desired alteration of a biological system.
• an “effective amount” for therapeutic use may be the amount of the pharmaceutical composition comprising one or more compounds, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs, and tautomers thereof, as disclosed herein required to provide a clinically significant decrease in a disorder.
• an appropriate“effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
• the expression“effective amount” may generally refer to the quantity for which the active substance has therapeutic effects.
• the active substance may be an inhibitor of the inflammasome.
• the terms“treat” or“treatment” are meant to indicate a postponement of development of disorders; preventing the development of disorders; and/or reducing severity of such symptoms that will or are expected to develop. Thus, these terms may include
• ameliorating existing disorder symptoms preventing additional symptoms; ameliorating or preventing the underlying causes of symptoms; inhibiting the disorder, e.g., arresting the development of the disorder; relieving the disorder; causing regression of the disorder; relieving a symptom caused by the disorder; or stopping or alleviating the symptoms of the disorder.
• pharmaceutically acceptable or“pharmacologically acceptable” may refer to a material which is not biologically, or otherwise, undesirable— the material may be administered to an individual without causing any substantially undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• carrier may encompass carriers, excipients, and diluents and may mean a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a
• Carriers should be selected on the basis of compatibility and the release profile properties of the desired dosage form.
• Exemplary carrier materials may include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, e.g., Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.
• IC 50 may refer to concentrations at which a measurable activity, phenotype or response, for example growth or proliferation of cells such as tumor cells, is inhibited by 50%. IC50 values can be estimated from an appropriate dose-response curve, for example by eye or by using appropriate curve fitting or statistical software. More accurately,
• IC 50 values may be determined using non-linear regression analysis.
• administering may refer to either directly administering one or more compounds.
• alkyl may mean a straight chain or branched saturated chain having from 1 to 10 carbon atoms.
• Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl,
• alkyl group can be unsubstituted or substituted.
• Alkyl groups containing three or more carbon atoms may be straight or branched.
• “lower alkyl” means an alkyl having from 1 to 6 carbon atoms.
• an“alkenyl” may include an unbranched or branched hydrocarbon chain containing 2-12 carbon atoms.
• The“alkenyl” group contains at least one double bond.
• the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
• alkenyl groups may include, but are not limited to, ethylenyl, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2- butenyl, 4-(2-methyl-3-butene)-pentenyl and the like.
• An alkenyl group can be unsubstituted or substituted.
• Alkenyl, as defined herein, may also be branched or straight.
• “alkynyl” may include an unbranched or branched unsaturated hydrocarbon chain containing 2-12 carbon atoms.
• The“alkynyl” group contains at least one triple bond.
• the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
• alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- l-butynyl, 4-propyl-2-pentynyl, 4-butyl - 2-hexynyl and the like.
• An alkynyl group can be unsubstituted or substituted.
• halo or“halogen” refers to fluorine, chlorine, bromine, or iodine.
• haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichlorom ethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl,
• annular atoms refers to the total number of ring atoms present in the system. “Annular atoms” therefore does not include the atoms present in a substituent attached to the ring. Thus, the number of“annular atoms”
• an 2-indolyl ring, M is considered a 5-membered heteroaryl, but is also a heteroaryl containing 9 annular atoms.
• pyridine is considered a 6-membered heteroaryl, and is a heteroaryl containing 6 annular atoms.
• Cycloalkyl refers to a single saturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C 3 -C 2 o cycloalkyl), for example from 3 to 15 annular atoms, for example, from 3 to 12 annular atoms.
• the cycloalkyl group is either monocyclic
• Cycloalkyl includes ring systems where the cycloalkyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkyl ring containing the point of attachment. Examples of cycloalkyl groups
• cycloalkyl rings can be further characterized by the number of annular atoms.
• a cyclohexyl ring is a C 6 cycloalkyl ring with 6 annular atoms
• 2-(2, 3 -dihydro- lH-indene) is a Cscycloalkyl ring with 9 annular atoms.
• 9-fluorenyl is a C cycloalkyl ring with 13 annular atoms
• 2-adamantyl is a C 6 cycloalkyl with 10 annular atoms.
• a C 3 -Ci 0 cycloalkyl has 3-14 annular atoms. In certain embodiments, a C 3 -Ci 0 cycloalkyl has 3-10 annular atoms. In certain embodiments, a
• C 3 -Ciocycloalkyl has 3-l2annular atoms.
• a C 3 -C 7 cycloalkyl has 3-7 annular atoms.
• a C 3 -C9cycloalkyl has 3-14 annular atoms.
• a C 3 -C 9 cycloalkyl has 3-10 annular atoms.
• a C 3 -C 9 cycloalkyl has 3-9 annular atoms.
• a C 3 -C 8 cycloalkyl has
• a C 3 -C 8 cycloalkyl has 3-14 annular atoms.
• a C 3 -C 7 cycloalkyl has 3-14 annular atoms.
• a C 3 -C 7 cycloalkyl has 3-10 annular atoms.
• a C 3 -C 7 cycloalkyl has 3-7 annular atoms.
• cycloalkenyl may refer to a partially saturated, monocyclic, fused or spiro polycyclic, all carbon ring having from 3 to 18 carbon atoms per ring and contains at least one double bond.
• Cycloalkenyl includes ring systems where the cycloalkenyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkenyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkenyl ring containing the point of attachment. Cycloalkenyl rings can be further characterized by the number of annular atoms. Examples of cycloalkenyl include l-cyclohex-l- enyl and cyclopent-l-enyl.
• the cycloalkenyl has 3-14 annular atoms. In certain embodiments, the cycloalkenyl has 3-10 annular atoms. In certain embodiments, the
• cycloalkenyl has 3-9 annular atoms. In certain embodiments, the cycloalkenyl has 3-7 annular atoms. In certain embodiments, a C 3 -Ciocycloalkenyl has 3-14 annular atoms. In certain embodiments, a C 3 -Ciocycloalkenyl has 3-10 annular atoms. In certain embodiments, a
• C 3 -C 9 cycloalkenyl has 3-9 annular atoms.
