WO2026030578A1 - Composés pour l'inhibition du récepteur de la thyréostimuline - Google Patents

Composés pour l'inhibition du récepteur de la thyréostimuline

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Publication number
WO2026030578A1
WO2026030578A1 PCT/US2025/040102 US2025040102W WO2026030578A1 WO 2026030578 A1 WO2026030578 A1 WO 2026030578A1 US 2025040102 W US2025040102 W US 2025040102W WO 2026030578 A1 WO2026030578 A1 WO 2026030578A1
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Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
acceptable salt
6alkyl
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English (en)
Inventor
Li Ren
Joseph P. Lyssikatos
Alex Andrew KELLUM
David Austin MORENO
Alexandra Nicole SMITH
Samuel Kintz
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Enliven Inc
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Enliven Inc
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Publication of WO2026030578A1 publication Critical patent/WO2026030578A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure relates generally to compounds and compositions thereof for inhibition of thyrotropin or thyroid stimulating hormone receptor (TSHR).
  • TSHR thyroid stimulating hormone receptor
  • TSHR thyroid stimulating hormone receptor
  • GPCR G-protein coupled receptor
  • TSH thyroid stimulating hormone
  • TSH binding to TSHR stimulates multiple intracellular signaling pathways including the second messengers cyclic adenosine monophosphate (cAMP), inositol 1,4,5 tripoliosphate (IP3) and diacylglycerol (DAG), as well as the b-arrestins which together promote thyroid hormone release, proliferation of thyroid cells and organ homeostasis (Girnita, L., Smith, T. J., & Janssen, J. a. M. J. L. (2022). It takes two to tango: IGF-I and TSH receptors in thyroid eye disease. The Journal of Clinical Endocrinology & Metabolism, /(//(Supplement 1), SI-
  • TSHR belongs to the glycoprotein-hormone receptor family of GPCRs, along with lutropin receptor (LHR) and foilitropin receptor (FSHR) (Nagayama et al.) (Rapoport et al.).
  • LHR lutropin receptor
  • FSHR foilitropin receptor
  • the GPCRs possess extracellular leucine rich repeats responsible for binding their cognate hormones, eliciting a conformational change that transmits the signal across the plasma membrane to promote downstream signaling (Nagayama et al.) (Rapoport et al.).
  • TSHR Aberrant activation of TSHR is the underlying cause of several different thyroid- mediated pathologies including Grave’s disease.
  • Grave’s disease autoantibodies mimic TSH by binding and stimulating TSHR to drive excessive thyroid hormone release and consequent hyperthyroidism (Girnita et al.).
  • the insulin-like growth factor- 1 receptor (IGFR) is also thought to be involved in IGFR.
  • TSHR activating mutations are found in non- autoimmune thyroid diseases and thyroid cancer cells are sensitive to TSHR targeting therapies 1 . Therefore, a small molecule antagonist of TSHR may be useful for the treatment of these diseases as well.
  • a small molecule inhibitor with good pharmacokinetic and pharmacodynamic properties would also be advantageous to combine with the IGFR targeting therapies that are currently used clinically for TED.
  • a compound of Formula (A” is absent or a bond, wherein when — is a bond, R° and R z are absent; A f and A 2 are CR W ; A 3 is
  • CR W and A 4 is N, or A 3 is N and A 4 is CR W ; wherein at least one of A 1 , A 2 , A 3 , and A 4 is CR W that is not CH or CD;
  • R w is independently at each occurrence H, halo, -CN, -NO2, -NH2, - S(O) q (C1-6alkyl), -S(O) q (C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted -NH(C1-6haloalkyl), optionally substituted C1-6alkylene-C3-8 cycloalkyl, optionally substituted Cnealkyl, optionally substituted -NH(C1-6alkylene)-C3-6cycloalkyl, optionally substituted C1-6alkylene-C
  • a compound of Formula (A”-C) pharmaceutically acceptable salt thereof, wherein: — is absent or a bond, wherein when — is a bond, R 6 and R z are absent; m is 0 or 1 ; A 1 , A 2 , A J , and A 4 are each independently CR W or N, wherein R w is independently at each occurrence H, halo, -CN, -NO?., -NH?, -S(O) q (C1-6alkyl), -S(O) q (C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted - NHC(0)NHC1-6alkyl, optionally substituted -NH(C1-6haloalkyl), optionally substituted Cu 6alkylene-C3-6 cycloalkyl, optionally substituted C1-6alkyl
  • ehaloalkyl optionally substituted Cushaloalkoxyl, optionally substituted Cs-6cycloalkyl, optionally substituted Ch-ehalocycloalkyl, optionally substituted -O-C3-8cycloalkyl, optionally- substituted -O-Cj -6alkylene-C3-6cycloalkyl, optionally substituted -O-C3-8halocycloalkyl, optionally substituted -O-CN-sheterocyclyl, optionally substituted -O-(5- to 10-membered heteroaryl), optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C3- ehalocycloalkyl, optionally substituted -NH-Ci-scyanoalkyl, optionally substituted -NH-C4- gheterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, optionally substituted Ce
  • B ‘, B 4 and B are each independently CR X or N, wherein R x is independently at each occurrence H, halo, -CN, -NO?, -NH?, -S(O) q (C1-6alkyl), -S(O) q (C.3.
  • 6cycloalkyl 6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1- 6alkyl)(C1-6alkyl), optionally substituted Cnealkyl, optionally substituted Cnehy dr oxyalkyl, optionally substituted Cnecyanoalkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3- scycloalkyl, optionally substituted -O-C3-6cycloalkyl, optionally substituted -O-C1-salkylene- C3-6cycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1, or 2; X is -
  • a f , A 2 , A ’, and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (Cb6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(Ci .galkyl), optionally substituted -N(Cb6alkyl)(C1-6alkyl), optionally substituted - NHC(O)NHC1-6alkyl, optionally substituted CnsalkyL optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyi, optionally substituted Cnshaloalkoxyl, optionally substituted Cj-ecycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted -O-C3- 6cycloalkyl, optionally substituted -O-Q-
  • B l , B 2 , B 3 , B 4 and B 5 are each independently -CR X ⁇ or -N-, wherein R K is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-salkyl), optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C3- 6cycloalkoxy, optionally substituted Cnehaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3-6cycloalkyI, optionally substituted C/ushalocycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Cs-ioaryL or optionally substituted
  • X is -C(O)R 8 or optionally substituted 5-6 membered heteroaryl
  • R l and R 2 if present, are each independently H, deuterium, F, optionally substituted C1- eaikyl, optionally substituted Cnehaloalkyl, optionally substituted C3- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ ! and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloaikyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 5 and R 6 are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ and R b are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalky 1 ;
  • R' is H, deuterium, optionally substituted Cnealkyl, or optionally substituted Cn ehaloalky 1;
  • R 8 is -NHR y , -OCH3, optionally substituted Cnealkyl, optionally substituted Cn ehaloalky 1, optionally substituted C.necycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Cnealkyl is unsubstituted or is substituted with 1, 2, 3, 4, or
  • Cnealkyl is other than tert- butyl when R x is optionally substituted aryl and the 3-8 membered heterocycloalkyl is not pyrrolidinyl; is H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • a compound of Formula (A’) or a pharmaceutically acceptable salt thereof wherein: m is 0 or 1;
  • a 1 , A 2 , A J , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NOz, -NHz, -S(O) q (C1-6alkyl), - S(O) q (C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C]-6alkyl)(C1-6alkyl), optionally substituted - NHC(O)NHC1-6alkyl, optionally substituted C1-6alkyl, optionally substituted Cnealkoxy, optionally substituted Cnehaloalkyl, optionally substituted C1-shaloalkoxyl, optionally substituted Cwecycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted -O-C3- 6cycloalkyl, optionally substituted -O-Ca
  • B 1 , B 2 , B 3 , B 4 and B 5 are each independently -CRN or -N-, wherein R x is independently at each occurrence H, halogen, -CN, -NOz, -NHz, -S(O) q (Cu6alky1), - S(O)q(C.v6cycloalkyl), -OH, optionally substituted -NH(C1-5alkyl), optionally substituted -N(C1-6a1kyl)(C1-6alkyl), optionally substituted Cnealkyl, optionally substituted Cnealkoxy, optionally substituted Cn ehaioalkyl, optionally substituted C nehaloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6halocycloalkyi, or optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5- 10 membered heteroaryl
  • X is -C(O)R 8 or optionally substituted 5-6 membered heteroaryl
  • R 1 and R 2 if present, are each independently H, deuterium.
  • F optionally substituted C1- ealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3- ecycloalkyi, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R 3 and R 4 are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cs-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted €3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R 5 and R 6 are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cs-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ and R'' are taken together with the carbon atom to which they are attached to form an optionally substituted C/nscycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl ;
  • R' is H, deuterium, optionally substituted Cnealkyl, or optionally substituted Cn ehaloalkyl; is -NHR y , -OCH3, optionally substituted C1-6alkyl, optionally substituted Cn ehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the C1-6alkyl is unsubstituted or is substituted with 1, 2, 3, 4, or
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -OH, optionally substituted - NHC(O)NHC1-6alkyl, optionally substituted Cn6alkyl, optionally substituted Cuealkoxy, optionally substituted Cushaloalkyl, optionally substituted C1-shaloalkoxyl, optionally substituted C/uecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • X is -C(())R 8 or optionally substituted 5-6 membered heteroaryl
  • R K is independently at each occurrence halogen, -CN, optionally substituted C1- ealkyl, optionally substituted C1-6alkoxy, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyL or optionally substituted 3-8 membered heterocycloalkyl;
  • R l and R 2 are each independently H, optionally substituted C1-salkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ ! and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyL or optionally substituted 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, optionally substituted (' : ⁇ .aik ⁇ I. optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R 5 and R 6 are each independently H, optionally substituted (' : ⁇ .aik ⁇ I. optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ and R b are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R' is H, optionally substituted C1-6alkyl, or optionally substituted Cj-shaloalkyl;
  • R 8 is -NHR y , -OCH3, optionally substituted C1-salkyl, optionally substituted Cu rJhaloalkyl, optionally substituted C I3-6CV cloalky 1, or optionally substituted 3-8 membered heterocycloalkyl; and R y is H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • a pharmaceutical composition comprising a compound of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a method of inhibiting a thyroid stimulation hormone receptor comprising contacting the TSHR with an effective amount of the compound of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition thereof.
