Compounds for inhibition of thyroid stimulating hormone receptor

Abstract

The present disclosure relates generally to compounds and compositions thereof for inhibition of thyroid stimulating hormone receptor (TSHR).

Description

COMPOUNDS FOR INHIBITION OF THYROID SIMULATING HORMONE RECEPTORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit to U.S. Provisional .Application Nos. 63 / 678,455, filed August 1, 2024; 63 / 720,695, filed November 14, 2.02.4; 63 / 762,570, filed February 24, 2025; and 63 / 799,269, filed May 2, 2025, the disclosures of each of which are her`by incorporated herein by reference in their entireties for all purposes.FIELD

[0002] The present disclosure relates generally to compounds and compositions thereof for inhibition of thyrotropin or thyroid stimulating hormone receptor (TSHR).BACKGROUND

[0003] The thyrotropin or thyroid stimulating hormone receptor (TSHR) is a transmembrane-spanning G-protein coupled receptor (GPCR) that is primarily expressed on thyroid follicular cells, as well as adipocytes, fibroblasts, bone and certain immune cell subtypes (Nagayama, Y., & Nishihara, E. (2022). Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases. EndocrineJournal, 69(11), 1285-1293. https: / / doi.org / 10.1507 / endocrj.ej22-0391). Its ligand, thyroid stimulating hormone (TSH), is a glycoprotein hormone released from the pituitary gland (Nagayama et al.) (Rapoport, B., Chazenbalk, G. D., Jaume, J. C., & McLachlan, S. M. (1998). The Thyrotropin (TSH)-Releasing Hormone Receptor: Interaction with TSH and Autoantibodies*. Endocrine Reviews, 19(6), 673-716. https: / / doi.org / 10.1210 / edrv.19.6.0352). 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-S12. htps: / / doi.org / 10.1210 / clinem / dgac045). 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.). The GPCRs possess extracellular leucine rich repeats responsible for binding their cognate hormones, eliciting a conformational changethat transmits the signal across the plasma membrane to promote downstream signaling (Nagayama et al.) (Rapoport et al.).

[0004] Aberrant activation of TSHR is the underlying cause of several different thyroid- mediated pathologies including Grave’s disease. In Grave’s disease, autoantibodies mimic TSH by binding and stimulating TSHR to drive excessive thyroid hormone release and consequent hyperthyroidism (Girnita et al.). About 40% of patients suffering from Grave’s disease will develop a secondary pathology known as grave’s ophthalmology or thyroid eye disease (GO / TED), in which orbital fibroblasts expressing TSHR are stimulated by the autoantibodies, causing inflammation and reorganization of the extracellular makeup of the periorbital space and significantly impacting the quality of life of patients (Girnita et al.) (Elia, G., Fallahi, P., Ragusa, F., Paparo, S. R, Mazzi, V., Benvenga, S., Antonelli, A., & Ferrari, S. (2021). Precision medicine in graves’ disease and ophthalmopathy. Frontiers in Pharmacology, 12. https: / / doi.org / 10.3389 / fphar.2021.754386). Current therapies for Grave’s disease target the production and release of thyroid hormones from the stimulated thyroid follicular cells, thus combating a subset of the negative effects of hyperthyroidism however these approaches do not address the symptoms of TED, where thyroid hormone release is not driving the pathology (Elia et al.).

[0005] The insulin-like growth factor- 1 receptor (IGFR) is also thought to be involved inTED, and there is evidence for a functional interaction of IGF and TSH signaling in normal thyroid and orbital fibroblast biology-’. Preclmical experiments have demonstrated IGF signaling can induce similar effects as Grave’s disease-related autoantibodies and that TSHR stimulation alone does not fully model the disease phenotype3. Furthermore, evidence indicates that IGFR may also be an autoantigen in TED patients. Accordingly, IGFR-targeted antibody therapies, have yielded positive effects in TED patients leading up to their approval for the treatment of this indication3’4. This evidence supports a possible combination strategy targeting both IGFR and TSHR in Grave’s disease patients with TED.

[0006] Apart from Grave’s disease, TSHR activating mutations are found in non- autoimmune thyroid diseases and thyroid cancer cells are sensitive to TSHR targeting therapies1. 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.9

[0007] Currently there are few small molecule antagonists of TSHR, and one challenge in development is specificity for TSHR over family member FSHR, as agonist or antagonist effects against it causes negative reproductive side effects.[GOGS ] Accordingly, there is a need in the art for a potent and selective small molecule antagonist of TSHR.BRIEF SUMMARY

[0009] In one aspect, provided herein is a compound of Formula (A”);pharmaceutically acceptable salt thereof, wherein: — is absent or a bond, wherein when — is a bond, R° and Rzare absent; Afand A2are CRW; A3isCRWand A4is N, or A3is N and A4is CRW; wherein at least one of A1, A2, A3, and A4is CRWthat is not CH or CD; Rwis 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-C1-6alkoxy, optionally substituted Cnshydroxyalkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted Ci -filial oalkoxyl, optionally substituted C3-6cycloalk.yl, optionally substituted C3- fihalocycloalkyl, optionally substituted -O-C3-8cycloalkyl, optionally substituted -O-C1- 6alkylene-Cv6Cycloalkyl, optionally substituted -O-Cs-ghalocycloalkyl, optionally substituted -O-C1-sheterocyclyl, optionally substituted -0-5-10 membered heteroaryl, optionally substituted -NH-C i-wydoaikyk optionally substituted -NH-C3-8halocycloalkyl, optionally substituted -NH-Cu6cy anoalkyl , optionally substituted -NH-Ca-sheterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-waryl, optionally substituted -O-Cs-ioaryl, or optionally substituted 5-10 membered heteroaryl, wherein at least one Rwis not H or D, B1, B2, B3, B" and B5are each independently CRXor N, wherein Rxisindependently 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)(C1-6alkyi), optionally substituted C1-6alkyl, optionally substituted C1-6hy dr oxyalkyl, optionally substituted Cnecyanoalkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3- 6cyc1oalkyl, optionally substituted -O-C1-scycloalkyl, optionally substituted -O-C1-salkylene- C3-6cycloalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Cs-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1 , or 2; X is -C(O)R8, -C(S)R8, -S(O)?.R9, or optionally substituted 5-6 membered heteroaryl; R3and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- 6cyc1oalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R3and R4are 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; R5is H, halo, optionally substituted Co6alkyl, optionally substituted Curhaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, R6, if present, is H, optionally substituted Co6alkyl, optionally substituted Cixhaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R3and Rbare 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; R7, if present, is H, optionally substituted Cnealkyl, or optionally substituted Cixhaloalkyl, R8is - NHRy, -OCH3, optionally substituted Cnealkyl, optionally substituted Cs-ehaloalkyl, optionally substituted Ca-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Cnealkyl is unsubstituted or is substituted with I , 2, 3, 4, or 5 instances of independently selected halo, and wherein the Ci-ealkyl is other than tert-butyl when Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl; R9is optionally substituted C1-6alkyl; and Ryis H, optionally substituted Cu ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; wherein one or more hydrogen atoms of the compound, if present, are optionally replaced with deuterium.