• a C 3 -C 8 cycloalkenyl has 3-8 annular atoms.
• a C 3 -C 8 cycloalkenyl has 3-14 annular atoms.
• a C 3 -C 7 cycloalkenyl has 3-14 annular atoms.
• a C 3 -C 7 cycloalkenyl has 3-10 annular atoms.
• a C 3 -C 7 cycloalkenyl has 3-7 annular atoms.
• aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
• an aryl group has 5 to 20 annular carbon atoms, 5 to 14 annular carbon atoms, or 5 to 12 annular carbon atoms.
• Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl).
• Aryl includes ring systems where the aryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, and wherein the point of attachment is on an aryl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbon atoms in the aryl ring containing the point of attachment.
• aryl groups include phenyl and 5-(2,3-dihydro-lH-indene):
• aryl rings can be further characterized by the number of annular atoms.
• phenyl is a C 6 aryl with 6 annular atoms
• 5-(2,3-dihydro-lH-indene) is a C 6 aryl with 9 annular atoms.
• the aryl ring is a C 6 -aryl with 6-14 annular atoms. In certain embodiments the aryl ring is a C 6 aryl with 6-10 annular atoms. In certain embodiments the aryl ring is a C 6 aryl with 6-12 annular atoms. In certain embodiments the aryl ring is a C 6 aryl with 6 annular atoms.
• Heterocyclyl refers to a single saturated or partially unsaturated non aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 annular atoms, for example from 5 to 15 annular atoms, for example from 5 to 10 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
• single saturated or partially unsaturated rings e.g., 3, 4, 5, 6 or 7-membered rings
• heterocyclyl includes ring systems where the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl,
• heterocyclic rings can be further characterized by the number of annular atoms.
• heterocyclic groups include piperidinyl (6-membered heterocycle with 6 annular atoms), azepanyl (7-membered heterocycle with 7 annular atoms), and 3-chromanyl
• a 3-7 membered heteocyclyl has 3-7 annular atoms. In certain embodiments, a 3-6 membered heteocyclyl has 3-6 annular atoms. In certain embodiments, a 3-5 membered heteocyclyl has 3-5 annular atoms. In certain embodiments, a 3-5 membered heteocyclyl has 3-9 annular atoms. In certain embodiments, a 3-7 membered heteocyclyl has 3-14 annular atoms. In certain embodiments, a 3-7 membered heteocyclyl has 3-12 annular atoms. In certain embodiments, a 3-7 membered heteocyclyl has 3-10 annular atoms.
• heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such aromatic ring.
• the term includes single heteroaryl rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
• the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
• Heteroaryl includes ring systems where the heteroaryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl,
• heterocyclyl, aryl or heteroaryl groups wherein the point of attachment is on a heteroaryl ring, and, in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring containing the point of attachment.
• Heteroaryl rings can be further characterized by the number of annular atoms.
• pyridine is a 6-membered heteroaryl having 6 annular atoms.
• the heteroaryl ring is a 5-6 membered heteroaryl with 5-15 annular atoms. In certain embodiments the heteroaryl ring is a 5-6 membered heteroaryl with 5-10 annular atoms. In certain embodiments the heteroaryl ring is a 5-6 membered heteroaryl with 5-6 annular atoms. In certain embodiments the heteroaryl ring is a 5-6 membered heteroaryl with 5-12 annular atoms. In certain embodiments the heteroaryl ring is a 5-membered heteroaryl with 5-15 annular atoms. In certain embodiments, the 5-membered heteroaryl has 5 annular atoms.
• the 5-membered heteroaryl has 5-8 annular atoms. In certain embodiments, the 5-membered heteroaryl has 5-9 annular atoms. In certain embodiments, the 5-membered heteroaryl has 5-10 annular atoms. In certain embodiments, the 5-membered heteroaryl has 5-12 annular atoms. In certain embodiments the heteroaryl ring is a 6-membered heteroaryl with 6-15 annular atoms. In certain embodiments the heteroaryl ring is a 6-membered heteroaryl with 6-10 annular atoms. In certain embodiments the heteroaryl ring is a 6 membered heteroaryl with 6-14 annular atoms.
• the 6-membered heteroaryl has 6- 13 annular atoms. In certain embodiments, the 6-membered heteroaryl has 6 annular atoms. In certain embodiments, the 6-membered heteroaryl has 6-9 annular atoms. In certain embodiments, the 6-membered heteroaryl has 6-10 annular atoms. In certain embodiments, the 6-membered heteroaryl has 6-12 annular atoms.
• Numerical ranges may include sequential integers. For example, a range expressed as“from 0 to 5” would include 0, 1, 2, 3, 4 and 5.
• the term“unsubstituted” may mean that the specified group bears no substituents beyond the moiety recited (e.g., where valency satisfied by hydrogen).
• pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof and pharmaceutical compositions comprising one or more compounds as described herein, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof.
• the disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers, prodrugs, or tautomers thereof.
• the use of the terms“salt,”“hydrate,”“solvate,”“prodrug,”“ester,” and the like, is intended to equally apply to the salt, hydrate, solvate, prodrug, or ester of enantiomers, isomers, prodrugs, rotamers, tautomers, positional isomers, or racemates of the disclosed compounds.
• isomeric forms are included within the present disclosure, including mixtures thereof.
• the term“isomer” may refer to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric or positional isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of the disclosure may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
• Individual isomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, isomers. If the compound contains a double bond, the substituent may be in the E or Z configuration or cis or trans configuration or mixtures of any of the foregoing. Disclosed assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry or constitution (e.g., geometric or positional isomers).
• the compounds of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms.