  • a method of treating a TSHR-mediated disease, disorder, or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of Formula (A), (A’), (A’ ’), or (A’ -C), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition thereof.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the present disclosure as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • patient refers to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
  • mammal includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en ⁇ 2 ⁇ yl), and butenyl (e.g., but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l- yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl).
  • propenyl e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en ⁇ 2 ⁇ yl
  • butenyl e.g., but-l-en-l-
  • the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond.
  • the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group.
  • alkynyl refers to an unsaturated branched or straightchain alkyl group having the indicated number of carbon atoms (e.g,, 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-l-yn-l-yl, prop-2-yn-l-yl) and butynyl (e.g., but-l -yn-l-yl, but-l-yn-3-yl, but-3-yn-l -yl).
  • the alkynyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon triple bond.
  • the “alkynyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon triple bond is located elsewhere along the branched or straightchain alkyl group.
  • cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., Cs-Cr, cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices.
  • cycloalkyl encompasses C.i-Ce cycloalkyl, (h-Ce cycloalkyl, Cs-Ce cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or ( ;-(' ⁇ cycloalkyl.
  • cycloalkyl may be further described as a “spirocycloalkyl” or a “fused cycloalkyl”.
  • spirocycloalky 1 refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices, wherein the hydrocarbon ring is attached to the rest of the molecule at a single ring vertex (e.g. , ring carbon atom) by two covalent bonds.
  • fused cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices, wherein the hydrocarbon ring is attached to the rest of the molecule at two ring vertices (e.g. two carbon atoms) by two covalent bonds.
  • cycloalkyl is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12 alkane, etc.
  • one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon.
  • a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group
  • l,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety' is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.
  • heterocycloalkyl refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quatemized, as ring atoms.
  • a “heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic, bridged or fused ring system, spirocyclic or a polycylic ring system.
  • heterocycloalkyl can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.
  • heterocycloalkyl encompasses3- to 10- membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 6- to 10-membered heterocycloalkyl, 7- to 10-membered heterocycloalkyl, 8- to 10-membered heterocycloalkyl, 9- to 10-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 4- to 9-membered heterocycloalkyl, 5- to 9-membered heterocycloalkyl, 6- to 9-membered heterocycloalkyl, 7- to 9-membered heterocycloalkyl, 8- to 9-membered heterocycloalkyl, 3- to 8-membered
  • heterocycloalkyl may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom.
  • heterocycloalkyl encompasses C3-C9 heterocycloalkyl, C3-C8 heterocycloalkyl, C3-C7 heterocycloalkyl, C3-C6 heterocycloalkyl, C3-C5 heterocycloalkyl, C3-C4 heterocycloalkyl, C4-C9 heterocycloalkyl, C4-C8 heterocycloalkyl, C4- C7 heterocycloalkyl, C4-C6 heterocycloalkyl, C4-C5 heterocycloalkyl, C5-C9 heterocycloalkyl, C5-C8 heterocycloalkyl, C5-C7 heterocycloalkyl, C5-C6 heterocycloalkyl, C6-C9 heterocycloalkyl
  • heterocycloalkyl as described by the number of ring atoms may also be described by number of carbon atoms in the ring.
  • a piperazinyl ring may be described as a C4 heterocycloalkyl ring or a 6-membered heterocycloalkyl ring; an azetidinyl or oxetanyl ring may each be described as a C3 heterocycloalkyl ring or a 4-membered heterocycloalkyl ring.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalky 1.
  • C1-C4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, difluoromethyl, and the like.
  • haloalkyl haloalkoxy 1
  • halocycloalkyl indicate that the alkyl, alkoxyl, or cycloalkyl is substituted with 1 , 2, 3, 4, 5, or more independently selected halo groups.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together.
  • aryl encompasses Cs-Cuaryl, Cs-Cuaryl, Cio-Cwaryl, Cn-Cuaryl, Ce-Cnaryl, Cs-Cuaryl, Cio-Cnaryl, C6-Cjoaryl, Cs-Cioaryl, or
  • both rings of a polycyclic aryl group are aromatic (e.g., naphthyl).
  • polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
  • a l,2,3,4-tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
  • 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety' is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group.
  • aryl does not encompass or overlap with “heteroaryl,” as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups).
  • aryl is phenyl or naphthyl. In certain instances, aryl is phenyl.
  • heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom as valency permits. In some instances, both rings of a polycyclic heteroaryl group are aromatic.
  • polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
  • 4,5,6,7-tetrahydrobenzo[djthiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.
  • Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pynrnindinyl, triazinyl, qumolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazimyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotri azolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyndines, benzothiaxolyl, benzofuranyl, benzothienyl, ind
  • heteroaryl encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl.
  • alkyl alkyl
  • aryl alkyl
  • heteroaryl alkyl
  • aminosulfonyl sulfonyl
  • unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency -allowed position on the system.
  • a substituted group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another.
  • a substituted group or moiety bears from one to five substituents.
  • a substituted group or moiety bears one substituent.
  • a substituted group or moiety bears two substituents.
  • a substituted group or moiety bears three substituents.
  • a substituted group or moiety bears four substituents.
  • a substituted group or moiety bears five substituents.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S), boron (B), and silicon (Si).
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary’ and tertiary amines, including substituted animes, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N' ⁇ dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g. , separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom.
  • isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), J H, l l C, t3 C, !4 C, k> N, 15 N, j5 0, 17 O, !8 O, 32 P, 33 P, 35 S, i8 F, 3o Cl, l23 I and 125 I.
  • Certain isotopically labeled compounds of the present disclosure e.g, those labeled with 3 H or 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon-14 ( i4 C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (ft?., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, lj N, n C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
  • treatment is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.
  • Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the di sease.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (u) attenuates, ameliorates, or el iminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • — is absent or a bond, wherein when — is a bond, R 6 and R 7 are absent;
  • a 1 and A 2 are CR W ;
  • a 3 is CR W and A 4 is N, or A 3 is N and A 4 is CR W ; wherein at least one of A’, A 2 , A ⁇ ’, and A 4 is CR W that is not CH or CD;
  • R w is independently at each occurrence H, halo, -CN, -NOs, -NHfe, -S(O) q (C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyi), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted -NH(C1-6haloalkyl), optionally substituted C1-6alkylene-C3-6 cycloalkyl, optionally substituted C1-6alkyl, optionally substituted -NH(C1- 6alkylene)-C3-6cycloalkyl, optionally substituted C1-salkylene-C1-6alkoxy, optionally substituted C1-6hydroxyalkyl, optionally substituted C1-salkoxy, optionally substituted Cuehaloalkyl, optionally substituted Cushaloalkoxyl,
  • B 1 , B 2 , B 3 , B 4 and B 5 are each independently CR X or N;
  • R x is independently at each occurrence H, halo, -CN, -NO?, -NH2, -S(O)q(Ci -ealkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(Ci -ealkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted Cuealkyl, optionally substituted Cuehydroxyalkyl, optionally substituted C1-6cyanoalkyl, optionally substituted Ci -ealkoxy, optionally substituted Ci -ehaloalky 1, optionally substituted Cuehaloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted -O- C3-6cycloalkyl, optionally substituted -O-C1-6alkylene-Ca-ecycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted 3-8 membered heterocycloalky
  • X is -C(O)R S , -C(S)R 8 , -S(O)2R 9 , or optionally substituted 5-6 membered heteroaryl;
  • R and R 4 are each independently H, optionally substituted C1-6alkyl, optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3.8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 5 is H, halo, optionally substituted Cnealkyl, optionally substituted Cs-ehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R b if present, is H, optionally substituted C1-6alkyl, optionally substituted C1- ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 7 if present, is H, optionally substituted C1-6alkyl, or optionally substituted Cn shaloalkyl;
  • a R s is -NHR y , -OCH3, optionally substituted C1-salkyl, optionally substituted C1- ehaloalkyl, optionally substituted Ctyecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Cnealkyl is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the Cuealky 1 is other than tert-butyl when R x is optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;
  • R 9 is optionally substituted Cuealkyl
  • R y is H, optionally substituted C1-salkyl, optionally substituted Cuehaloalkyl, optionally substituted Cs ⁇ cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; wherein one or more hydrogen atoms of the compound, if present, are optionally replaced with deuterium,
  • — is absent or a bond, wherein when — is a bond, R b and R'' are absent; m is 0 or 1;
  • a 1 , A 2 , A 3 , and A 4 are each independently CR W or N, wherein R w is independently at each occurrence H, halo, -CN, -NO2, -M Lu -S(O) q (Cuealkyl), -S(O) q (C3- ecycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted - N(Ci-ealkyl)(Cuealky1), optionally substituted -NHC(O)NHCnealkyl, optionally substituted -NH(C1-6haloalkyl), optionally substituted C1-salkylene-C3-8 cycloalkyl, optionally substituted Cnealky 1, optionally substituted -NH(C1-6alkylene)-C3- ecycloalkyl, optionally substituted C1-6alkylene-C1-6alkoxy, optionally substituted Cnehy dr oxyalky
  • B 1 , B 2 , B 3 , B 4 and B 3 are each independently CR X or N, wherein R x is independently at each occurrence H, halo, -CN, -NO?, -NHz, -S(O) q (Ci -ealkyl), -S(O) q (C3- scycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted - N(C1-6alkyl)(C1-salkyl), optionally substituted Cnealkyl, optionally substituted Cu ehy dr oxy alkyl, optionally substituted C1-scyanoalkyl, optionally substituted Cn ealkoxy, optionally substituted Cuehaloalkyl, optionally substituted Cn ehaloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted -O-C3- ecycloalkyl, optionally substituted
  • X is -C(O)R 8 , -C(S)R 8 , -S(O)zR 9 , or optionally substituted 5-6 membered heteroaryi;
  • R 1 and R 2 are each independently H, optionally substituted Cnealkyl, optionally substituted C1-ghal oalkyl, optionally substituted Ca-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R J and R 4 are each independently H, optionally substituted Cnsalkyl, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecy cl oalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R" are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 5 is H, halo, optionally substituted C1-6alkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R° if present, is H, optionally substituted Cnsalkyl, optionally substituted C1- ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 7 if present, is H, optionally substituted Cnealkyl, or optionally substituted C1- shaloalkyl;
  • R 8 is -NHR y , -OCHr, optionally substituted Cnsalkyl, optionally substituted C1- shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Chalky! is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the Cnsalkyl is other than tert-butyl when R x is optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;
  • R 9 is optionally substituted C1-salkyl
  • R' is H, optionally substituted Cnealkyl, optionally substituted Cnshaloalkyl, optionally substituted Ca-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein one or more hydrogen atoms of the compound, if present, are optionally replaced with deuterium.