[0010] In one aspect, provided is a compound of Formula (A”-C):pharmaceutically acceptable salt thereof, wherein: — is absent or a bond, wherein when — is a bond, R6and Rzare absent; m is 0 or 1 ; A1, A2, AJ, and A4are each independently CRWor N, wherein Rwis 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, optionally substituted -NH(Cn 6alkylene)-C3-6cycloalkyl, optionally substituted Cnealkylene-Cuealkoxy, optionally substituted Cnehydroxyalkyl, optionally substituted C1-salkoxy, optionally substituted Cj. 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 -O-Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl; B!, By B ‘, B4and B:are each independently CRXor N, wherein Rxis independently at each occurrence H, halo, -CN, -NO?, -NH?, -S(O)q(C1-6alkyl), -S(O)q(C.3. 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 5-10membered heteroaryl; q is 0, 1, or 2; X is -C(O)R8, -C(S)R8, -S(O)2R9, or optionally substituted 5-6 membered heteroaryl; R1and R2if present, are each independently H, optionally substituted Cnealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cs-bCycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R1and R2are taken together with the carbon atom to which they are attached to form an optionally substituted Ch-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; R3and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted C1- ehaloalkyl, optionally substituted C1-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R3and R4are taken together with the carbon atom to which they are attached to form an optionally substituted Cug cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; R:' is H, halo, optionally substituted Cuealkyl, optionally substituted C1-shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, Rb, if present, is H, optionally substituted Cnsalkyl, optionally substituted C1-shaloalkyl, optionally substituted (h-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R5and R6are 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', if present, is El, optionally substituted C1-salkyl, or optionally substituted C1-6haloalkyl; Rsis -NHRy, -OCHs, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Cuealkyl is unsubstituted or is substituted with 1 , 2, 3, 4, or 5 instances of independently selected halo, and wherein the Cu ealkyl is other than tert-butyl when Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl; R9is optionally substituted Ci-ealkyl, and Ryis H, optionally substituted Ci-ealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; wherein one or more hydrogen atoms of the compound, if present, are optionally replaced with deuterium.

[0011] In one aspect, provided herein is a compound of Formula (A’)(A’l or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1 ,Af, A2, A ’, and A4are each independently -CRW- or -N-, wherein Rwis 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-sheterocycle, optionally substituted -NH-C3-8cycloalkyl, optionally substituted -NH-C4- gheterocycle, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl;Bl, B2, B3, B4and B5are each independently -CRX~ or -N-, wherein RKis 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 5-10 membered heteroaryl; q is 0, 1, or 2;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;Rland R2if 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, orR’!and R2are 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;R3and R4are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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;R5and R6are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’ and Rbare 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;R8is -NHRy, -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, or5 instances of independently selected halo, and wherein the Cnealkyl is other than tert- butyl when Rxis 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.

[0012] In one aspect, provided herein is a compound of Formula (A’)or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1;A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis 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-sheterocycle, optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C4- gheterocycle, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl;B1, B2, B3, B4and B5are each independently -CRN or -N-, wherein Rxis 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 substitutedCnealkyl, 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; q is 0, 1, or 2;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;R1and R2if 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, orR’1and R2are 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 ;R3and R4are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cs-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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 ;R5and R6are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cs-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’ 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 -NHRy, -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, or5 instances of independently selected halo, and wherein the C1-6alkyl is other than tert-butyl when Rxis optionally substituted aryl and the 3-8 membered heterocycloalkyl is not pyrrolidinyl; is H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.

[0013] In one aspect, provided herein is a compound of Formula (A):(A), or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; is an integer from 0 to 5;A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis 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(())R8or optionally substituted 5-6 membered heteroaryl;RKis 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;Rland R2if present, are each independently H, optionally substituted C1-salkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’!and R2are 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;R3and R4are each independently H, optionally substituted (' : <.aik\ I. optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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 ;R5and R6are each independently H, optionally substituted (' : <.aik\ I. optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’ and Rbare 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;R8is -NHRy, -OCH3, optionally substituted C1-salkyl, optionally substituted Cu rJhaloalkyl, optionally substituted C I3-6CV cloalky 1, or optionally substituted 3-8 membered heterocycloalkyl; andRyis H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.

[0014] In another aspect, provided herein is 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.

[0015] In another aspect, provided herein is a method of inhibiting a thyroid stimulation hormone receptor (TSHR) 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.

[0016] In another aspect, provided herein is 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.DETAILED DESCRIPTION

[0017] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.I. DEFINITIONS

[0018] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0019] The term “excipient” as used herein 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. 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 forparenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextnn, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose de (de = “directly compressible”), honey de, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch de, sucrose, etc.; dismtegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc,; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcry stall me cellulose, etc.

[0020] The terms “individual”, “subject” and “patient” refer 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.

[0021] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0022] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration

[0023] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-Cr, means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass C1-C6 alkyl, C1-Q alkyl, C3-C6alkyl, C-Cr, alkyl, C5-C6alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-Qalkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3alkyl, C2-C3 alkyl, or C1-C2 alkyl.

[0024] As used herein, the term “alkenyl” 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 double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). 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). In some embodiments, the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond. In other embodiments, 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.

[0025] As used herein, the term “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). In some embodiments, the alkynyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon triple bond. In other embodiments, 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.

[0026] The term “cycloalkyl”, “carbocyclic”, or “carbocycle” 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. In some embodiments, “cycloalkyl” encompasses C.i-Ce cycloalkyl, (h-Ce cycloalkyl, Cs-Ce cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or ( ;-(' ■ cycloalkyl. In some embodiments, the term “cycloalkyl” may be further described as a “spirocycloalkyl” or a “fused cycloalkyl”. The term “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. The term “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 orhaving 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. In some embodiments, “cycloalkyl”, “cycloalkyl”, “carbocyclic”, or “carbocycle” 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. In addition, 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. For example, 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, while 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.

[0027] The term “heterocycloalkyl”, “heterocyclic”, “heterocyclyl”, or “heterocycle” 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. In some embodiments, a “heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic, bridged or fused ring system, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalky 1,” “heterocyclic,” or “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidme, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(lH,3H)- dione, 1 ,4-dioxane, morpholine, thiomorpholine, thiornorpholine-5-oxide, thiomorpholine- S,S-oxide, piperazine, pyran, pyridone, 3-pyrroltne, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl,” “heterocyclic,” or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “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, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-memberedheterocycloalkyl, 3- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 5-membered heterocycloalkyl, or 3- to 4-membered heterocycloalkyl. In other embodiments, “heterocycloalkyl” may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom. For example, in some embodiments, “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, Ce-Cg heterocycloalkyl, Cs-C? heterocycloalkyl, C7-C9 heterocycloalkyl, C7- Cs heterocycloalkyl, or C8-C9 heterocycloalkyl. It should be recognized that “heterocycloalkyl” as described by the number of ring atoms may also be described by number of carbon atoms in the ring. For example, 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.[002S] The terms “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. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, difluoromethyl, and the like. In some embodiments, terms such as “haloalkyl,” “haloalkoxy 1,” or “halocycloalkyl” indicate that the alkyl, alkoxyl, or cycloalkyl is substituted with 1 , 2, 3, 4, 5, or more independently selected halo groups.