• stereoisomers may refer to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms, but differ in three dimensional structure.
• stereoisomer may refer to any member of this set of compounds.
• a stereoisomer may be an enantiomer or a diastereomer. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
• the term“enantiomers” may refer to a pair of stereoisomers which are non- superimposable mirror images of one another.
• the term“enantiomer” may refer to a single member of this pair of stereoisomers.
• the term“racemic” may refer to a 1 : 1 mixture of a pair of enantiomers.
• Each compound herein disclosed may include all the enantiomers (which may exist even in the absence of asymmetric carbons) that conform to the general structure of the compound, unless the stereochemistry is specifically indicated.
• the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
• the chiral centers of the present disclosure may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the synthetic route may produce a single enantiomer or a mixture of enantiomers.
• the compounds of the disclosure are enantiomers.
• the compounds of the disclosure are the (S)-enantiomer.
• the compounds of the disclosure are the (R)-enantiomer.
• the compounds of the disclosure may be (+) or (-) enantiomers.
• the term“diastereomers” may refer to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations may be considered to be diastereomers.
• the term“diastereomer” may refer to any member of this set of compounds.
• the synthetic route may produce a single diastereomer or a mixture of diastereomers.
• the disclosure may include diastereomers of the compounds described herein.
• compositions of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein.
• An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, at least 80, at least 85, at least 90, at least 95, at least 96, at least 97, at least 98, at least 99, at least 99.5 or even 100 mol percent.
• the compositions described herein enriched in one enantiomer may be substantially free of the other enantiomer, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the pharmaceutical composition or compound mixture.
• substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the pharmaceutical composition or compound mixture.
• a pharmaceutical composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2 mol percent of the second enantiomer.
• the pharmaceutical compositions of the disclosure may be enriched to provide predominantly one diastereomer of a compound disclosed herein.
• a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, at least 80, at least 85, at least 90, at least 95, at least 96, at least 97, at least 98, at least 99, at least 99.5, or even 100 mol percent.
• compositions described herein enriched in one diastereomer may be substantially free of other diastereomers, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of other disastereomers, e.g., in the pharmaceutical composition or compound mixture.
• Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
• Enantiomers can also be separated by use of a chiral HPLC column.
• some of the compounds of the disclosure may be atropisomers or rotameric forms and are considered as part of this disclosure.
• Compounds of the disclosure may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure. Also, it should be noted that the sulfonimidamidyl ureas described here have tautomeric forms. The structures have been graphically represented as one form throughout this document, but it is noted that the tautomers can exist in an equilibrium.
• tautomers are tautomers. All tautomeric forms for each compound are embraced although only one tautomeric form may be represented for each compound, which may be a major tautomeric form or a minor tautomeric form.
• the disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein.
• A“pharmaceutically acceptable salt” may be acceptable for use in humans or domestic animals and may refer to those salts that retain the biological effectiveness and properties of the free forms, which are not biologically or otherwise undesirable.
• Representative “pharmaceutically acceptable salts” may include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4, 4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium,
• polygalacturonate propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
• Pharmaceutically acceptable salts may also include both acid and base addition salts.
• “Pharmaceutically acceptable acid addition salt” may refer to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which may be formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- lO-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- l,2-d
• “Pharmaceutically acceptable base addition salt” may refer to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts.
• Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, /V-ethylpiperidine, polyamine resins and the like.
• the disclosure may include zwitterions of the compounds disclosed herein.
• a “zwitterion” may refer to a molecule that has both positively-charged and negatively-charged groups but has no overall charge, i.e., the + and - charges are balanced within the molecule.
• the compounds of the disclosure may include protonated amino groups and
• solvates may refer to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
• the compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds.
• An“isotopically” or“radio-labeled” compound may be a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
• hydrogen atoms are replaced or substituted by one or more deuterium or tritium.
• Certain isotopically labeled compounds of this disclosure for example, those incorporating a radioactive isotope, may be useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e., 3 H, and carbon 14, i.e., 14 C may be particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• the compound comprises at least one deuterium atom.
• one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
• the compound comprises two or more deuterium atoms.
• the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms.
• Suitable isotopes that may be incorporated in compounds described herein include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl , 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I.
• Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, can be useful in Positron Emission Topography (PET) studies.
• PET Positron Emission Topography
• Isotopically labelled compounds of the compounds disclosed herein can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an appropriate isotopically labelled reagent for a non- isotopically labelled reagent.
• R 1 is (i) or (ii):
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b ,
• Ci-C 6 alkyl Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl
• R 1 is a fused pyrazole of formula
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6-membered heteroaryl; wherein the 3-7-membered heterocyclyl and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and
• R lx is H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , -NR 7a S(0) 2 R 8a ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6-membered aryl or heteroaryl; wherein the C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6-membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C3-Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl,
• 6-membered heteroaryl, and C 6 aryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring;
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 21a , and R 22a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents
• R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 21b , and R 22b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• the compound is other than a compound in Table IX and pharmaceutically acceptable salts, solvates, isomers, and tautomers thereof.
• the compound herein, such as a compound of Formula (I) is other than a compound selected from one or more of Compound Nos. lx-30x in Table IX, and
• the compounds of the disclosure, and methods of using the compounds detailed herein encompass any of the compounds of Formula (I), including those listed Table IX and pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers thereof.
• a compound of Formula (I), or a salt e.g., a
• R 2 is as defined herein, and R 1 is a monocyclic pyrazole which is optionally substituted as detailed herein.
• the compound is other than a compound selected from one or more of Compound Nos. lx-30x in Table IX and pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers thereof.
• R 2 is a 4-pyrazolyl which is optionally substituted as detailed herein, provided that R 1 is other than 1,3- dimethylpyrazol-4-yl.
• R 2 is 4-pyrazolyl which is optionally substituted as detailed herein, provided that the compound is other than Compound lx in Table 1 and pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers thereof.