  • a f , A 2 , A ’, and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (Cb6alkyl), - S(O) q (C3-6cycioalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted - NHC(O)NHC1-6alkyl, optionally substituted CnsalkyL optionally substituted C1-6alkoxy, optionally substituted C1-ghaloalkyl, optionally substituted Cnshaloalkoxyl, optionally substituted Cj-ecycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted -O-C3- 6cycloalkyl, optionally substituted -O
  • B 1 , B 2 , B 3 , B 4 and B 5 are each independently -CR X ⁇ or -N-, wherein R K is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-salkyl), optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C3- 6cycloalkoxy, optionally substituted C1-6haloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted Co-ehalocycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10
  • X is -C(O)R 8 or optionally substituted 5-6 membered heteroaryl
  • R 1 and R 2 are each independently H, deuterium, F, optionally substituted C1- salkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- bcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R l and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R J and R 4 are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; are each independently H, deuterium, optionally substituted Ci- ealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C.cecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R' is H, deuterium, optionally substituted Cj ⁇ alkyl, or optionally substituted C1- ehaloalkyl;
  • R 8 is -NHR y , -OCH3, optionally substituted Cnealky 1, optionally substituted Ci- ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Ci-ealkyl is unsubstituted or is substituted with 1, 2, 3, 4, or
  • Ci-ealkyl is other than tert-butyl when R x is optionally substituted aryl and the 3-8 membered heterocycloalkyl is not pyrrolidinyl,
  • R y is H, optionally substituted Cnealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cwecycloalkyl, or optionally substituted 3-8 membered heterocycloalky I .
  • a 1 , A 2 , A J , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO2, -NHz, -S(O) q (C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted - NHC(0)NHC1-6alkyl, optionally substituted C1-6alkyl, optionally substituted Cnealkoxy, optionally substituted Cnehaloalkyl, optionally substituted Cnshaloalkoxyl, optionally substituted Cuecycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted -O-C3- 6cycloalkyl, optionally substituted -O-Ca-sheterocycle
  • B ⁇ B 2 , B 3 , B 4 and B 5 are each independently -CRN or -N-, wherein R x is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (Cu6alky1), - S(O) q (C3-6cycloalky1), -OH, optionally substituted -NH(C1-5alkyl), optionally substituted -N(C1-6a1kyl)(C1-6alkyl), optionally substituted Chalky!, optionally substituted Cnealkoxy, optionally substituted Cu shaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C.cecycloalkyl, optionally substituted C.cehalocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1 , or 2;
  • X is -C(O)R 8 or optionally substituted 5-6 membered heteroaryl
  • R 1 and R 2 are each independently H, deuterium, optionally substituted Cn ealkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R 3 and R 4 are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cwhaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl ;
  • R 5 and R b are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl ;
  • R 8 is -NHR y , -OCH3, optionally substituted C1-6alkyl, optionally substituted Cu ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the C1-6alkyl is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the C1-6alkyl is other than tert-butyl when R x is optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;
  • R y is H, optionally substituted C1-6alkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • the compound of formula (.A’) is a compound of Formula
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N ⁇ , wherein R w is independently at each occurrence H, halogen, -CN, -OH, optionally substituted - NHC(O)NHC1-6alkyl, optionally substituted C1-6alkyl, optionally substituted Cuealkoxy, optionally substituted Cuehaloalkyl, optionally substituted C1-shaloalkoxyl, optionally substituted Cuecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • X is -C(O)R 8 or optionally substituted 5-6 membered heteroaryl
  • R x is independently at each occurrence halogen, -CN, optionally substituted C1- ealkyl, optionally substituted C1-6alkoxy, optionally substituted Cuehaloalkyl, optionally substituted C3-6cycloalkyL or optionally substituted 3-8 membered heterocycloalkyl;
  • R’ ! and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, optionally substituted ( ' : r.a 1 ky L optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R 5 and R 6 are each independently H, optionally substituted ( ' : r.a 1 ky I, optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R’ and R b are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I ;
  • R' is H, optionally substituted Cusalkyl, or optionally substituted Cj-shaloalkyl;
  • R 8 is -NHR y , -OCH3, optionally substituted Cusalkyl, optionally substituted Cu rJhaloalkyl, optionally substituted (?3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; and
  • R y is H, optionally substituted Cnsalkyl, optionally substituted Cuehaloalkyl, optionally substituted Ca-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NCh, -NH2, -S(O) q C1-6alkyl), - S(O) q (C3-6cycloalkyl), -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), - NHC(O)NHC1-6alkyl, C1-6alkyl, C1-6alkoxy, C3-6cycloalkoxy, C1- ehaloalkyl, C1-6haloalkoxyl, Cb-ecycloalkyl, C3-6halocycloalkyl, -O-C3- 6cycloalkyl, -O-C4-8heterocycle, -NH-CAecycloalkyl, -
  • B 1 , B 2 , B 3 , B 4 and B 5 are each independently -CR X ⁇ or -N-, wherein R K is independently at each occurrence H, halogen, -CN, -NO2, -NHs, -S(O) q (C1-6alkyl), -S(O) q (C3- ecycloalkyl), -OH, -NH(C1-6aikyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1- ealkoxy, Ci -ehaloalky 1, Ci -ehaloalkoxy 1, Ca-ecycloalkyl, Cvehalocycloalkyl, 3-8 membered heterocycloalkyl, Ce-ioaryl, or 5-10 membered heteroaryl; q is 0, l, or 2;
  • X is ⁇ C'(O)R 8 or 5-6 membered heteroaryl
  • R’ ! and R 2 if present, are each independently H, deuterium, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, or 3-8 membered heterocycloalkyl, or
  • R ! and R 2 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, deuterium, C1-6alkyl, C1-ghaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an Cwscycloalkyl, or 3-8 membered heterocycloalkyl;
  • R’ and R b are each independently H, deuterium, C1-salkyl, Cuehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 5 and R b are taken together with die carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R’' is H, deuterium, C1-6alkyl, or Cnehaloalkyl
  • R 8 is -NHR y -OCH3, C1-6alkyl, C1-6haloaikyl, Cmecycloalkyl, or 3-8 membered heteroaryl
  • R y is H, Cnealkyl, C1-ghaioalkyl, C3-6cycloalkyi, or 3-6 membered heterocycloalkyl.
  • a ⁇ A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO?, -NH?, -S(O) q C1-6alkyl), - S(O) q (C3-6cycloalkyl), -OH, -NHl'C1-6alkyl), -N(Ci..6alkyl)(Ci.
  • X is -C(O)R 8 or 5-6 membered heteroaryl
  • R 1 and R 2 are each independently H, deuterium, Ci-ealkyl, Ci -ehaloalkyl, C3- ecycloalkyL or 3-8 membered heterocycloalkyl, or
  • R 1 and R 2 are taken together with the carbon atom to which they are atached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, deuterium, C1-6alkyl, Cj -ehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an (N-scycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 5 and R 6 are each independently H, deuterium, C1-6alkyl, C1-shaloalkyl, C/i-scycloalkyl, or 3-6 membered heterocycloalkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R' is H, deuterium, Cuealkyl, or C1-shaloalkyl
  • R 8 is -NHR y , -OCH3, C1-salkyl, Ci-ehaloalkyl, Cr-ecycloalkyl, or 3-8 membered heteroaryl;
  • R y is H, C1-6alkyl, C1-ghaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • a 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -OH, -NHC(O)NHCj -ealkyl, Co ealkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxyl, Cb-ecycloalkyl, or 3- 8 membered heterocycloalkyl;
  • X is -C(O)R 8 or 5-6 membered heteroaryl
  • R x is independently at each occurrence halogen, -CN, C1-6alkyl, Ci -ealkoxy, C1- ehaloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 1 and R 2 are each independently H, C1-6alkyl, C1-6haloalkyl, Cb-ecycloalkyl, or 3-8 membered heterocycloalkyl, or
  • R : and R 2 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, CuealkyL C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an Cs-gcycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 3 and R° are each independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 3 and R 3 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 7 is H, C1-6alkyl, or C1-shaloalkyl;
  • R 8 is -NHR y , -OCH.% C1-salkyl, Cnehaloalkyl, C3-6cycloalkyl, or 3-8 membered heteroaryl;
  • R y is H, C 1. ealkyl, C1-ghaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • m is 0 or 1 ;
  • n is an integer from 0 to 5;
  • X is C(O)R 8 ;
  • a 1 , A 2 , A J , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, optionally substituted Cnsalkyl, optionally substituted C1-salkoxy, optionally substituted C1-shaloalkyl, optionally substituted Cs-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R x is independently at each occurrence halogen, -CN, optionally substituted C1-
  • 6alkyl optionally substituted C1-6alkoxy, optionally substituted Cuehaloalkyl, optionally substituted Ca-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R 1 and R 2 are each independently H, optionally substituted Cnsalkyl, optionally substituted C1-shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R : and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, optionally substituted C1-6alkyl, optionally substituted Cnshaloalkyl, optionally substituted C/uscycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R : and R° are each independently H, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R' is H, optionally substituted Cuealkyl, or optionally substituted Cnehaloalkyl
  • R 8 is -NHR y , optionally substituted C1-6alkyl, optionally substituted Ci .ehaloalkyl, optionally substituted (A-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; and
  • R y is H, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I .