[0029] The term “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. In some embodiments, “aryl” encompasses Cs-Cuaryl, Cs-Cuaryl, Cio-Cwaryl, Cn-Cuaryl, Ce-Cnaryl, Cs-Cuaryl, Cio-Cnaryl, C6-Cjoaryl, Cs-Cioaryl, orCe-C-8 aryl. In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, 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. Thus, a l,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 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. Similarly, a l,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term “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). In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl.

[0030] The term “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. In other instances, 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. For example, 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, while 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.

[0031] 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, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, ptendinyl, imidazolyl, tnazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to10-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.

[0032] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxy carbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term “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. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0033] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “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. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0034] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), boron (B), and silicon (Si).

[0035] As used herein, the term “pharmaceutically acceptable salts” is 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. When compounds of the present disclosure contain relatively acidic functionalities, 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. Examples of 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. When compounds of the present disclosure contain relatively basic functionalities, 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. Examples of 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. Also included are 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.

[0036] 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.

[0037] 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.

[0038] 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. For example, 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. All 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 as2H (“D”),JH,l lC,t3C,!4C,k>N,15N,j50,17O,!8O,32P,33P,35S,i8F,3oCl,l23I and125I. Certain isotopically labeled compounds of the present disclosure (e.g, those labeled with3H or14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (i4C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (ft?.,2H) 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 as15O,ljN,nC, and18F 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.

[0039] “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. As used1herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, 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. Also encompassed by “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.

[0040] “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.

[0041] The phrase “therapeutically 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.

[0042] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0043] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination wasindividually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcomb mations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.IL COMPOUNDS

[0044] In one aspect, provided herein is a compound of Formula (A’):(A”), or a pharmaceutically acceptable salt thereof, wherein:— is absent or a bond, wherein when — is a bond, R6and R7are absent;A1and A2are CRW;A3is CRWand A4is N, or A3is N and A4is CRW; wherein at least one of A’, A2, A~’, and A4is CRWthat is not CH or CD;Rwis 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, optionally substituted C3-8cycloalkyl, optionally substituted C3.6halocycloalk.yl, optionally substituted -O-Cv-scycloalkyl, optionally substituted -O-C1-salkylene- C3-6cycloalkyl, optionally substituted -O-C3-6halocycloalkyl, optionally substituted -O-C+sheterocyclyl, optionally substituted -0-5-10 membered heteroaryl..3optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C3- ehalocycloalkyl, optionally substituted -NH-C1-6cyanoalkyl, optionally substituted -NH-C4-8heterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryi, optionally substituted -O-Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl, wherein at least one Rwis not H or I);B1, B2, B3, B4and B5are each independently CRXor N;Rxis 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 heterocycloalkyl, optionally substituted Ce-joaryl, or optionally substituted 5-10 membered heteroaryl ; q is 0, 1, or 2;X is -C(O)RS, -C(S)R8, -S(O)2R9, or optionally substituted 5-6 membered heteroaryl;R and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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;R5is H, halo, optionally substituted Cnealkyl, optionally substituted Cs-ehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,Rb, if present, is H, optionally substituted C1-6alkyl, optionally substituted C1- ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R5and R6are 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;R7, if present, is H, optionally substituted C1-6alkyl, or optionally substituted Cn shaloalkyl;ARsis -NHRy, -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 Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;R9is optionally substituted Cuealkyl; andRyis 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,

[0045] In one aspect, provided herein is a compound of Formula (A”-C)(A”-C), or a pharmaceutically acceptable salt thereof, wherein;— is absent or a bond, wherein when — is a bond, Rband R'' are absent; m is 0 or 1;A1, A2, A3, and A4are each independently CRWor N, wherein Rwis 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 oxyalkyl, optionally substituted Cuealkoxy, optionally substituted Cu ehaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3-ecycloalkyl, optionally substituted Cb-ehalocycloalkyl, optionally substituted -O~ C3-6cycloaikyl, optionally substituted -O-C1-6alkylene-C3-6cycloalkyl, optionally substituted -O-Cb-shalocycloalkyl, optionally substituted -O-G-sheterocyclyi, optionally substituted -O-(5- to 10-membered heteroaryi), optionally substituted - NH-C3-6cycloalkyl, optionally substituted -NH-Cb-ehalocycloalkyl, optionally substituted -NH-Cnecyanoalkyl, optionally substituted -NH-C4-8heterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Cs- loaryl, optionally substituted -O-Cg-ioaryl, or optionally substituted 5-10 membered heteroaryl;B1, B2, B3, B4and B3are each independently CRXor N, wherein Rxis 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 -O-Ci -ealky lene-C3-6cy cl oalkyl, optionally substituted C3-6halocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-joaryl, or optionally substituted 5-10 membered heteroaryl ; q is 0, 1, or 2;X is -C(O)R8, -C(S)R8, -S(O)zR9, or optionally substituted 5-6 membered heteroaryi;R1and R2if present, are each independently H, optionally substituted Cnealkyl, optionally substituted C1-ghal oalkyl, optionally substituted Ca-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR1and R2are 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;RJand R4are each independently H, optionally substituted Cnsalkyl, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecy cl oalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and 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;.6R5is 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 R5and R6are 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;R7, if present, is H, optionally substituted Cnealkyl, or optionally substituted C1- shaloalkyl;R8is -NHRy, -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 Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;R9is optionally substituted C1-salkyl; andR' 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.

[0046] In one aspect, provided herein is a compound of Formula (A’)(A’), or a pharmaceutically acceptable salt thereof, wherein:HI is 0 or 1 ;Af, A2, A ’, and A4are each independently -CRW- or -N-, wherein Rwis 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-C^sheterocycle, optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C4- gheterocycle, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl;B1, B2, B3, B4and B5are each independently -CRX~ or -N-, wherein RKis 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 membered heteroaryl, q is 0, 1, or 2;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;R1and R2if present, 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, or8Rland R2are 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;RJand R4are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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, orR5and R6are 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;R8is -NHRy, -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, or5 instances of independently selected halo, and wherein the Ci-ealkyl is other than tert-butyl when Rxis optionally substituted aryl and the 3-8 membered heterocycloalkyl is not pyrrolidinyl,Ryis H, optionally substituted Cnealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cwecycloalkyl, or optionally substituted 3-8 membered heterocycloalky I .

[0047] In one aspect, provided herein is a compound of Formula (A’),9(A’)5or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1;A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis 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, optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C4- gheterocycle, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-joaryl, or optionally substituted 5-10 membered heteroaryl;B\ B2, B3, B4and B5are each independently -CRN or -N-, wherein Rxis 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, optionallysubstituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1 , or 2;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;R1and R2if present, are each independently H, deuterium, optionally substituted Cn ealkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR1and R2are 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 ;R3and R4are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cwhaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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 ;R5and R6are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cwhaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR5and Rbare 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 Cuealkyl, or optionally substituted Cu ehaloalkyl;R8is -NHRy, -OCH3, optionally substituted C1-6alkyl, optionally substituted Cu ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, whereinthe 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 Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;Ryis H, optionally substituted C1-6alkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.