• R 2 is a 3-pyrazolyl which is optionally substituted as detailed herein, provided that the compound is other than a compound selected from one or more of Compound Nos.2x- 30x in Table IX and pharmaceutically acceptable salts, solvates, isomers, prodrugs, and tautomers thereof.
• R 100 is H, -CN, -C(0)R 3b , or Ci-C 6 alkyl; wherein the Ci-C 6 alkyl is unsubstituted or substituted with C 6 aryl. In one variation, R 100 is H.
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 - C iocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5- membered heteroaryl, 6-membered heteroaryl, and C 6 aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , - S
• R 23a and R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
• C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OH, -0-Ci-C 6 alkyl, -NH 2 ,
• R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -NHS(0) 2 CH 3 , Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl.
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C3-
• Ciocycloalkyl 3-7-membered heterocyclyl, 5-membered heteroaryl,
• Ci-C 6 alkyl, C3-Ciocycloalkyl, 3-7 membered heterocyclyl, and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , - S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a , -(CH 2 )i -4 C3-Ciocycloalkyl, C3-Ciocycloalkyl, C 6
• X 2 is N or CR 2a ;
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ;
• X 6 and X 7 are independently N or CR 2 ' 1 , wherein at least one of X 6 and X 7 is N;
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -P(0)R 15b R 16b , -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or -NR 15a S(0) 2 R 16a , wherein the Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are independently
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 193 , and NR 19a R 20a ;
• each R 2j , R 2k , R 2m , and R 2n is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 173 , -C(0)R 17b ,
• R 2 ', R 2k , R 2m , and R 2n together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 193 , and NR 19a R 20a ;
• R 15a , R 16a , R 17a , R 18a , R 19a , and R 20a are independently, at each occurrence, H, D,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH,
• R 15b , R 16b , R 17b , and R 18b are independently, at each occurrence, H, D, -OH,
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 - Ciocycloalkyl, -C(0)NR 15a R 16a , -C(0)OR 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , - NR 15a C(0)NR 16a , or -NR 15a S(0) 2 R 16a , wherein the Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7- membered heterocyclyl, and
• R 2a is H, halogen, -CN,-OR 15a ,
• Ci-C(0)OR 15a or Ci-C 6 alkyl; wherein the Ci-C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -P(0)R 15b R 16b , -NR 15a R 16a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• R 2a is H, halogen, -CN,-OR 15a , -C(0)OR 15a , or Ci- C 6 alkyl; wherein the Ci-C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 - C l0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl.
• R 2a is H or F.
• R 2a is H.
• R 2a is F.
• each R 2b , R 2c , R 2d , R 2e , and R 2f is
• R 2 is selected from the group consisting of
• X i is CR 2c ;
• X 4 is CR , 2 Z d;.
• X D is CR , 2 z e, wherein:
• C 3 -Cmcycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl wherein the C3-Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ; and
• each R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 17a , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl, C 2 -C 6 alkenyl,
• C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a ,
• R 2 is selected from the group consisting of
• X 3 is CR 2c ;
• X 4 is CR 2d ; and
• X 5 is CR 2e , wherein:
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ; and
• R 2d is H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 17a , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C2-C 6 alkenyl
• R 2 is selected from the group consisting of
• R 2 is selected from the group
• R 2 is selected from the group consisting of
• X 5 is CR 2e . In some of these embodiments, X 5 is N. In some of
• R 2 is selected from the group consisting , and
• a compound of Formula (I), or a salt e.g., a
• R lw is selected from the group consisting of H, D, - CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7- membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected
• C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• a compound of Formula (I), or a salt e.g., a
• R 2 is as defined herein
• R 1 is a fused pyrazole of formula wherein either R lw and R ly together with the atoms to which they are attached can form a fused ring or R lx and R ly together with the atoms to which they are attached can form a fused ring.
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocydyl or 5-6-membered heteroaryl; wherein the 3-7- membered heterocydyl and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and R lx is H, D, halogen, -
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cydoalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7-membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6-membered aryl or heteroaryl; wherein the C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6-membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents, or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring; and R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , - C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , - NR 9a C(O)NR 10a , -NR 9a C
• a compound of Formula (I), or a salt e.g., a pharmaceutically acceptable salt
• solvate e.g., hydrate
• prodrug metabolite or derivative thereof
• R 2 is as defined herein, and R 1 is selected from the group consisting of
• R lz is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a 3-7-membered heterocyclyl; wherein the C 3 -Ci 0 cycloalkyl and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 13a , -C(0)R 13b , -P(0)R 13b R 14b , -S(0) 2 R 13b , -S(0)R 13b , -NR 13a R 14a , -NR 13a C(0)R 14a , -NR 13a C(0)0R 14a , -NR 13a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 7a , R 8a , R lla , R 12a , R 13a , and R 14a are independently, at each occurrence, H, D,
• Ci-C 8 alkyl C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH,
• R 71 , R 8 t> ⁇ R n b ⁇ R R i a anc j R i4b are independent ⁇ a t each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -NHS(0) 2 CH 3 , Ci-C 8 alkyl,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting wherein R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C2-C 6 alkenyl, C 4 -C 8 cycloalkenyl, C2-C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered hetero