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, Cuealkyl, Cs-ealkoxy, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl;
  • X is C(())R 8 ;
  • R x is independently at each occurrence halogen, -CN, Cuealkyl, Cuealkoxy, Cu ehaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl;
  • R 1 and R 2 if present are each independently H, Cuealkyl, Ci -ehaloalkyl, Ca-ecycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an Cj-scycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 5 and R 6 are each independently H, C1-6alkyl, Cuehaloalkyl, Cr-ecycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R' is H, Chalky!, or Cushaloalkyl
  • R 8 is -NHR y , C1-6alkyl, or C3-8cycloalkyl
  • R y is H, C1-6alkyl, C1-ghaloalkyl, Ch-ecycloalkyl, or 3-6 membered heterocycloalkyl.
  • a 1 , A 2 , A J , and A 4 are each independently -N- or -CR W ⁇ , wherein R w is independently at each occurrence H, halogen, -CN, Cusalkyl, -NHC(O)NHC1-6alkyl, - N(C1-6alkyl)(C1-6alkyl), Ci -ealkoxy, C1-6haloalkoxyl, Cs-gcycloalkyl, or 3-8 membered heterocycloalkyl wherein, the C1-6alky 1 of R w is optionally substituted with one or more - OH or C1-6a1koxy, and the Cs-bCycloalkyl of R w is optionally substituted with one or more halo;
  • B 1 , B 2 , B 3 , B 4 , and B 5 are each independently -N- or -CR X -, R x is independently at each occurrence H, halogen, -CN, -N(CMalkyl)(C1-6alkyl), C1-salkyl, C1- shaloalkyl, Ci.6haloalkoxyl, C1-6alkoxy, C3-8cycloalkyl, or 3-8 membered heterocycloalkyl wherein, the C1-salky 1 of R x is optionally substituted with one or more - OH or -CN, the Cnealkoxy of R x is optionally substituted with one or more Co-ecycloalkyl, and the C3-6cycloalkoxy of R x is optionally substituted with one or more -CN;
  • X is C(O)R 8 or 5-6 membered heteroaryl
  • R’ ! and R 2 if present, are each H;
  • R 3 and R 4 are each independently H or C1-6alkyl
  • R’ and R'' are each H;
  • R 7 is H
  • R 8 is -M IR'. -OCH3, or C1-6alkyl
  • R y is H or C1-6alkyl.
  • a 1 , A 2 , A J , and A 4 are each independently -N- or -CR W -, wherein R w is independently at each occurrence H, halogen, -CN, C1-6alkyl, -NHC(O)NHC1-6alkyl, - N(C1-6alkyl)(C1-6alkyl), C1-6alkoxy, C1-6haloalkoxyl, C3-8cycloalkyl, or 3-8 membered heterocycloalkyl wherein, the alkyl of R w is optionally substituted with one or more -OH or C1-6alkoxy, and the C/i-gcycloalkyl of R w is optionally substituted with one or more halo;
  • B 2 , B 3 , B 4 , and B 5 are each independently -N ⁇ or ⁇ CR X ⁇ , R x is independently at each occurrence H, halogen, -CN, -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1- 6haloalkyl, Cwhaloalkoxyl, Ci -ealkoxy, Co-ecycloalkyl, or 3-8 m embered heterocy cloal ky 1 ;
  • R 5 and R 6 are each H; R 7 is H;
  • R y is H or Cbealkyl.
  • R x is independently at each occurrence halogen, -CN, C1-6alkyl, or C1-6alkoxy;
  • R 1 and R 2 if present, are each H;
  • R 3 and R 4 are each independently H or C1-6alkyl
  • R 5 and R 6 are each H
  • R is H
  • R 8 is -NHR y , -OCH3, or ( ' : ,.a!kyh and
  • n is an integer from 0 to 2
  • a 1 , A 2 , A J , and A 4 are each independently -CR W -, wherein R w is independently at each occurrence H, halogen, -CN, C1-salkyl, or -NHC(O)NHC1-6alkyl;
  • X is C(O)R 8 ;
  • R x is independently at each occurrence halogen, -CN, C1-6alkyl, or C1-salkoxy;
  • R >! and R 2 if present, are each H;
  • R 3 and R 4 are each independently H or C1-6alkyl; R 5 and R 6 are each H;
  • R is H
  • R 8 is -NHR y , -OCH3, or ( ' : ,.a!kyh and
  • R y is H or C1-6alkyl.
  • the compound of Formula (A’) is a compound of Formula
  • the compound of Formula (A), (A’), (A”), or (A”-C) is a compound of Formula (I):
  • the compound of Formula (F) Is a compound of Formula (F-a), or (F-b):
  • R 2 , R:y R 4 , R 5 , R 6 , R 7 , and R 8 are defined as in Formula (F).
  • provided is a compound of Formula (F-a).
  • provided is a compound of Formula (F-a).
  • the compound of Formula (I) or (!’ ) is a compound of Formula (I-a), or (I-b):
  • the compound of Formula (A’) is a compound of Formula (II):
  • the compound of Formula (A), (A’), (A’ ’), or (A 7 ’-C) is a compound of Formula (11): or a pharmaceutically acceptable salt thereof, wherein A f , A 2 , A 3 , A 4 , R’ ! , Ry R J , R 4 , R ? , R 6 ,
  • Ry R x . and n are defined as in Formula (A), and ring A is an optionally substituted 3-8 membered heteroaryl.
  • the compound of Formula (IF) is a compound of Formula (IF -a) or (H’-b):
  • R ⁇ R 3 , R 4 , R ⁇ R°, and R ? are defined as in Formula (II’), and ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, provided is a compound of Formula (IF -a). In some embodiments, provided is a compound of Formula (ll’-b).
  • the compound of Formula (II) or (IF) is a compound of Formula (Il-a) or (Il-b):
  • ring .A is a 3-8 membered heteroaryl.
  • ring .A is an optionally substituted 5-6 membered heteroaryl.
  • provided is a compound of Formula (Il-a).
  • pro vided is a compound of Formula (Il-b).
  • ring A is 3-8 membered heteroaryl.
  • ring A is 3-6 membered heteroaryl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is
  • ring A is 5-6 membered heteroaryl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is
  • m is 0 or 1
  • m is 0.
  • m is 1.
  • a 1 , At A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (C1-6a1kyI), -S(O) q (C;c 6cycloalkyl),-OH, optionally substituted -NH(Cn6alkyl), optionally substituted -.N(Cj.
  • 6alkyl (Ci-6alkyl), optionally substituted -NHC(O)NHCb6alky1, optionally substituted C1- ealkyl, optionally substituted Cuealkoxy, optionally substituted Cnehaloalkyl, optionally substituted Cnshaloalkoxyl, optionally substituted Ca-ecycloalkyl, optionally substituted C3- fihalocycloalkyl, optionally substituted -O-Ca-scycloalkyl, optionally substituted -O-C4- gheterocycle, optionally substituted -NH-C3-6cycloalkyl, optionally substituted -.NFI-Ca- sheterocycle, or optionally substituted 4-8 membered heterocycloalkyl.
  • a 1 , A 2 , Af and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (C1-6aIkyl), -S(O) q (C3- 6cycloalkyl), -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -NHC(O)NHC1-6alkyl, C1-6alkyl, Cneaikoxy, Cnehaioalkyl, Cnshaloalkoxyl, Cj-scycioalkyl, C3-8halocycloalkyl, -O-C3- 6cycloalkyi, -0-Ci-sheteroc.ycle, -NH-C3-6cycloalkyl, -NH-Q-sheterocycle, or 4
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -OH, optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted Cnealkyl, optionally substituted C1- ehaloalkoxyl, optionally substituted Cusalkoxy, optionally substituted C1-6haloalkyl, optionally substituted Cr-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted Ci -ealkyl, optionally substituted Cuealkoxy, optionally substituted Ci -ehaloalky 1, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments.
  • a 1 , A 2 , A J , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -OH, -NHC(O)NHC1-6alkyl, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1- ehaloalkoxyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-6alkyl, C1-6alkyl, Cuealkoxy, C1-6haloalkyl, Cs- 6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • a 1 , A 2 , A J , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -NHC(())NHC f -6alkyl, or Cuealkyl.
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence FI, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted Cnealkoxy, optionally substituted Cj-shaloalkyl, optionally substituted Cuecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • a 1 , A 2 , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C.u ecycloaikyl, or 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen.