[0048] In some embodiments, the compound of formula (.A’) is a compound of Formula(A), or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; is an integer from 0 to 5;A1, A2, A3, and A4are each independently -CRW- or -N~, wherein Rwis 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)R8or optionally substituted 5-6 membered heteroaryl;Rxis 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;Rland R2if present, are each independently H, optionally substituted Cnealkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’!and R2are 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;R3and R4are each independently H, optionally substituted ( ' : r.a 1 ky L optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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 ;R5and R6are each independently H, optionally substituted ( ' : r.a 1 ky I, optionally substituted Cuehaloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR’ and Rbare 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;R8is -NHRy, -OCH3, optionally substituted Cusalkyl, optionally substituted Cu rJhaloalkyl, optionally substituted (?3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; andRyis H, optionally substituted Cnsalkyl, optionally substituted Cuehaloalkyl, optionally substituted Ca-scycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl.

[0049] In some embodiments of a compound of Formula (A’):A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -NCh, -NH2, -S(O)qC1-6alkyl), - 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, -NH-C4- sheterocycle, 4-8 membered heterocycloalkyl, C6-ioaryl, or 5-10 membered heteroaryl;B1, B2, B3, B4and B5are each independently -CRX~ or -N-, wherein RKis 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)R8or 5-6 membered heteroaryl;R’!and R2if present, are each independently H, deuterium, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, or 3-8 membered heterocycloalkyl, orR!and R2are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R3and R4are each independently H, deuterium, C1-6alkyl, C1-ghaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an Cwscycloalkyl, or 3-8 membered heterocycloalkyl;R’ and Rbare each independently H, deuterium, C1-salkyl, Cuehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR5and Rbare 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;R8is -NHRy-OCH3, C1-6alkyl, C1-6haloaikyl, Cmecycloalkyl, or 3-8 membered heteroaryl; andRyis H, Cnealkyl, C1-ghaioalkyl, C3-6cycloalkyi, or 3-6 membered heterocycloalkyl.

[0050] In some embodiments of a compound of Formula (A’ ):A\ A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -NO?, -NH?, -S(O)qC1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, -NHl'C1-6alkyl), -N(Ci..6alkyl)(Ci.6alkyl), - NHC(O)NHC1-6alkyl, C1-6alkyl, C1-6alkoxy, C1-ghaloalkyl, C1- ehaloalkoxyl, Co-ecycloalkyl, C3-6halocycloalkyl, -O-C3-6cycloalkyl, -O- Cr-sheterocycle, -NH-C3-6cycloalkyl, -NH-Q-sheterocycle, 4-8 membered heterocycloalkyl, Cs-ioaryl, or 5-10 membered heteroaryl;By B2, B3, B4and B5are each independently -CIO- or -N~, wherein Rxis independently at each occurrence H, halogen, -CN, -NO2, -NTI2, -S(O)q(C1-6alkyl), -S(O)q(C3- ecycloalkyl), -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), Cwalkyl, C1- ealkoxy, C1-6haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, CAehalocycloalkyi, 3-8 membered heterocycloalkyl, Ce-ioaryl, or 5-10 membered heteroaryl; q is 0, 1 , or 2;X is -C(O)R8or 5-6 membered heteroaryl;R1and R2if present, are each independently H, deuterium, Ci-ealkyl, Ci -ehaloalkyl, C3- ecycloalkyL or 3-8 membered heterocycloalkyl, orR1and R2are taken together with the carbon atom to which they are atached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R3and R4are each independently H, deuterium, C1-6alkyl, Cj -ehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an (N-scycloalkyl, or 3-8 membered heterocycloalkyl;R5and R6are each independently H, deuterium, C1-6alkyl, C1-shaloalkyl, C / i-scycloalkyl, or 3-6 membered heterocycloalkyl, orR5and R6are 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;R8is -NHRy, -OCH3, C1-salkyl, Ci-ehaloalkyl, Cr-ecycloalkyl, or 3-8 membered heteroaryl; andRyis H, C1-6alkyl, C1-ghaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.

[0051] In some embodiments of a compound of Formula (A), (A’), (A”), or (A”-C): / V, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis 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)R8or 5-6 membered heteroaryl;Rxis independently at each occurrence halogen, -CN, C1-6alkyl, Ci -ealkoxy, C1- ehaloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl;R1and R2if present, are each independently H, C1-6alkyl, C1-6haloalkyl, Cb-ecycloalkyl, or 3-8 membered heterocycloalkyl, orR:and R2are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R3and R4are each independently H, CuealkyL C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an Cs-gcycloalkyl, or 3-8 membered heterocycloalkyl;R3and R° are each independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R3are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R7is H, C1-6alkyl, or C1-shaloalkyl;R8is -NHRy, -OCH.% C1-salkyl, Cnehaloalkyl, C3-6cycloalkyl, or 3-8 membered heteroaryl; andRyis H, C 1. ealkyl, C1-ghaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.

[0052] In some embodiments of a compound of Formula (A), (A’), (A”), or (A”-C): m is 0 or 1 ; n is an integer from 0 to 5;X is C(O)R8;A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis 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,Rxis 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,R1and R2if present, are each independently H, optionally substituted Cnsalkyl, optionally substituted C1-shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR:and R2are 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;R3and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted Cnshaloalkyl, optionally substituted C / uscycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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, orR5and R6are 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;R8is -NHRy, optionally substituted C1-6alkyl, optionally substituted Ci .ehaloalkyl, optionally substituted (A-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; andRyis H, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalky I .

[0053] In some embodiments of a compound of Formula (A), (A’), (A”), or (A”-C):A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, Cuealkyl, Cs-ealkoxy, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl;X is C(())R8;Rxis independently at each occurrence halogen, -CN, Cuealkyl, Cuealkoxy, Cu ehaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl;R1and R2if present, are each independently H, Cuealkyl, Ci -ehaloalkyl, Ca-ecycloalkyl, or 3-6 membered heterocycloalkyl, orR1and R2are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R3and R4are each independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an Cj-scycloalkyl, or 3-8 membered heterocycloalkyl;R5and R6are each independently H, C1-6alkyl, Cuehaloalkyl, Cr-ecycloalkyl, or 3-6 membered heterocycloalkyl, orR5and R6are 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;R8is -NHRy, C1-6alkyl, or C3-8cycloalkyl, andRyis H, C1-6alkyl, C1-ghaloalkyl, Ch-ecycloalkyl, or 3-6 membered heterocycloalkyl.

[0054] In some embodiments of a compound of Formula (A’):A1, A2, AJ, and A4are each independently -N- or -CRW~, wherein Rwis 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 Rwis optionally substituted with one or more - OH or C1-6a1koxy, and the Cs-bCycloalkyl of Rwis optionally substituted with one or more halo;B1, B2, B3, B4, and B5are each independently -N- or -CRX-, Rxis 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 Rxis optionally substituted with one or more - OH or -CN, the Cnealkoxy of Rxis optionally substituted with one or more Co-ecycloalkyl, andthe C3-6cycloalkoxy of Rxis optionally substituted with one or more -CN;X is C(O)R8or 5-6 membered heteroaryl;R’!and R2if present, are each H;R3and R4are each independently H or C1-6alkyl;R’ and R'' are each H;R7is H;R8is -M IR'. -OCH3, or C1-6alkyl; andRyis H or C1-6alkyl.