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b ,
• Ci-C 6 alkyl, C2-C 6 alkenyl, C 4 -C 8 cycloalkenyl, C2-C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 73 , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , -NR 7a S(0)
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7-membered
• heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 93 , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a ,
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 93 , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a ,
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C3-Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl,
• 6-membered heteroaryl and C 6 aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,
• Ci-C 6 haloalkyl C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ciocycloalkyl, C 6 aryl,
• R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 21a , R 22a , R 23a , and R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C3-Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted
• R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -OR 3a , -C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C l0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -C l0 cycloalkyl, 3-7-membered
• heterocyclyl 5-membered heteroaryl, ; wherein the Ci-C 6 alkyl, C 3 -C l0 cycloalkyl, 3-7-membered heterocyclyl, and
• 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a ,
• X 2 is N or CR 2a ;
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ;
• X 6 and X 7 are independently N or CR 2 ' 1 , wherein at least one of X 6 and X 7 is N;
• R lw is selected from the group consisting of H, D, -CN, -C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 , -SR 7a , -OR 7a , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , -NR 7a S(0) 2 R 8a , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl or 5-6 membered heteroaryl; wherein the 3-7-membered
• heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 93 , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a ,
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ciocycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)R 18a , -NR 17a C(0)0R 18a , -NR 17a C(0)NR 18a , -NR 17a S(0) 2 R 18a , Ci-C 6 alkyl,
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5 -6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and
• each R 2j , R 2k , R 2m , and R 2n is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2j , R 2k , R 2m , and R 2n together with the atoms to which they are attached can form C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ciocycloalkyl, C 6 aryl,
• C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a ,
• R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 15b , R 17b , R 18b R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl),
• R 100 is selected from the group consisting of H, D, -Cl, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lw is selected from the group consisting of H, D, -CN, C(0)R 5b , -S(0) 2 R 5b , -S(0)R 5b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl,
• C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 53 , -C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a ,
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 ,-SR 7a , -OR 7a , -C(0)R 7b ,
• 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl; wherein the 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and -NR 9a S(O) 2 R 10a ; or
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, or a 5-6 membered aryl or heteroaryl; wherein the C 3 -Ci 0 cydoalkyl, 3-7-membered heterocyclyl, and 5-6 membered aryl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a ,
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ciocycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C
• C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C3-Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• R 19a and R 20a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl),
• R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b , R 15b , R 17b , and R 18b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -
• R 1 is selected from the group consisting of
• Ci-C 6 alkyl, C2-C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ciocycloalkyl or a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, C 6 aryl, and -NR 2g R 2h ; wherein the Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl,
• 6-membered heteroaryl and C 6 aryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,
• Ci-Cehaloalkyl C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ciocycloalkyl, C 6 aryl,
• C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -OR 21a , -C(0)R 21b , -P(0)R 21b R 22b , -S(0) 2 R 21b , -S(0)R 21b , -NR 21a R 22a , -NR 21a C(0)R 22a ,
• R 3a , R 4a , R 7a , R 8a , R l la , R 12a , R 13a , R 14a , R 21a , R 22a , R 23a , and R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -Cxalkenyl, C 2 -C 8 alkynyl, C3-Ciocycloalkyl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7- membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered
• heterocyclyl 5-membered heteroaryl
• Ci-C 6 alkyl C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl
• 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 23a ,-C(0)R 23b , -P(0)R 23b R 24b , -S(0) 2 R 23b , -S(0)R 23b , -NR 23a R 24a , -NR 23a C(0)R 24a , -NR 23a C(0)0R 24a , -NR 23a C(0)NR 24a , -NR 23a S(0) 2 R 24a ,
• X 2 is N or CR 2a ;
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ;
• X 6 and X 7 are independently N or CR 2n , wherein at least one of X 6 and X 7 is N;
• R lz is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, Cx-Cxcycloalkenyl, C2-C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, Cx-Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ciocycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 17a , -C(0)R 17b ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• each R 2j , R 2k , R 2m , and R 2n is independently H, D, halogen, -CN, -N0 2 , -SR 17a ,
• C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, -OR 173 , -C(0)R 17b ,
• R 2 ', R 2k , R 2m , and R 2n together with the atoms to which they are attached can form C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 193 , and NR 19a R 20a ; each R 2g and R 2h is independently H, Ci-C 6 alkyl, C 3 -Ciocycloalkyl, 3-7-membered heterocyclyl, C 6 aryl, or 5-membered heteroaryl, wherein the 3-7-membered heterocyclyl and 5-membere
• 3-7-membered heterocyclyl, C 6 aryl, or 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -0R 21a ,-C(0)R 21b , -P(0)R 21b R 22b , -S(0) 2 R 21b ,-S(0)R 21b , -NR 21a R 22a , -NR 21a C(0)R 22a , -NR 21a C(0)0R 22a , -NR 21a C(0)NR 22a , -NR 21a S(0) 2 R 22a , C 3 -C 10 cycloalkyl,