  • R w is independently at each occurrence H, halogen, -CN, optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted Cisalkyl, optionally substituted C1-6alkoxy, optionally substituted C1-shaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted C1- ⁇ alkyl, optionally substituted C1-salkoxy, optionally substituted C1-shaloalkyL optionally substituted C3-6cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, -OH, -NHC(O)NHC1-6alkyl, Cnealkyl, C1-6alkoxy, C1- ehaloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, -NHC(O)NHC1- ealkyl, Cj-salkyl, C1-6alkoxy, Cushaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-3alkyl, Cjoalkyl, Ciualkoxy, Ci-ohaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-6alkyl, or C1-6alkyl.
  • R w is independently at each occurrence H, halogen, -CN, -NHC(())NHC1-6alkyl, or C1.3alkyl.
  • R w is independently at each occurrence H, Cl, -CN, - NHC(O)NH(isopropyl), or methyl. In some embodiments, R w is independently at each occurrence II or halogen. In some embodiments, R w is independently at each occurrence H or Cl. In some embodiments, R w is independently at each occurrence H or -CN. In some embodiments, R w is independently at each occurrence H or -NHC(())NHCn6alkyl. In some embodiments, R w is independently at each occurrence H or -NHC(O)NHCi-3alkyl. In some embodiments, R w is independently at each occurrence H or -NHC(())NH(isopropyl).
  • R w is independently at each occurrence H or Cuealkyl. In some embodiments, R w is independently at each occurrence H or C1-ralkyl. In some embodiments, R w is independently at each occurrence H or methyl.
  • R w is independently at each occurrence H, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, optionally substituted C1-salkyl, optionally substituted C1-salkoxy, optionally substituted C1-3haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R w is independently at each occurrence H, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R w is independently at each occurrence H, halogen, -CN, C1-ralkyl, C1-3alkoxy, C1-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R w is independently at each occurrence H, halogen, -CN, or C1-6alkyl. In In some embodiments, R w is independently at each occurrence H, halogen, -CN, or C1-salkyl. In some embodiments, R w is independently at each occurrence H, Cl, -CN, or methyl. In some embodiments, R w is independently at each occurrence H or halogen.
  • R w is independently at each occurrence H or Cl. In some embodiments, R w is independently at each occurrence II or -CN. In some embodiments, R w is independently at each occurrence FI or C1-6alkyl. In some embodiments, R w is independently at each occurrence FI or C1-3alky1. In some embodiments, R w is independently at each occurrence H or methyl.
  • R w is independently at each occurrence H, Cl, or F.
  • R* is independently at each occurrence H or -N(methyl)2.
  • R w is independently at each occurrence H or Cnealkyl, wherein the C1-salkyl of R w is optionally substituted with one or more -OH or Cu6alkoxy.
  • R w is independently at each occurrence II, methyl, ethyl, isopropyl, -CH2OH, -CH2OCH3.
  • R w is independently at each occurrence II, halogen, C1-6alkoxy, or C1-ghaloalkoxyl. In some embodiments, R w is independently at each occurrence H, F, -OCII3, -OCH2CH3, - OCHfCHsh. or -OCF3. In some embodiments, R w is independently at each occurrence H or C3-6cycloalkyl, wherein the Cb-ecycloalkyl of R w is optionally substituted with one or more halo. In some embodiments, R w is independently at each occurrence H or C3-6cyclopropyl, wherein the C3-6cyclopropyl of R w is optionally substituted with one or more F. In some embodiments, R w is independently at each occurrence H or 3-8 membered heterocvcloalkvl.
  • R" is independently at each occurrence H, , or —I— .
  • A’ ! , A 2 , A 3 , and A 4 are each independently -CR W ⁇ or ”N ⁇ .
  • each of A 1 , A 2 , A 4 , and A 4 is -CR W ⁇ .
  • each of A 1 , A 2 , A 3 , and A 4 is -CH-.
  • one of A 1 , A 2 , A J , and A 4 is other than ⁇ CH-.
  • one of A 1 , A 2 , A 3 , and A 4 is -N ⁇ .
  • n is an integer from 0 to 5. In some embodiments, n is an integer from 1 to 3. In some embodiments, n is an integer from 0 to 2. In some embodiments, r? is 0. In some embodiments, n is 1 or 2. In some embodiments, n isl. In some embodiments, n is 2. In some embodiments, n is 3.
  • each of B ! , B 2 , Bf B 4 , and B 5 is -CR X -.
  • each of B 1 , B 2 , B' ⁇ B 4 , and B 5 is -CH-.
  • B l , B 2 , B J , B 4 , and B 3 is other than -CH-.
  • one of B 1 , B 2 , B 3 , B 4 , and B 5 is -N-.
  • R x is independently at each occurrence H, halogen, -CN, -NOi, -NFb, -S(O) q (C1- 6alkyl), -S(O) q (C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted C1-6alkyl, optionally substituted Cnealkoxy, optionally substituted C1-6haloalkyl, optionally substituted C1-ghaloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6halocycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R x is independently at each occurrence H, halogen, -CN, -NOz, -NH2, -S(O) q (C1-6alkyl), -S(O) q (C3-6cycloalkyl), - OH, -NH(C1-6alkyl), -N(C]-6alkyl)(C1-6alkyl), C1-6alkyl, C1-salkoxy, C1-6haloalkyl, C1- ehaloalkoxyl, C3-6cycloalkyl, C3-6halocycloalkyl, or 3-8 membered heterocycloalkyl.
  • R x is independently at each occurrence H, halogen or C1-6alkyl.
  • R x is independently at each occurrence H or -CN. In some embodiments, R x is independently at each occurrence H, halogen, or -N(C1-6alkyl)(C1-6alkyl). In some embodiments, wherein R x is independently at each occurrence H, or Cuealkoxy. In some embodiments, R x is independently at each occurrence H, halogen or Cj-ecycloalkyl. In some embodiments, R x is independently at each occurrence H, halogen or, or 3-8 membered heterocycloalkyl.
  • R x is independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O) q (C1- 6alkyl), -S(O) q (C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alkyl), optionally substituted C1-galkyl, optionally substituted Cnealkoxy, optionally substituted C3-8cycloalkoxy, optionally substituted C1-6haloalkyl, optionally substituted Cnehaloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-8halocycloalkyl, or optionally substituted 3-8 membered heterocycloalkyd.
  • R x is independently at each occurrence H, halogen, -CN, -NO2, -NH2, - S(O) q (C1- 6 alkyl), -S(O) q (C3-6tycloalkyl), -OH, -NH(C1-salkyl), -N(C1- 6 alkyl)(C h-salkyl), Cu ealkyl, C1-salkoxy, C1-scycloalkoxy, C1-6haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, C3- ehalocycloalkyl, or 3-8 membered heterocycloalkyl.
  • R x is independently at each occurrence H, halogen, C1-salkyl, C3-6cycloalkoxy, or C3-6cycloalky1. In some embodiments, R x is independently at each occurrence H, halogen or C3-6cycloalky1, wherein the C3-6cycloalkyl is optionally substituted with one 1-3 CN. In some embodiments, the C1-6alkyl of R x is optionally substituted with 1-3 CN. In some embodiments, the Cn ealkoxy of R x is optionally substituted with one or more Ca-ecycloalkyl.
  • R x is independently at each occurrence H, halogen or (Nealkyl, wherein the Cn ealkyl of R x is optionally substituted with one or more -OH. In some embodiments, R x is independently at each occurrence H, or Cnealkoxy, wherein the C h -ealkoxy of R x is optionally substituted with one or more Ca-ecycloalkyl. In some embodiments, the C1-6alkyl of R x is optionally substituted with one or more -OH. In some embodiments, the C a .ealkoxy of R x is optionally substituted with one or more C/i-ecycloalkyl.
  • R x is independently at each occurrence H, halogen or C1-6alkyl, wherein the Cuealkyl of R x is optionally substituted with one or more -OH. In some embodiments, R x is independently at each occurrence H, or C1-6alkoxy, wherein the Ci-ealkoxy of R x is optionally substituted with one or more C3-6cycloalkyl.
  • R x is independently at each occurrence halogen, - CN, optionally substituted C1-6alkyl, optionally substituted Ci-ealkoxy, optionally substituted Cuehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R x is independently at each occurrence halogen, - CN, optionally substituted C1-salkyl, optionally substituted Cmalkoxy, optionally substituted C1-shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyd. In some embodiments, R x is independently at each occurrence halogen, - CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R x is independently at each occurrence halogen, -CN, C1-salkyl, C1- ealkoxy, C1-shaloalkyl, C1-scycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, R x is independently at each occurrence halogen, -CN, Cnsalkyl, or C1-6alkoxy, In some embodiments, R x is independently at each occurrence halogen. In some embodiments, R x is independently at each occurrence Cl or F. In some embodiments, R x is - CN. In some embodiments, R x is independently at each occurrence halogen or C1-6alkyl. In some embodiments, R x is independently at each occurrence Cl, F, or methyl. In some embodiments, R x is Cnealkoxy.
  • the moiety represented by is selected from the group consisting of some embodiments, the moiety represented by
  • R 1 and R 2 are each independently H, deuterium, optionally substituted C1- ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 1 and R 2 are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted Cmecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 1 and R 2 are each independently H, Cnsalkyl, C1-6haloalkyl, C3- 6cycloalkyl, or 3-8 membered heterocycloalkyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 1 and R 2 are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 1 and R z if present, are each independently H, Cnsalkyl, C1-6haloalkyl, C3- gcycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are different. In some embodiments, R 1 and R 2 are each H. In some embodiments, m is 1 , and R 1 and R 2 are each H.
  • R 1 and R 2 if present are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 1 and R z if present are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3- 6cycloalkyl, or optionally substituted 3-8 membered heterocycloalky 1, or R 3 and R' 1 are taken together with the carbon atom to which they are attached to form an optionally substituted C3- scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are each independently H, C1-6alkyl, Cnshaloalkyl, Cr-scycloalkyl, or 3-8 membered heterocycloalkyl, or R J and R 4 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted CnehaloalkyL optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are each independently H, deuterium, C1-6alkyl, Cnshaloalkyl, Cn-scycloalkyl, or 3-8 membered heterocycloal ky 1.