[0055] In some embodiments of a compound of Formula (A’):A1, A2, AJ, and A4are each independently -N- or -CRW-, wherein Rwis 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 Rwis optionally substituted with one or more -OH or C1-6alkoxy, and the C / i-gcycloalkyl of Rwis optionally substituted with one or more halo;By B2, B3, B4, and B5are each independently -N~ or ~CRX~, Rxis 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 ;X is C(O)R8or 5-6 membered heteroaryl;R1and R2if present, are each H;R3and R4are each independently H or C1-6alkyl;R5and R6are each H;R7is H;R8is -X H R>. -OCH or Ci-ealkyi; andRyis H or Cbealkyl.

[0056] In some embodiments of a compound of Formula (A), (A’), (A”), or (A”-C): n is an integer from 0 to 2;A1, A2, A3, and A4are each independently -CRW~, wherein Rwis independently at each occurrence H, halogen, -CN, Cnealkyl, or -NHC(O)NHC1-6alkyl;X is C(O)R8or 5-6 membered heteroaryl;Rxis independently at each occurrence halogen, -CN, C1-6alkyl, or C1-6alkoxy;R1and R2if present, are each H;R3and R4are each independently H or C1-6alkyl;R5and R6are each H;R is H;R8is -NHRy, -OCH3, or ( ' : ,.a!kyh andRyi s H or C 1 -6alky 1.

[0057] In some embodiments of a compound of Formula ( A), (A’ ), ( A”), or (A”-C): n is an integer from 0 to 2,A1, A2, AJ, and A4are each independently -CRW-, wherein Rwis independently at each occurrence H, halogen, -CN, C1-salkyl, or -NHC(O)NHC1-6alkyl;X is C(O)R8;Rxis independently at each occurrence halogen, -CN, C1-6alkyl, or C1-salkoxy;R>!and R2if present, are each H;R3and R4are each independently H or C1-6alkyl;R5and R6are each H;R is H;R8is -NHRy, -OCH3, or ( ' : ,.a!kyh andRyis H or C1-6alkyl.

[0058] In some embodiments, the compound of Formula (A’) is a compound of Formula(D, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound of Formula (A), (A’), (A”), or (A”-C) is a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compound of Formula (F) Is a compound of Formula (F-a), or (F-b):(I’-a) (F-b) or a pharmaceutically acceptable salt thereof, wherein .A1, A2, A3, A4, B1, B2, By B4, B5, R1,R2, R:y R4, R5, R6, R7, and R8are defined as in Formula (F). In some embodiments, provided is a compound of Formula (F-a). In some embodiments, provided is a compound of Formula[0061 [ In some embodiments, the compound of Formula (I) or (!’ ) is a compound of Formula (I-a), or (I-b):(I-a) (I-b) or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, Ry R2, Ry R4, R5, R6, Ry R8, Rx, and n are defined as in Formula (I). In some embodiments, provided is a compound of Formula (I-a). In some embodiments, provided is a compound of Formula (I-b).

[0062] In some embodiments, the compound of Formula (A’) is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein Af, A2, A3, A4, B’!, Rf By B4, By R1,Ry RJ, R4, R?, R6, and R' are defined as in Formula (A’), and ring A is an optionally substituted 5-6 membered heteroaryl.

[0063] In some embodiments, the compound of Formula (A), (A’), (A’ ’), or (A7’-C) is a compound of Formula (11):or a pharmaceutically acceptable salt thereof, wherein Af, A2, A3, A4, R’!, Ry RJ, R4, R?, R6,Ry Rx. and n are defined as in Formula (A), and ring A is an optionally substituted 3-8 membered heteroaryl.

[0064] In some embodiments, the compound of Formula (IF) is a compound of Formula (IF -a) or (H’-b):(ir-a), (ir-b) or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, B1, By B3, B4, B3, R’!,R\ R3, R4, 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).[0065| In some embodiments, the compound of Formula (II) or (IF) is a compound of Formula (Il-a) or (Il-b):(n-b) or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, R1, R2, R\ R4, R5, R6, R ', R8, Rx, and n are defined as in Formula (II), and ring .A is a 3-8 membered heteroaryl. In some embodiments, ring .A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, provided is a compound of Formula (Il-a). In some embodiments, pro vided is a compound of Formula (Il-b).

[0066] In some embodiments of Formula (II) or (IF), ring A is 3-8 membered heteroaryl.In some embodiments, ring A is 3-6 membered heteroaryl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is

[0067] In some embodiments of Formula (IF), ring A is 5-6 membered heteroaryl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is

[0068] In some embodiments, of Formula (A), ( A’), (A ” ), or (A”-C), or a pharmaceutically acceptable salt thereof, m is 0 or 1, In some embodiments, m is 0. In some embodiments, m is 1.

[0069] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof A1, At A3, and A4are each independently -CRW- or -N-, wherein Rwis 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. In some embodiments. A1, A2, Af and A4are each independently -CRW- or -N-, wherein Rwis 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 4-8 membered heterocycloalkyl.

[0070] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0071] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis 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. In some embodiments. A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis 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. A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis 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. In some embodiments, A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-6alkyl, C1-6alkyl, Cuealkoxy, C1-6haloalkyl, Cs- 6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -NHC(())NHCf-6alkyl, or Cuealkyl.

[0072] In some embodiments of Formula (A), ( A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis 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. In some embodiments, A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C.u ecycloaikyl, or 3-6 membered heterocycloalkyl.

[0073] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, Rwis independently at each occurrence H, halogen.-CN, -OH, optionally substituted -NHC(O)NHC1-6alkyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-ghaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, Rwis 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. In some embodiments, Rwis 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. In some embodiments, Rwis 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. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, -NHC(O)NHC1- ealkyl, Cj-salkyl, C1-6alkoxy, Cushaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-3alkyl, Cjoalkyl, Ciualkoxy, Ci-ohaloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, -NHC(O)NHC1-6alkyl, or C1-6alkyl. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, -NHC(())NHC1-6alkyl, or C1.3alkyl. In some embodiments, Rwis independently at each occurrence H, Cl, -CN, - NHC(O)NH(isopropyl), or methyl. In some embodiments, Rwis independently at each occurrence II or halogen. In some embodiments, Rwis independently at each occurrence H or Cl. In some embodiments, Rwis independently at each occurrence H or -CN. In some embodiments, Rwis independently at each occurrence H or -NHC(())NHCn6alkyl. In some embodiments, Rwis independently at each occurrence H or -NHC(O)NHCi-3alkyl. In some embodiments, Rwis independently at each occurrence H or -NHC(())NH(isopropyl). In some embodiments, Rwis independently at each occurrence H or Cuealkyl. In some embodiments, Rwis independently at each occurrence H or C1-ralkyl. In some embodiments, Rwis independently at each occurrence H or methyl.