• R 24a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
• C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 15b , R 17b , R 18b , R 21b , R 22b , R 23b , and R 24b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl),
• R 100 is selected from the group consisting of H, Cl, D, -CN, -N0 2 , -0R 3a ,-C(0)R 3b , -S(0) 2 R 3b , -S(0)R 3b , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R 1 is selected from the group consisting of
• R lz is H, D, halogen
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C4-C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a
• R la and R lb two geminal groups R la and R lb ; R lc and R ld ; R le and R lf ; or R lg and R lh , when present, can form an oxo group;
• R 2a is H, D, halogen, -CN,-OR 15a , Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, -C(0)NR 15a R 16a , -C(0)0R 15a ; -NR 15a R 16a , -NR 15a C(0)R 16a , -NR 15a C(0)0R 16a , -NR 15a C(0)NR 16a , or
• Ci-C 6 alkyl and C 3 -Ciocycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -OR 15a , -C(0)R 15b , -NR 15a R 16a , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently H, D, halogen, -CN, -N0 2 , -SR 17a , -OR 173 , -C(0)R 17b , -P(0)R 17b R 18b , -S(0) 2 R 17b , -S(0)R 17b , -NR 17a R 18a , -NR 17a C(0)R 18a ,
• R 2b , R 2c , R 2d , R 2e , and R 2f together with the atoms to which they are attached can form C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, -CN, Ci-C 6 alkyl, -OR 19a , and NR 19a R 20a ;
• R 3a , R 4a , R 7a , R 8a , R lla , R 12a , R 13a , R 14a , R 15a , R 16a , R 17a , and R 18a are independently, at each occurrence, H, D, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH, -0-Ci-C 6 alkyl, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocycly
• R 3b , R 4b , R 7b , R 8b , R llb , R 12b , R 13b , R 14b , R 15b , R 17b , and R 18b are independently, at each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
• R 1 is selected from the group consisting of -S(0)R
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 7a ,
• each R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is independently selected from H, D, halogen, -CN, -N0 2 ,-SR lla , -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• Ci-C 6 alkyl C 2 -C 6 alkenyl, C 4 -Cxcycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl,
• Ci-C 6 alkyl, C 2 -C 6 alkenyl, C -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocydyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR lla ,
• R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh when present, together with the atoms to which they are attached can form a C 3 -Ciocycloalkyl or a
• 3-7-membered heterocydyl wherein the C 3 -Ci 0 cycloalkyl and 3-7-membered heterocydyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 13a , -C(0)R 13b , -P(0)R 13b R 14b , -S(0) 2 R 13b , -S(0)R 13b , -NR 13a R 14a , -NR 13a C(0)R 14a , -NR 13a C(0)0R 14a , -NR 13a C(0)NR 14a , and
• R 7a , R 8a , R lla , R 12a , R 13a , and R 14a are independently, at each occurrence, H, D,
• Ci-C 8 alkyl C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl,
• Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -Ciocycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl,-OH,
• R 71 , R 8 t> ⁇ R n b ⁇ R R i a anc j R i4b are independent ⁇ a t each occurrence, H, D, -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -NHS(0) 2 CH 3 , Ci-C 8 alkyl,
• R 100 is H.
• R 100 is Ci-C 6 alkyl, wherein the Ci-C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and
• R 100 is Ci-C 6 alkyl, wherein the Ci-C 6 alkyl is unsubstituted or substituted with C 6 aryl.
• R 2 is selected from the group consisting of Ci-C 6 alkyl
• R 2 is 6-membered heteroaryl.
• the 6- membered heteroaryl has 6-10 annular atoms.
• the 6-membered heteroaryl has 6-9 annular atoms.
• the 6-membered heteroaryl has 6 annular atoms.
• R 2 is a 6-membered heteroaryl containing 1 or 2 nitrogens. In certain embodiments, R 2 is a 6-membered heteroaryl containing 1 nitrogen. In certain embodiments, R 2 is a 6-membered heteroaryl containing 2 nitrogens.
• the 6-membered heteroaryl wherein X is N or CR 2c ; X 4 is N or CR 2d ; X 5 is N or CR 2e ; and X 6 and X 7 are independently N or CR 2n ’.
• R 2 is an unsubstituted or substituted 6-membered heteroaryl
• 6-membered heteroaryl is selected from the group consisting of
• R z is 6-membered heteroaryl is substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 6 aryl, -OR 23a , C 3 -Ciocycloalkyl, C2-C 6 alkenyl, -CN, and
• R 2 is C 6 aryl.
• the aryl ring is a C 6 -aryl with 6-14 annular atoms.
• the aryl ring is a C 6 aryl with 6-10 annular atoms.
• the aryl ring is a C 6 aryl with 6-12 annular atoms.
• the aryl ring is a C 6 aryl with 6 annular atoms.
• R 2 is selected from the group consisting of Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, -NR 2g R 2h ,
• X 3 is N or CR 2c ;
• X 4 is N or CR 2d ;
• X 5 is N or CR 2e ; and X 6 and X 7 are independently N or CR 2n ’.
• R 2 is Ci-C 6 alkyl. In certain embodiments, R 2 is Cialkyl,
• R 2 is Ci-C 6 alkyl substituted with one or more C 6 aryl.
• R 2 is a C3-Ciocydoalkyl. In certain embodiments, the C 3 -Ciocycloalkyl has 3-14 annular atoms. In certain embodiments, the C 3 -Ciocycloalkyl has 3-12 annular atoms. In certain embodiments, the C 3 -Ci 0 cycloalkyl has 3-10 annular atoms. In certain embodiments, R 2 is a C 3 -C 9 cycloalkyl with 3-9 annular atoms. In certain embodiments, R 2 is a C 3 -C9cycloalkyl with 3-14 annular atoms. In certain embodiments, R 2 is a
• R 2 is a C 3 -C9cycloalkyl with 3-10 annular atoms.
• R 2 is a C 3 -C 8 cycloalkyl with 3-8 annular atoms.
• R 2 is a C 3 -C 8 cycloalkyl with 3-14 annular atoms.
• R 2 is a C 3 -C 7 cycloalkyl with 3-14 annular atoms.
• R 2 is a C 3 -C 7 cycloalkyl with 3-10 annular atoms. In certain embodiments, R 2 is a C 3 -C 7 cycloalkyl with 3-7 annular atoms.
• R 2 is C 5 cycloalkyl, C 6 cycloalkyl, or C 7 cycloalkyl.
• cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl and 9-fluorenyl noted above, cycloalkyl rings can be further characterized by the number of annular atoms.
• a cyclohexyl ring is a C 6 cycloalkyl ring with 6 annular atoms
• 2-(2,3-dihydro- lH-indene) is a C cycloalkyl ring with 9 annular atoms.
• 9-fluorenyl is a
• C cydoalkyl ring with 13 annular atoms and 2-adamantyl is a C 6 cycloalkyl ring with 10 annular atoms.
• R 2 is an unsubstituted or substituted C 3 -Ci 0 cycloalkyl, where
• R 2 is C 3 -Ci 0 cycloalkyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl and C 6 aryl.