  • R J and R 4 are each independently H, optionally substituted C1-salkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are each independently H, Cusalkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 3 and R 4 are the same. In some embodiments, R 3 and R 4 are different.
  • R 3 and R 4 are each independently H or C1-salkyl. In some embodiments one of R 3 and R 4 is H and the other of R J and R 4 is methyl. In ome embodiments, R 3 and R 4 are each H.
  • R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted CR-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R 3 and R 4 are taken together with the carbon atom to winch they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 5 and R 6 are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3- 6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R' and R°are taken together with the carbon atom to which they are attached to form an optionally substituted C3- scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R' is H, deuterium, optionally substituted Cn6alkyl, or optionally substituted Cn ehaloalkyl.
  • R/ is H, deuterium, Cnealkyl, or C1-shaloalkyl
  • R 7 is H, optionally substituted C1-6alkyl, or optionally substituted C1-6haloalkyl.
  • R ? is H, C1-6alkyl, or C1- ehaloalkyl.
  • X is 3-8 membered heteroaryl. In some embodiments, X is 3-6 membered heteroaryl. In some embodiments, X is 5-6 membered heteroaryl. In some embodiments, X is 5 membered heteroaryl. In some embodiments, X is
  • R 8 is -NHR y , optionally substituted C1-galkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the C1-6alkyl is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the C1-6alkyl is other than tert-butyl when R x is optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl.
  • R 8 is -NHR y optionally substituted Ct-galkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R 8 is -NHR y , C1-6alkyl, Cnehaloaikyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl.
  • R 8 is -XI HF .
  • R 8 is -NHR y , -OCH3, optionally substituted C1-salkyl, optionally substituted Ciohaloalkyl, optionally substituted Ce-ecycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R 8 is -NHR y , -OCH3, Cuialkyl, Ciohaloalkyl, C3- ecycloalkyl, or 3-6 membered heterocycloalkyl.
  • 3-8 membered heterocycloalkyl is not pyrrolidinyi.
  • R 8 is -NHR y , C1-6alkyl, optionally substituted C>. 6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein: C1-salkyl is substituted with 0, 1, 2, 3, 4, or 5 instances of independently selected halo; and
  • 3-8 membered heterocycloalkyl is not pyrrolidinyi.
  • R 8 is -NHR y , C1-6alkyl, optionally substituted C>. 6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein: C1-salkyl is optionally substituted with 0, 1, 2, 3, 4, or 5 instances of independently selected halo; and
  • 3-8 membered heterocycloalkyl is not pyrrolidinyi.
  • R 8 is -OCH3.
  • R 8 is optionally substituted C1-6alkyl.
  • R 8 is C1-6alkyl.
  • R 8 is optionally substituted Cioalkyl.
  • R 8 is C1-salkyl.
  • R 8 IS C1-6alkyl optionally substituted with 0, 1, 2, 3, 4, or 5 instances of independently selected halo.
  • R 8 is C1-salkyl optionally substituted with halo.
  • R 8 is methyl or ethyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl.
  • R 8 is -NHR y , such that the compound is a compound of Formula (I ’-A):
  • R 8 is -NHR y , such that the compound is a compound of Formula (I- A):
  • R y is H, optionally substituted Ci-ealkyl, optionally substituted Cj. ehaloalkyl, optionally substituted CAficycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.
  • R y is H, Cnealkyl, (>.. filial oalkyl, Cs.ficycloalkyl, or 3-6 membered heterocycloalkyl.
  • R y is H or Cnsalkyl.
  • R y is H.
  • R y is C1-salkyl.
  • R y is Cisalkyl.
  • R y is methyl.
  • m is 0 or 1;
  • a 1 , A 2 , A 3 , and A 4 are each independently -N- or -CR W ⁇ , wherein R'' is independently at each occurrence H, halogen, -CN, Cnsalkyl, -NHC(O)NHCi.6alkyl. - N(Cu6alkyl)(C1-6aikyl), Ci-6alkoxy, Ci .ghaloalkoxyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl wherein, the alkyl of R w is optionally substituted with one or more -OH or Cnealkoxy, and the Cb-ecycloalkyl of R w is optionally substituted with one or more halo;
  • B 1 , B 2 , B 3 , B 4 , and B 5 are each independently -N- or -CR X -, R x is independently at each occurrence H, halogen, -CN, -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, Cu shaloalkyl, Cnehaloalkoxyl, Cj.6alkoxy, C3-8cycloalkyl, or 3-8 membered heterocy cloalky 1 ; q is 0, 1 , or 2;
  • X is C(O)R 8 or 5-6 membered heteroaryl
  • R 1 and R 2 if present, are each H;
  • R 5 and R° are each H
  • R 7 is H
  • R 8 is -NHR y , -OCHs, or C1-6alkyl
  • R y is H or C1-6alkyl.
  • n is an integer from 0 to 2;
  • X is -C(O)R 8 ;
  • a ⁇ A 2 , A 3 , and A 4 are each independently -CR W -, wherein R w is independently at each occurrence H, halogen, -CN, or Cnsalkyl;
  • R x is independently at each occurrence halogen, -CN, Cuealkyl, or Cuealkoxy;
  • R 1 and R 2 if present, are each H;
  • R 3 and R 4 are each independently H or Cuealkyl
  • R 5 and R b are each H
  • R 7 is H
  • R 8 is -NHR y ;
  • the compound is a compound of formula (S’-l ), In some embodiments, the compound is a compound of formula (S’-2). In some embodiments, the compound is a compound of formula (S-l). In some embodiments, the compound is a compound of formula (S-2).
  • the compound or the pharmaceutically acceptable salt is not: l-(7-(difluoromethyl)-l -(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3 ⁇ yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-2-oxo- l,2,3,4-tetrahydroquino1in-3-yl)urea; l-(7-chloro-l-(5-(difluoromethyl)-2-fluorobenzyl)-2- oxo-1 ,2,3, 4-tetrahydroquinolin-3-yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-7-methy1- 2-oxo-l,2,3,4-tetrahydroqu
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof wherein the composition contains no more than 5% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof is provided wherein the composition contains no more than 3% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof is provided wherein the composition contains no more than 1% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof is provided wherein the composition contains no more than 0.5% impurity.
  • a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein.
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g, intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g, intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound, or a pharmaceutically acceptable salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g, nasal spray or inhalers), gels, suspensions (e.g, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof can be used m the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • a formulation such as a pharmaceutical formulation
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-weting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • compositions may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof maybe administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds, or a pharmaceutically acceptable salt thereof, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt thereof, can be formulated as a 10 mg tablet.
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, provided herein are also described.
  • the composition comprises a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof is provided.
  • the composition is for use as a human or veterinary medicament.
  • the composition is for use in a method described herein.
  • the composition is for use in the treatment of a disease or disorder described herein.
  • compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described.
  • the co-administration can be simultaneous or sequential in any order.
  • a compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.).
  • co-administration can be, for example, 1) concurrent delivery-, through the same route of delivery' (e.g., tablet or i.v.), 2) sequential delivery- on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery.
  • route of delivery' e.g., tablet or i.v.
  • sequential delivery- on the same day through the same route or different routes of delivery
  • 3) delivery on different days through the same route or different routes of delivery.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of Formula (A’) or (.A), such as a compound of Formula (I’), (I), (T-a), (I’-b), (La), (Lb), (I ’-A), (LA), (IL), (II), (IF -a), (II ’-b), (ILa), or (ILb), or any variation thereof provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality’ control assays.
  • a method of inhibiting a thyroid stimulation hormone receptor comprising contacting the TSHR with an effective amount of a compound or composition provided herein.
  • the compounds provided herein are selective for inhibiting TSHR.
  • the compound or composition described herein is used in a method of treating a disease or disorder mediated by TSHR activity.
  • the disease or disorder is selected from the group consisting of Grave’s disease. Grave’s ophthalmology (GO)/thyroid eye disease (TED), a non-autoimmune thyroid disease, and thyroid cancer.
  • the disease or disorder is selected from the group consisting of Grave’s disease, Grave’s ophthalmology and thyroid eye disease.
  • the disease, disorder, or condition is Grave’s disease.
  • the dose of a compound described herein, or a pharmaceutically acceptable salt thereof, administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated.
  • the amount of the compound, or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.
  • the compounds provided herein, or a pharmaceutically acceptable salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously over a period of time.
  • the dosing frequency can also be intermittent. Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • the present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt thereof, a composition described herein, or one or more unit dosages described herein m suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein, or a pharmaceutically acceptable salt thereof, thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease, disorder, or condition described herein, for example for the treatment of Grave’s disease, Grave’s ophthalmology (GO)/thyroid eye disease (TED), a non autoimmune thyroid disease, and/or thyroid cancer.
  • kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • embodiment numbers referenced in this set refer to those within set A, For example, ' ⁇ ‘Embodiment 1” recited in embodiment A2 refers to embodiment Al. Al.