[0074] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, Rwis independently at each occurrence H, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substitutedCnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, Rwis 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, Rwis independently at each occurrence H, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-8cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, C1-ralkyl, C1-3alkoxy, C1-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, -CN, or C1-6alkyl. In In some embodiments, Rwis independently at each occurrence H, halogen, -CN, or C1-salkyl. In some embodiments, Rwis independently at each occurrence H, Cl, -CN, or methyl. In some embodiments, Rwis independently at each occurrence H or halogen. In some embodiments, Rwis independently at each occurrence H or Cl. In some embodiments, Rwis independently at each occurrence II or -CN. In some embodiments, Rwis independently at each occurrence FI or C1-6alkyl. In some embodiments, Rwis independently at each occurrence FI or C1-3alky1. In some embodiments, Rwis independently at each occurrence H or methyl.

[0075] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, Rwis independently at each occurrence H, Cl, or F. In some embodiments, R* is independently at each occurrence H or -N(methyl)2. In some embodiments, Rwis independently at each occurrence H or Cnealkyl, wherein the C1-salkyl of Rwis optionally substituted with one or more -OH or Cu6alkoxy. In some embodiments, Rwis independently at each occurrence II, methyl, ethyl, isopropyl, -CH2OH, -CH2OCH3. In some embodiments, Rwis independently at each occurrence II, halogen, C1-6alkoxy, or C1-ghaloalkoxyl. In some embodiments, Rwis independently at each occurrence H, F, -OCII3, -OCH2CH3, - OCHfCHsh. or -OCF3. In some embodiments, Rwis independently at each occurrence H or C3-6cycloalkyl, wherein the Cb-ecycloalkyl of Rwis optionally substituted with one or more halo. In some embodiments, Rwis independently at each occurrence H or C3-6cyclopropyl, wherein the C3-6cyclopropyl of Rwis optionally substituted with one or more F. In some embodiments, Rwis independently at each occurrence H or 3-8 membered heterocvcloalkvl.<> QIn some embodiments, R" is independently at each occurrence H, , or —I— .

[0076] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, A’!, A2, A3, and A4are each independently -CRW~ or ”N~. In some embodiments, each of A1, A2, A4, and A4is -CRW~. In some embodiments, each of A1, A2, A3, and A4is -CH-. In some embodiments one of A1, A2, AJ, and A4is other than ■■ CH-.

[0077] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, one of A1, A2, A3, and A4is -N~.[007§] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, the moiety representedoptionally substituted phenyl. In some embodiments, the moiety represented

[0079] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt

[0080] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, the moiety represented

[0081] In some embodiments of Formula ( A), or a pharmaceutically acceptable salt thereof, 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.

[0082] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof each of B!, B2, Bf B4, and B5is -CRX-. In some embodiments, each of B1, B2, B'\ B4, and B5is -CH-. In some embodiments, Bl, B2, BJ, B4, and B3is other than -CH-. In some embodiments, one of B1, B2, B3, B4, and B5is -N-.

[0083] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, Rxis 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. In some embodiments, Rxis 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. In some embodiments, Rxis independently at each occurrence H, halogen or C1-6alkyl. In some embodiments, Rxis independently at each occurrence H or -CN. In some embodiments, Rxis independently at each occurrence H, halogen, or -N(C1-6alkyl)(C1-6alkyl). In some embodiments, wherein Rxis independently at each occurrence H, or Cuealkoxy. In someembodiments, Rxis independently at each occurrence H, halogen or Cj-ecycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen or, or 3-8 membered heterocycloalkyl.

[0084] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, Rxis 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. In some embodiments, Rxis independently at each occurrence H, halogen, -CN, -NO2, -NH2, - S(O)q(C1-6alkyl), -S(O)q(C3-6tycloalkyl), -OH, -NH(C1-salkyl), -N(C1-6alkyl)(C h-salkyl), Cu ealkyl, C1-salkoxy, C1-scycloalkoxy, C1-6haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, C3- ehalocycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen, C1-salkyl, C3-6cycloalkoxy, or C3-6cycloalky1. In some embodiments, Rxis 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 Rxis optionally substituted with 1-3 CN. In some embodiments, the Cn ealkoxy of Rxis optionally substituted with one or more Ca-ecycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen or (Nealkyl, wherein the Cn ealkyl of Rxis optionally substituted with one or more -OH. In some embodiments, Rxis independently at each occurrence H, or Cnealkoxy, wherein the C h -ealkoxy of Rxis optionally substituted with one or more Ca-ecycloalkyl. In some embodiments, the C1-6alkyl of Rxis optionally substituted with one or more -OH. In some embodiments, the C a .ealkoxy of Rxis optionally substituted with one or more C / i-ecycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen or C1-6alkyl, wherein the Cuealkyl of Rxis optionally substituted with one or more -OH. In some embodiments, Rxis independently at each occurrence H, or C1-6alkoxy, wherein the Ci-ealkoxy of Rxis optionally substituted with one or more C3-6cycloalkyl.

[0085] In some embodiments of Formula ( A), (A’ ), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, Rxis independently at each occurrence halogen, - CN, optionally substituted C1-6alkyl, optionally substituted Ci-ealkoxy, optionally substitutedCuehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, Rxis 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, Rxis independently at each occurrence halogen, - CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence halogen, -CN, C1-salkyl, C1- ealkoxy, C1-shaloalkyl, C1-scycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence halogen, -CN, Cnsalkyl, or C1-6alkoxy, In some embodiments, Rxis independently at each occurrence halogen. In some embodiments, Rxis independently at each occurrence Cl or F. In some embodiments, Rxis - CN. In some embodiments, Rxis independently at each occurrence halogen or C1-6alkyl. In some embodiments, Rxis independently at each occurrence Cl, F, or methyl. In some embodiments, Rxis Cnealkoxy.

[0086] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, the moiety represented

[0087] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt

[0088] In some embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, the moiety represented byis selected from the group consisting ofsome embodiments, the moiety represented by

[0089] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt

[0090] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R1and R2if present, 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 R1and R2are 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.

[0091] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R1and R2if present, are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted Cmecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R1and R2are 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. In some embodiments, R1and R2if present, are each independently H, Cnsalkyl, C1-6haloalkyl, C3- 6cycloalkyl, or 3-8 membered heterocycloalkyl, or R1and R2are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0092] In some embodiments of Formula (A), (A’), (A ”), or (A”-C), or a pharmaceutically acceptable salt thereof, R1and R2if present, are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R1and Rzif present, are each independently H, Cnsalkyl, C1-6haloalkyl, C3- gcycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, R1and R2are the same. In some embodiments, R1and R2are different. In some embodiments, R1and R2are each H. In some embodiments, m is 1 , and R1and R2are each H.

[0093] In some embodiments of Formula (A), (A’), (A ”), or (A”-C), or a pharmaceutically acceptable salt thereof, R1and R2if 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. In some embodiments, R1and Rzif present, are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0094] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R3and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-ghaloalkyl, optionally substituted C3- 6cycloalkyl, or optionally substituted 3-8 membered heterocycloalky 1, or R3and R'1are 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. In some embodiments, R3and R4are each independently H, C1-6alkyl, Cnshaloalkyl, Cr-scycloalkyl, or 3-8 membered heterocycloalkyl, or RJand R4are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0095] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R3and R4are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted CnehaloalkyL optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R3and R4are each independently H, deuterium, C1-6alkyl, Cnshaloalkyl, Cn-scycloalkyl, or 3-8 membered heterocycloal ky 1.