• R 2 is a 3-7 membered heteocyclyl. In certain embodiments, the 3-7 membered heteocyclyl has 3-7 annular atoms. In certain embodiments, the 3-7 membered heteocyclyl has 3-14 annular atoms. In certain embodiments, the 3-7 membered heteocyclyl has 3-12 annular atoms. In certain embodiments, the 3-7 membered heteocyclyl has 3-10 annular atoms. In certain embodiments, R 2 is a 3-6 membered heteocyclyl. In certain embodiments, the 3-6 membered heteocyclyl has 3-6 annular atoms.
• R 2 is a 3-5 membered heteocyclyl.
• the 3-5 membered heteocyclyl has 3-5 annular atoms.
• the 3-5 membered heteocyclyl has 3-9 annular atoms.
• R 2 is an unsubstituted or substituted 3-7 membered
• R 2 is 3-7 membered heterocyclyl substituted with one or more Ci-C 6 alkyl.
• R 2 is a 5-membered heteroaryl.
• the 5-membered heteroaryl has 5 annular atoms.
• the 5-membered heteroaryl has 5-8 annular atoms.
• the 5-membered heteroaryl has 5-9 annular atoms.
• the 5-membered heteroaryl has 5-10 annular atoms.
• the 5-membered heteroaryl has 5-12 annular atoms.
• R 2 is a 5-membered heteroaryl containing 1 or 2 nitrogens. In certain embodiments, R 2 is a 5-membered heteroaryl containing 1 nitrogen. In certain embodiments, R 2 is a 5-membered heteroaryl containing 2 nitrogens.
• R 2 is an unsubstituted or substituted 5-membered heteroaryl
• R 2 is 5-membered heteroaryl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 6 aryl, oxo, and -(CH 2 )i-4C3-Ciocycloalkyl.
• R 2 is 5-membered heteroaryl is selected from the group
• X 6 and X 7 are independently N or CR 2n ’, wherein at least one of X 6 and X 7 is N. In certain embodiments, one of X 6 and X 7 is N. In certain embodiments, X 6 and X 7 are N.
• R 2 is -NR 2g R 2h .
• each R 2g and R 2h is independently H, D, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the Ci-C 6 alkyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7 membered heterocyclyl,, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, -0R 21a ,-C(0)R 21b , -P(0)R 21b R 22b , -S(0) 2 R 21b , -S(0)R 21b
• R 2g is H and R 2h is D, Ci-C 6 alkyl,
• X 2 is CR 2a . In certain embodiments, X 2 is N.
• R 2a is H, halogen, Ci-C 6 alkyl, or -COR 3b . In certain instances, R 2a is H, fluoro, chloro, methyl, or -COOH.
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently selected from the group consisting of H, D, halogen, Ci-C 6 alkyl, C 3 -Ciocycloalkyl, and -CN.
• each R 2b , R 2c , R 2d , R 2e , and R 2f is independently selected from the group consisting of H, halogen, and Ci-C 6 alkyls.
• two of R 2b , R 2c , R 2d , R 2e , and R 2f is
• R 2b , R 2c , R 2d , R 2e , and R 2f is independently selected from the group consisting of halogen and Ci-C 6 alkyl.
• R 2b and R 2f are Ci-C 6 alkyl. In certain instances, R 2d is halogen.
• X is N; X is CR ; and X is CR In certain embodiments, X 3 is CR 2c ; X 4 is N; and X 5 is CR 2d . In certain embodiments, X 3 is CR 2c ; X 4 is CR 2d ; and X 5 is N.
• R 1 is selected from the group consisting of
• R 1 is R1X . In certain embodiments, R 1 is R1X
• R lw and R ly do not come together with the atoms to which they are attached to form a 3-7-membered heterocyclyl.
• R lx and R ly do not come together with the atoms to which they are attached to form a C 3 -Ci 0 cycloalkyl or a 3-7-membered heterocyclyl.
• R ly and the atoms to which it is attached, does not come together with either R lx or R lw , or their attached atoms, to form a C 3 -Ciocycloalkyl or a
• R lw , R lx , and Rly are other than H. In certain embodiments one of R lw , R lx , and R ly is other than H. In certain embodiments, R lw , R lx , and R ly are other than H. In certain embodiments, R lw , R lx , and R ly are H.
• R lw is selected from the group consisting of H, D,
• C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -0R 5a ,-C(0)R 5b , -P(0)R 5b R 6b , -S(0) 2 R 5b ,-S(0)R 5b , -NR 5a R 6a , -NR 5a C(0)R 6a , -NR 5a C(0)0R 6a , -NR 5a C(0)NR 6a , -NR 5a S(0) 2 R 6a , C 3 -C 10 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl.
• each R lx and R ly is independently, H, D, halogen, -CN, -N0 2 ,-SR 7a , -OR 73 , -C(0)R 7b , -P(0)R 7b R 8b , -S(0) 2 R 7b , -S(0)R 7b , -NR 7a R 8a , -NR 7a C(0)R 8a , -NR 7a C(0)0R 8a , -NR 7a C(0)NR 8a , -NR 7a S(0) 2 R 8a , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -Ciocycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the Ci-C 6 alkyl, C 2 -C
• C 3 -Ci 0 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• R lw is H or Ci-C 6 alkyl.
• R lx is H or Ci-C 6 alkyl.
• R ly is H or Ci-C 6 alkyl.
• R lw and R ly together with the atoms to which they are attached can form a 3-7-membered heterocyclyl; wherein the 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and -NR 9a S(O) 2 R 10a .
• substituents selected from the group consisting of D, -CN, halogen, Ci-C 6 alkyl, -OR 9a , -C(0)R 9b ,
• R lw and R ly when R lw and R ly come together with the atoms to which they are attached to form a 3-7-membered heterocyclyl, R lw and R ly are adjacent.