  • a ⁇ A 2 , A J , and A 4 are each independently -CR W ⁇ or -N-, wherein R w is independently at each occurrence H, halogen, -GN, -OH, optionally substituted -NHC(O)NHC1- ealkyl, optionally substituted C1-6alkyl, optionally substituted Cnsalkoxy, optionally substituted C1-6haloalkyl, optionally substituted Cnehaloalkoxyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ;
  • R x is independently at each occurrence halogen, -CN, optionally substituted C1-salkyl, optionally substituted C1-salkoxy, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 1 and R z if present are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R: 1 and R 4 are each independently H, optionally substituted C1-salkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cb-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 3 and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 5 and R° are each independently H, optionally substituted Cnealkyi, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycioalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted Cb-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R'' is H, optionally substituted Cnealkyi, or optionally substituted C1-6haloalkyl
  • R 8 is -NHR y , -OCH3, optionally substituted Cnealkyi, optionally substituted C1- shaloalkyl, optionally substituted Cnecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R y is H, optionally substituted Cnealkyi, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ,
  • a 1 , A z , A 3 , and A 4 are each independently -CR W - or -N-, wherein R w is independently at each occurrence H, halogen, -CN, -OH, -NHC(O)NHCi -ealkyl, Cnealkyi, Cn ealkoxy, Cnehaloalkyl, Cnehaloalkoxyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl,
  • R x is independently at each occurrence halogen, -CN, C1-6alkyl, Ci-ealkoxy, Ci. ehaloalkyl, C.cecycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 1 and R 2 are each independently H, Cnealkyi, Cnehaloalkyl, C3- ecycloalkyl, or 3-8 membered heterocycloalkyl, or
  • R f and R 2 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyd, or 3-8 membered heterocycloalkyl;
  • R ’ and R 4 are each independently H, C1-6alkyl, C1-6haloalkyl, Cb-ecycloalkyl, or 3-6 membered heterocycloalkyl, or
  • R J and R 4 are taken together with the carbon atom to which they are attached to form an C3-8cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R 5 and R° are each independently H, Cnealkyi, Cnehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
  • R z is H, C1-6alkyl, or C1-6haioalkyl
  • R 8 is -NHR y , -OCH3, C1-6alkyl, C1-6haloalkyl, Cmscycloalkyl, or 3-8 membered heteroaryl;
  • R y is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.
  • A8 The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R w is independently at each occurrence H, halogen, -CN, - NHC(O)NHCi. 6 alkyl, or Chalky],
  • a 10 The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R w is independently at each occurrence H or Cl.
  • a 17 The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein one of A 1 , A z , A 3 , and A 4 is other than -CH-.
  • A33 The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein R 8 is -NHR y , Cnealkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein: C1-salkyl is substituted with 0, 1, 2, 3, 4, or 5 instances of independently selected halo; and
  • A44 A method of treating a TSHR-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of Embodiments 1-41, or a pharmaceutically acceptable salt thereof, or a therapeutically effecti ve amount of the pharmaceutical composition of Embodiment 42.
  • Embodiment 44 or 45 The method of Embodiment 44 or 45, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease. Grave’s ophthalmology and thyroid eye disease.
  • embodiment numbers referenced in this set refer to those within set B.
  • embodiment B2 refers to embodiment Bl.
  • R J and R 4 are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • a 1 , A 2 , A 3 , and A 4 are each independently -N- or -CR W -, wherein R w is independently at each occurrence H, halogen, -CN, Cuealkyl, -NHC(O)NHC1-6alkyl.
  • B 1 , B 2 , B 3 , B 4 , and B’ are each independently -N- or -CR X -, R x is independently at each occurrence H, halogen, -CN, -N(Ci-6alkyl)(Cb6alkyl), Crealkyl, Cj. shaloalkyl, Cnehaloalkoxyl, C i.,-.aikox> , C3-8cycloalkyl, or 3-8 membered heterocycloalkyl, wherein the Ci.galkyl of R x is optionally substituted with one or more -OH, and the Cnealkoxy of R x is optionally substituted with one or more Cb-ecycloalkyl;
  • X is C(())R 8 or 5-6 membered heteroaryl
  • R l and R 2 if present, are each H;
  • R J and R 4 are each independently H or C1-6alkyl
  • R 5 and R 6 are each H
  • R 7 is H
  • R 8 is -NHR y , -OCH3, orC1-6alkyl
  • R y is H or Cnealkyl.
  • a pharmaceutical composition comprising the compound of any one of embodiments 1- 54, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a method of inhibiting a thyroid stimulation hormone receptor comprising contacting the TSHR with an effective amount of the compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 55.
  • TSFIR thyroid stimulation hormone receptor
  • a method of treating a TSHR-mediated disease, disorder, or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 55.
  • embodiment numbers referenced in this set refer to those within set C.
  • embodiment 1 recited in embodiment C2 refers to embodiment Cl .
  • — is absent or a bond, wherein when — is a bond, R 6 and R 7 are absent; m is 0 or 1;
  • a ! , A 2 , A 3 , and A' 1 are each independently CR W or N, wherein R w is independently at each occurrence H, halo, -CN, -NOz, -NHz, -S(O) q (C1-6a1kyl), -S(O) q (C3- 6cycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted - N(C1-6alkyl)(C'.-6alkyl), optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted -NH(C1-6haloalkyl), optionally substituted C1-6alkylene-C3-6 cycloalkyl, optionally substituted C1-6alkyl, optionally substituted -NH(C1-6alkylene)-C3- ecycloalkyl, optionally substituted C1-6alkylene-C1-6alkoxy, optionally substituted C1-shy dr oxyal
  • B 1 , B 2 , B 3 , B 4 and B 5 are each independently CR S or N, wherein R x is independently at each occurrence H, halo, -CN, -NO?, -NH2, -S(O) q (C1-6alkyl), -S(O) q (C3- gcycloalkyl), -OH, optionally substituted -NH(C1-6alky1), optionally substituted - N(Cu6alkyl)(C1-6alkyl), optionally substituted C1-6alkyl, optionally substituted Cu shy dr oxy alkyl, optionally substituted C1-6cyanoalkyl, optionally substituted Cn 6alkoxy, optionally substituted Cnghaloalkyl, optionally substituted Ci.
  • ehaloalkoxyl optionally substituted C.cecycloalkyl, optionally substituted -O-C3- scycloalkyl, optionally substituted -O-C1-6alkylene-C3-6cycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted (Ze-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1, or 2;
  • X is -C(O)R 8 , -C(S)R 8 , -S(O)2R 9 , or optionally substituted 5-6 membered heteroaryl;
  • R f and R 2 if present are each independently H, optionally substituted Ci-ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cs-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or
  • R l and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 3 and R 4 are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyd, or
  • R J and R 4 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ;
  • R 5 is H, halo, optionally 7 substituted C1-salkyl, optionally' substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,
  • R b if present, is H, optionally substituted C1-6alkyl, optionally substituted Cu 6haIoalkyl, optionally substituted Cvecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;
  • R 7 if present, is H, optionally substituted C1-6alkyl, or optionally substituted Cn ehaloalkyl ;
  • R 8 is -NHR y , -OCH3, optionally substituted C1-salkyl, optionally substituted Cu ehaloalkyl, optionally substituted C3.6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the C1-6alkyl is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the C1-6alkyl is other than tert-butyl when R x is optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;
  • R 9 is optionally substituted Cnsalkyl
  • R y is H, optionally substituted C1-6alkyl, optionally substituted Cs-ehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered h eterocy cloalky 1 ; wherein one or more hydrogen atoms of the compound, if present, are optionally replaced with deuterium.