[0096] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, RJand R4are each independently H, optionally substituted C1-salkyl, optionally substituted C1-6haloalkyl, optionally substituted C3- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R3and R4are each independently H, Cusalkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, R3and R4are the same. In some embodiments, R3and R4are different. In some embodiments, R3and R4are each independently H or C1-salkyl. In some embodiments one of R3and R4is H and the other of RJand R4is methyl. In ome embodiments, R3and R4are each H.

[0097] In some embodiments of Formula (A), (A’), (A ”), or (A”-C), or a pharmaceutically acceptable salt thereof, R3and R4are 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, R3and R4are taken together with the carbon atom to winch they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0098] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R5and R6are 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. In some embodiments, R;and R6are each independently H, C1-6alkyl, Cnshaloalkyl, C1-scycloalkyl, or 3-8 membered heterocycloalkyl, or R5and R6are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0099] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R5and R6are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyL optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R;' and R6are each independently H, deuterium, Cnealkyl, C1-shaloalkyl, C3-8cycloalkyl, or 3-8 membered heterocycloal ky 1.

[0100] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R5and R.° are each independently H, optionally substituted C1-salkyl, optionally substituted Cuehaloalkyl, optionally substituted Cs- ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R5and R6are each independently H, CuealkyL C1-6haloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, R5and R6are the same. In some embodiments, R5and R6are different. In some embodiments, R5and R6are each H.

[0101] In some embodiments of Formula (A), (A’), (A ”), or (A”-C), or a pharmaceutically acceptable salt thereof, R5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted Cwscycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R5and R6are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0102] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R' is H, deuterium, optionally substituted Cn6alkyl, or optionally substituted Cn ehaloalkyl. In some embodiments, R / is H, deuterium, Cnealkyl, or C1-shaloalkyl,

[0103] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R7is H, optionally substituted C1-6alkyl, or optionally substituted C1-6haloalkyl. In some embodiments, R?is H, C1-6alkyl, or C1- ehaloalkyl. In some embodiments, Rzis H, optionally substituted Cioalkyl, or optionally substituted C1-6haloalkyl. In some embodiments, R' is H, C1-salkyl, or Ciohaloalkyl. In some embodiments, R7is H.

[0104] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, X is -C(O)R8or optionally substituted 3-8 membered heteroaryl. In some embodiments, X is -C(O)R8or 3-8 membered heteroaryl. In some embodiments, X is -C(O)R8or 3-6 membered heteroaryl. In some embodiments, X is - C(O)R8or 5-6 membered heteroaryl. In some embodiments, X is -C(O)R8. In some embodiments, 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 is5 membered heteroaryl. In some embodiments, X is

[0105] In some embodiments of formula (A’), 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

[0106] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R8is -NHRy, 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 Rxis optionally substituted aryl, andthe 3-8 membered heterocycloalkyl is not pyrrolidinyl.

[0107] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRyoptionally substituted Ct-galkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R8is -NHRy, C1-6alkyl, Cnehaloaikyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, R8is -XI HF . optionally substituted C1-jalkyl, optionally substituted C1-rhaloalkyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R8is -NHRy, C1-salkyl, C1-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.

[0108] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, -OCH3, optionally substituted C1- ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cj.gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, R8is -NHRy, - OCH3, C1-6alkyl, Cnehaloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl. In some embodiments, R8is -NHRy, -OCH3, optionally substituted C1-salkyl, optionally substituted Ciohaloalkyl, optionally substituted Ce-ecycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R8is -NHRy, -OCH3, Cuialkyl, Ciohaloalkyl, C3- ecycloalkyl, or 3-6 membered heterocycloalkyl.

[0109] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, optionally substituted C1-ghaloalkyl, or optionally substituted C3-6cycloalkyl. In some embodiments, R8is -NHRy, C1-shaloalkyl, or C3-6cycloalkyl. In some embodiments, R8is -NHRy, optionally substituted C1-jhaloalkyl, or optionally substituted C3-6cycloalkyl. In some embodiments, R8is -NHRy, C1-shaloalkyl, or C3-6cycloalkyl. In some embodiments, R8is -NHRy, or optionally substituted CAscycloalkyl. In some embodiments, R8is -NHRy, or C3-6Cycloalkyl. In some embodiments, R8is -NH2 or - XH(Cl h).

[0110] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, -OCH3, C1-6alkyl, 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; and3-8 membered heterocycloalkyl is not pyrrolidinyi.[Gill] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, 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; and3-8 membered heterocycloalkyl is not pyrrolidinyi.

[0112] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, 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; and3-8 membered heterocycloalkyl is not pyrrolidinyi.

[0113] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -OCH3.

[0114] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is optionally substituted C1-6alkyl. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is optionally substituted Cioalkyl. In some embodiments, R8is C1-salkyl. In some embodiments, R8IS C1-6alkyl optionally substituted with 0, 1, 2, 3, 4, or 5 instances of independently selected halo. In some embodiments, R8is C1-salkyl optionally substituted with halo. In some embodiments, R8is methyl or ethyl. In some embodiments, R8is methyl. In some embodiments, R8is ethyl.

[0115] In some embodiments of Formula (A’), or a pharmaceutically acceptable salt thereof, R8is -NHRy, such that the compound is a compound of Formula (I ’-A):(F-A) or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, B1, B2, B3, B4, B3, R!, R2, R3, R\ R5, R°, Ry, and m are defined as in Formula (A’).[Oil 6] In some embodiments of Formula (A), (A’), (A”), or (A”-C), or a pharmaceutically acceptable salt thereof, R8is -NHRy, such that the compound is a compound of Formula (I- A):(I-A) or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, R’1, R2, Ry R4, R5, R6, Rx, Ry, m and n are defined as in Formula (A).(0117] In some embodiments of Formula (A’), (A), (F-A), or (I-A), or a pharmaceutically acceptable salt thereof, Ryis H, optionally substituted Ci-ealkyl, optionally substituted Cj. ehaloalkyl, optionally substituted CAficycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl. In some embodiments, Ryis H, Cnealkyl, (>.. filial oalkyl, Cs.ficycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments Ryis H or Cnsalkyl. In someembodiments Ryis H. In some embodiments Ryis C1-salkyl. In some embodiments Ryis Cisalkyl. In some embodiments Ryis methyl.[0118| In some embodiments of Formula ( A’): m is 0 or 1;A1, A2, A3, and A4are each independently -N- or -CRW~, 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 Rwis optionally substituted with one or more -OH or Cnealkoxy, and the Cb-ecycloalkyl of Rwis optionally substituted with one or more halo;B1, B2, B3, B4, and B5are each independently -N- or -CRX-, Rxis 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)R8or 5-6 membered heteroaryl;R1and R2if present, are each H;R3and R4are each independently H or C1-6alkyl;R5and R° are each H;R7is H;R8is -NHRy, -OCHs, or C1-6alkyl; andRyis H or C1-6alkyl.