• R lx and R ly together with the atoms to which they are attached can form a C 3 -Ci 0 cycloalkyl or a 3-7-membered heterocyclyl; wherein the
• C 3 -Ci 0 cycloalkyl and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, -CN, halogen,
• Ci-C 6 alkyl Ci-C 6 alkyl, -OR 9a , -C(0)R 9b , -P(O)R 9b R 10b , -S(0) 2 R 9b , -S(0)R 9b , -NR 9a R 10a , -NR 9a C(O)R 10a , -NR 9a C(O)OR 10a , -NR 9a C(O)NR 10a , and -NR 9a S(O) 2 R 10a .
• R lx and R ly when R lx and R ly come together with the atoms to which they are attached to form a C 3 -Ciocycloalkyl or a 3-7-membered heterocyclyl, R lx and R ly are adjacent.
• R lx and R ly when R lx and R ly come together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, R lx and R ly are adjacent.
• R lz is H.
• R 1 is selected from the group consisting of
• R 1 is
• R 1 is
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is . In certain embodiments, R 1 is ,
• R 1 is . In certain embodiments, R 1 is , certain
• R 1 is selected from the group consisting of [0170] In certain embodiments, R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of [0177] In certain embodiments, R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R 1 is
• R 1 is selected from the group consisting of
• R 1 is selected from the group consisting of
• R la and R lb are H.
• R lc and R ld are independently H, halogen, -OR lla ,
• R lc and R ld are other than H.
• one of R lc and R ld is other than H.
• both R lc and R ld are other than H.
• R lc and R ld are H.
• R le and R lf are independently H, halogen, -OR lla ,
• R le and R lf are other than H.
• R le and R lf are other than H.
• R le and R lf are H.
• R lg and R lh are independently H, halogen, -OR lla , -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a ,
• R lg and R lh are other than H. In certain embodiments one of R lg and R lh is other than H. In certain embodiments one of R lg and R lh is other than H.
• both R lg and R lh are other than H. In certain embodiments, R lg and R lh are H.
• Compounds of the present disclosure can contain a basic amino group. Incorporation of a basic amino group to a compound of the present disclosure, which can also bear an acidic moiety, would be expected to exist as a zwitterion, having a net zero charge. Zwitterionic compounds can have different physicochemical properties than weak organic acids. Notably, there may be increased volumes of distribution in vivo as well as lowered plasma protein binding.
• At least one of R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a ,
• the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a .
• the 3-7-membered heterocyclyl contains a nitrogen.
• At least one of R la , R lb , R lc , R ld , R le , R lf , R lg , and R lh is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a ,
• Ci-C 6 alkyl, or 3-7-membered heterocyclyl wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of-NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of-NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a .
• the 3-7-membered heterocyclyl contains a nitrogen.
• R la and R lb are independently H, -C(0)R llb ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a ,
• R la is H and R lb is -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• -NR lla R 12a -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R la and R lb is other than H.
• one of R la and R lb is other than H.
• both R la and R lb are other than H.
• R la and R lb are independently H, -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of-NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of-NR lla R 12a ,
• R la is H and R lb is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR 1 la C(0)NR l 2a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R la and R lb is other than H.
• one of R la and R lb is other than H.
• both R la and R lb are other than H.
• R la and R lb are H.
• R lc and R ld are independently H, -C(0)R llb ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a ,
• R lc is H and R ld is -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7- membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R
• -NR lla R 12a -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R lc and R ld is other than H.
• one of R lc and R ld is other than H.
• both R lc and R ld are other than H.
• R lc and R ld are independently H, -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR 1 la S(0) 2 R l 2a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR lla R 12a ,
• R lc is H and R ld is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , and -NR lla S(0) 2 R 12a .
• R lc is H and R ld is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a ,
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R lc and R ld is other than H.
• one of R lc and R ld is other than H.
• both R lc and R ld are other than H.
• R le and R lf are independently H, -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12
• R le is H and R lf is -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb
• the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a
• the 3-7-membered heterocyclyl contains a nitrogen.
• R le and R lf are independently H, -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of-NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and
• R le is H and R lf is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , and -NR lla S(0) 2 R 12a
• R le is H and R lf is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a ,
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R le and R lf is other than H.
• one of R le and R lf is other than H.
• both R le and R lf are other than H.
• R lg and R lh are independently H, -C(0)R llb ,
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a ,
• R lg is H and R lh is -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or
• Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb ,
• -NR lla R 12a -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -C(0)R llb , -P(0)R llb R 12b , -S(0) 2 R llb , -S(0)R llb , -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a .
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R lg and R lh is other than H.
• one of R lg and R lh is other than H.
• both R lg and R lh are other than H.
• R lg and R lh are independently H, -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , -NR lla S(0) 2 R 12a , Ci-C 6 alkyl, or 3-7-membered heterocyclyl; wherein the Ci-C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR lla R 12a ,
• R lg is H and R lh is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , and -NR lla S(0) 2 R 12a
• R lg is H and R lh is -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a ,
• Ci-C 6 alkyl or 3-7-membered heterocyclyl; wherein the Ci- C 6 alkyl is substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a , -NR lla C(0)0R 12a , -NR lla C(0)NR 12a , and -NR lla S(0) 2 R 12a ; and wherein the 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NR lla R 12a , -NR lla C(0)R 12a ,
• the 3-7-membered heterocyclyl contains a nitrogen.
• at least one of R lg and R lh is other than H.
• one of R lg and R lh is other than H.
• both R lg and R lh are other than H.
• the present disclosure provides a compound, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, in which the formula is Formula (I) (e.g, Formula (1-1), (1-2), (1-3), (1-4), (1-5), and (1-6)):
• the present disclosure provides a compound, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, in which the formula is Formula (la):
• the present disclosure provides a compound, and pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers thereof, in which the formula is Formula (lb):
• the present disclosure provides a compound of formulae (I), (la), or (lb), having one, two, or three of the following features:
• R 100 is H

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