  • R w is independently at each occurrence H, halo, -NH(C1-6alkyl), -NH(C1- ehaloalkyl), -NH(C1- 3 alkylene-C3-6cycloalkyl), -N(C1-6alkyl)(C1- 6 alkyl), C1-salkyl, C1- ealkoxy, C1-shaloalkoxyl, C 3 -6cycloalkyl, C3-8halocycloalkyl, -O-Cs ⁇ cycloalkyl, -O-Cn aalkylene-C.xecycloalkyl, -O-Ca-ehalocycloalkyl, -O-Ci-gheterocyclyl, -O-(5- to 10- membered heteroaryl), -O-Ce-joaryl, -NH-Cuecycloal
  • CMBP cyanomethylenetributylphosphorane
  • DCM di chloromethane
  • DIEA diisopropylethylamine
  • DMF dimethylformamide
  • DMAP 4-dimethylaminopyridine
  • DMSO dimethyl sulfoxide
  • ESI electrospray ionization
  • EtOAc ethyl acetate
  • EtOH ethanol or ethyl alcohol
  • f H NAIR proton nuclear magnetic resonance
  • HATU hexafluorophosphate azabenzotriazole tetramethyl uromum
  • HPLC high-performance liquid chromatography
  • LCMS liquid chromatography-mass spectrometry
  • m-CPBA meta- chloroperoxybenzoic acid
  • MeCN acetonitrile
  • MeOH methanol or methyl alcohol
  • MTBE methyl tert-butyl ether
  • TFA trifluoroacetic acid
  • THF tetrahydr
  • Step 2 Synthesis of l-[(3-chJorophenyl)methyl]-2-oxo ⁇ 3,4"dihydroqiiinolm ⁇ 3-ylurea
  • Step 1 Synthesis of 3-ammo ⁇ l ⁇ [(2 ⁇ chIoropheuyi)methyi]-3,4-dihydroquinolm ⁇ 2 ⁇ one
  • Step 2 l-[(2-chiorophenyl)methyl] ⁇ 2 ⁇ oxo ⁇ 3,4"dihydroqiiinolin ⁇ 3 ⁇ ylurea (Compound 2)
  • Step 1 Synthesis of 3-amino-l-[(4-chIorophenyl)methyl]-3,4-dihydroquinoIin-2-one
  • Step 2 l-[(4-chiorophenyI)methyl] ⁇ 2 ⁇ oxo ⁇ 3,4"dihydroquinolm ⁇ 3 ⁇ ylurea (Compound 3)
  • Step 1 Synthesis of 3 ⁇ ammo"l ⁇ (2 ⁇ phenylethyl) ⁇ 3,4 ⁇ dihydroqumoim ⁇ 2 ⁇ rme
  • Step 1 Synthesis of 3-amino-l-(3- €htoro-2-fluorobenzyl)-3,4-dihydroqumoIm-2(lH)-ooe
  • Step 2 l-(l"(3 ⁇ chlorO"2-fluorobenzy8)-2-oxO"1,233"tefrahydroquinoIin ⁇ 3 ⁇ yI)urea (Compound 5)
  • Step 1 Synthesis of 3-amino-l ⁇ (3 ⁇ chloro-4-fluorobenzyI)-3,4 ⁇ dihydroqiiinoIin”2(lH) ⁇ one
  • Step 1 Synthesis of 3-amino-l-[(5- €hioro-2-fluorophenyi)methyi]-3,4-dihydroquinoiin-
  • Step 2 Syn thesis of l ⁇ [(5” €hIoro-2-flnoropheiiyI)methyI]”2”Oxo-3,4 ⁇ dihydroqiiiiioIin-3- ylurea (Compound 7)
  • Example 8 Synthesis of cis-l-(l-(l-(3-chlorophenyl)ethyl)-2-oxo-l,2,3,4- tetrahydroqmnolin ⁇ 3 ⁇ yl)urea (Compound 8) & trans ⁇ ] ⁇ (l ⁇ (l ⁇ (3 ⁇ ehloi-'ophenyl)efhyl) ⁇ 2 ⁇ oxo ⁇ l,2,3,4-tetrahydroqumolin-3-yl)urea (Compound 9)
  • Step 1 Synthesis 3-amino-l-[l-(3-chloropheiiyI)ethyl] ⁇ 3,4"dihydroqiiinolm-2 ⁇ oiie
  • Step 2 Synthesis of ciS“l“(l“(l-(3-chIorophenyI)ethyl)-2-oxO”l,2,3 ? 4“ ⁇ etrahydroquinoiiii- 3-yl)urea (Compound 8) & trans-l-(l-(l-(3"chloropheiiyl)ethyl)"2"oxo-l, 2,3,4- tetrahydroquinohn-3-yi)urea (Compound 9) cis- trans-
  • Step 1 Synthesis of l-(l-(3-chlorobenzyl)"2"Oxo-l,2,3,4-tetrahydroquinoiin-3“yi)-3- methylnrea (Compound 10)
  • Step 2 Synthesis of l-(l-(4"ChIoropheiiethyl)-2-oxo-l,2,3 5 4-tetrahydroquinolin-3-yI)urea
  • Step 2 Synthesis of l-(l-(3"drlorophenethyI) ⁇ 2 ⁇ o:TOM,23ylTetrahydroqsHnolm-3-yl)urea
  • Step 1 Synthesis of 3-amino-l ⁇ [2 ⁇ (2 ⁇ chlorophenyI)ethyl] ⁇ 3,4"dihydroquinolin ⁇ 2 ⁇ one
  • Step 2 Synthesis of l-[2-(2-chIorophenyi)ethyI]-2-oxo ⁇ 3,4-dihydroquinoIin ⁇ 3 ⁇ yIurea
  • Step 1 Synthesis of 3-ammo-l-[(2,5 ⁇ dichloropheiiyI)methyl]”3,4-dihydroquinolm ⁇ 2 ⁇ oiie
  • Step 2 Synthesis of l-[(2,5-dichIorophenyJ)methyi]-2-oxo-3,4-dihydroquinoHn-3-yiurea
  • Step 1 Synthesis of 3 ⁇ ammo-l-[(5-chIoro ⁇ 2 ⁇ methyIphenyl)methyJ]"3,4-dihydroqumoIin- 2-one [0198] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.1 mg, 3.08 mmol) in toluene (10.0 mL) was added (5-chloro-2-methylphenyl)methanol (482.9 mg, 3.08 mmol) and CMBP (1.5 g, 6.22 mmol) at room temperature under N?. The resulting mixture was stirred at 110 c: 'C for 16 li under N2.
  • Step 2 Synthesis of l-[(5-chJorO”2 ⁇ methyIpheiiyl)methyl]-2 ⁇ oxo ⁇ 3,4"dihydroqiimoliii ⁇ 3 ⁇ yhirea (Compound 15)
  • Step 1 Synthesis of 3-amino-l-(2-chIoro-5-fluorobenzyl)-3,4-dihydroqninoIin-2(lH)-one
  • Step 1 Synthesis of 3-((3-amino-2-oxo-3,4-dihydroquinolin-l(2H) ⁇ yl)methyi)benzonitriie
  • Step 2 Synthesis of l-(l-(3-fluorobenzyJ)-2-oxo-l,2,3,4-tetrahydroqumoIin ⁇ 3-yl)ive
  • Step 1 Synthesis of 3-amino-l-[(3-methyiphenyi) methyi]-3,4-dihydroquinoiin-2-osie
  • Step 2 Synthesis of l-(l-(3,5 ⁇ dichIorobeiizyl)-2 ⁇ oxo ⁇ l,2,3>4-tetrahydroqnmoIiB-3- yl)urea (Compound 20)
  • Step 1 Synthesis of 3-amino-l-[(2,5 ⁇ diflMorophenyI)methyl]-3,4-dihydroqumoIiii-2-one [0210] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.2 mg, 3.08 mmol) in DMF (10.0 mL) was added NaH (123.3 mg, 60%) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then 2-(bromomethyl)-l,4-difluorobenzene (638.4 nig, 3.08 mmol) was added to the mixture at 0 °C under N?.
  • Step 2 Synthesis of l-[(2,5-difl «oropheiiyI)methy?]-2-oxo-3,4-dihydroquinoIin-3-yhjrea (Compound 21)
  • Step 1 Synthesis of tert-butyl (8-chIoro-2-oxo-l,2,3,4”ietrahydroquinoIin-3- yl)carbamate
  • Step 2 Synthesis of tert-butyl (8-chIoro-l-(5-chloro-2-fluorobenzyl)-2-oxo-1 ⁇ 23,4- tetrahydroquinolin-3 ⁇ yl)carbamate
  • Step 3 Synthesis of 3-amino-8-ch?oro ⁇ l ⁇ (5-chIoro-2-fluorobenzyl)-3,4-dihydroquinoIiii- 2(lH)-one
  • Step 1 Synthesis of tert-butyl (7-methyI ⁇ 2 ⁇ oxO”l,2,3»4 ⁇ tetrahydroquinolm-3- yl)carbamate [0216] To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (2.3 g, 6.98 mmol) in DMF (20.0 niL) was added Zn (843.0 mg, 12.89 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 li under N?.
  • Step 4 Syn thesis of l ⁇ (l ⁇ (5” €hloro-2 ⁇ fl «orobenzyi)"7-methyi-2-oxo ⁇ l,2,3?4" tetrahydroqumoIin-3-yI)iirea (Compound 23)
  • Step 1 Synthesis of tert-butyl N-(6-methyl-2-oxo-3,4-dihydro-lH-qumoIm-3- yl)carbamate
  • Step 2 Synthesis of tert-butyl N- ⁇ 1"[(5-cMoro-2-fluorophenyl)methyI]-6-methyi-2-oxo-
  • Step 3 Synthesis of 3-ammo ⁇ l ⁇ [(5 ⁇ chIoro-2-fluorophenyi)methyl]-6-methyl ⁇ 3,4" dihyd roquino! in -2-one
  • Step 4 Synthesis of l-[(5-chloro-2-f8uorophenyI)methyI]-6-methyI-2-oxo ⁇ 3,4- dihydroqisinoIin-3-yhsrea (Compound 24)
  • Step 1 Synthesis of tert-butyl (7-eyano-2-oxo-l,2,3,4"tetrahydroquinoiin-3- yl)carbamate > , [0224] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.3 g, 13.18 mmol) in DMF (20.0 mL) was added Zn (1.6 g, 24.36 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 h under N2.
  • Step 2 Synthesis of tert-butyi (l-(5-chIoro-2-fluorobenzyi) ⁇ 7-cyano-2-oxo-l,2,3?4- tetrahydroqMiiioiin-3-yi)carbainate
  • Step 4 Synthesis of l-(l ⁇ (5”Chloro-2-fl «orobenzyi)"7-cyano-2 ⁇ oxo ⁇ l,2,3,4“ tetrahydroqumolin-3-yl)iirea (Compound 25)
  • Step 1 Synthesis of 3-ammo-l-(3,5 ⁇ difluorobenzyl)-3,4-dihydroquinolm-2(lH)-one
  • Step 2 Synthesis of l-(l ⁇ (3,5-difliiorobenzyi)-2-oxo-l,2,3?4"tetrahydroqninoIin”3-yI)nrea (Compound 26)

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Abstract

La présente divulgation concerne de manière générale des composés et leurs compositions pour l'inhibition du récepteur de la thyréostimuline (TSHR).
PCT/US2025/040102 2024-08-01 2025-07-31 Composés pour l'inhibition du récepteur de la thyréostimuline Pending WO2026030578A1 (fr)

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WO2002053543A1 (fr) * 2000-12-28 2002-07-11 Shionogi & Co., Ltd. Derive de pyridone ayant une affinite pour le recepteur cannabinoide de type 2
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WO2002053543A1 (fr) * 2000-12-28 2002-07-11 Shionogi & Co., Ltd. Derive de pyridone ayant une affinite pour le recepteur cannabinoide de type 2
WO2005123685A1 (fr) * 2004-06-16 2005-12-29 Astrazeneca Ab Tetrahydroquinolones et aza-analogues associes utilises en tant qu'inhibiteurs de la dpp-iv dans le traitement du diabete
WO2024005113A1 (fr) * 2022-06-30 2024-01-04 キッセイ薬品工業株式会社 Composé 3,4-dihydroquinolin-2(1h)-one
WO2024026076A2 (fr) * 2022-07-29 2024-02-01 Septerna, Inc. Inhibiteurs de tshr substitués de 3,4-dihydroquinolinone
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