[0119] In some embodiments of Formula (A), (A’), (A” ), or (A”-C):n is an integer from 0 to 2;X is -C(O)R8;A\ A2, A3, and A4are each independently -CRW-, wherein Rwis independently at each occurrence H, halogen, -CN, or Cnsalkyl;Rxis independently at each occurrence halogen, -CN, Cuealkyl, or Cuealkoxy;R1and R2if present, are each H;R3and R4are each independently H or Cuealkyl;R5and Rbare each H;R7is H;R8is -NHRy; andRyis H or Cuealkyl.

[0120] In some embodiments, the compound of formula (A’), or a pharmaceutically acceptable salt thereof, the compound is a compound of formula (S’-l), (S ’ -2), (S-l), or (S- 2):some embodiments, 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).

[0121] In some embodiments, 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-tetrahydroqumolin-3-yl)urea, 1 -(7-(difluoromethyl)-l-(5-(dif1uoromethy1)-2- fluorobenzyl)-2-oxo-1 ,2,3,4-tetrahydroquinolm-3-yl)urea; l-(l-(5-(difluoromethyl)-2- fluorobenz.yl)-2-oxo-7-(trifluoromethyl)- 1 ,2,3,4-t.etrahydroquinolin-3-yl)urea; 1 -(1 -(5- (difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-2-oxo-l ,2,3,4-tetrahydroquinolm-3- yl)urea; 1 -(1 -(5-(difluoromethyl)-2-fluorobenzy l)-5,7-difluoro-2-oxo-l, 2,3,4- tetrahy droqui nol in-3 -yl)urea; 1 -( 7-(di fl uoromethyl)- 1 -(2-fl uoro-5 -(trifl uorom ethoxy)benzyl)- 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; 1 -(7-(difluoromethyl)-l-(2-fluoro-5-(l,l,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)benzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; 1-(1- (5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-7-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-3- yl)-3-methylurea; 1 -( 1 -(3-methy lbenzyl)-2-oxo- 1 ,2,3,4-tetrahydroquinolin-3-yl)urea; 1 -( 1 -(3- cyanobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(l-(3-methoxybenzyl)-2-oxo-1.2.3.4-tetrahydroquinolin-3-yl)urea; 1 -(l-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea; l-(l-((2,2-difluorobenzo[d][l,3]dioxol-4-yl)methyl)-2-oxo-1.2.3.4-tetrahydroqumolin-3-yl)urea; l-(7-methyl-2-oxo-l-(3-(trifluoromethyl)benzyl)~1.2.3.4-tetrahydroquinolin-3-yl)urea; l-(7-methoxy-2-oxo-l-(3-(trifluoromethyi)benzyl)-1.2.3.4-tetrahydroqumolin-3-yl)urea; l-(7-cyano-2-oxo-l-(3-(trifluoromethyl)benzyi)-1.2.3.4-tetrahydroquino1in-3-yl)urea; l-(5-fluoro-l-(2-fluoro-5-(trifluoromethyl)benzyl)-2- oxo-1, 2,3, 4-tetrahydroquinolin-3-yl)urea; l-(l-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-2-oxo-l,2,3,4-tetrahydroqumolin-3-yl)urea; l-(2-oxo-l-(3-(trifhioromethyl)benzyl)-1.2.3.4-tetrahydro-l,7-naphthyridin-3-yl)urea; l-(7-fluoro-l-(l-(2-fluoro-5-(trifhioromethy1)phenyl)ethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(2-oxo-l- phenethyl-l,2,3,4-tetrahydroquinolm-3-yl)urea; l-(2-fluoro-5-(trifluoromethyl)benzyl)-2- oxo-3-ureido-l,2,3,4-tetrahydroquinoline-7-carboxylic acid; l-(2-fluoro-5-(trifluoromethyl)benzyl)~2-oxo-3-ureido-1 ,2,3,4-tetrahydroquinolme-7-carboxamide; l-(7-(difluoromethyl)-l-(2-(hydroxymethyl)-5-(trifluoromethy1)benzyl)-2-oxo-l,2,3,4- tetrahydroqumo1in-3-yl)urea; l-(7-(difluoromethyl)-2-oxo-l-((6-(trifluoromethyl)pyridin-2- yl)methyl)-1 ,2,3,4-tetrahydroquinolin-3-yl)urea; l-(8-((dimethylamino)methyl)-l-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-y1)urea; or a pharmaceutically acceptable salt thereof

[0122] In some embodiments, provided is a compound selected from the compounds inTable 1, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.Table 1

[0123] As used herein, “trans” and “cis,” along with bold and hashed non- wedged (i.e., rectangular) bonds in a compound, indicate that the compound is a mixture of dif68ferentdiastereomers each with fixed cis- or trans-configuration. For example,cis- indicates that the compound is a mixture

[0124] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, isotopologues, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of acompound depicted. For example,, or a mixture thereof. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or noncrystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non- racemic, enantioenriched and scalemic mixtures of a compound are embraced.

[0125] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual ,

[0126] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-sait and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0127] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, 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.

[0128] Any variation or embodiment of m, n, q, A1, A2, A3, A4, B1, B2, B3, B4, B5, X, R1, R2, R3, R4, R', R°, R', R8, R9, Rw, Rx, Ry, and ring A provided herein can be combined with every other variation or embodiment of m, n, q, A1, A2, A3, A4, B>!, B2, B3, B4, B3, X, R>!, R2, R3, R4, R5, R°, R', R8, R9, Rw, Rx, Ry, and ring A, as if each combination had been individually and specifically described.

[0129] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.HI. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

[0130] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0131] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0132] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0133] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral.buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0134] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt thereof, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt thereof, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, 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. For instance, and without limitation, a composition of substantially pure (S) compoundmeans 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.

[0135] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, 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. In some embodiments, 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.

[0136] 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. 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.

[0137] 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. Depending on the therapeutic form of the system (e.g, transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, 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.Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitableformulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack PublishingCompany, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.

[0138] 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. Examples of 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. In addition, 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.

[0139] 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.

[0140] Compositions comprising a compound, or a pharmaceutically acceptable salt thereof, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

[0141] 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.). Furthermore, 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 ofdelivery, or 3) delivery on different days, through the same route or different routes of delivery.IV. METHODS OF USE

[0142] 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.

[0143] In one aspect, provided herein is a method of inhibiting a thyroid stimulation hormone receptor (TSHR) comprising contacting the TSHR with an effective amount of a compound or composition provided herein. In some embodiments, provided herein is 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 a compound or composition of the disclosure to the individual. In some variations, the compounds provided herein are selective for inhibiting TSHR.

[0144] In some embodiments, the compound or composition described herein is used in a method of treating a disease or disorder mediated by TSHR activity. In some embodiments, 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. In some embodiments, the disease or disorder is selected from the group consisting of Grave’s disease, Grave’s ophthalmology and thyroid eye disease. In some embodiments, the disease, disorder, or condition is Grave’s disease.V. DOSING AND ADMINISTRATION

[0145] The dose of a compound described herein, or a pharmaceutically acceptable salt thereof, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such astype and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt thereof, is a therapeutically effective amount.

[0146] 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.

[0147] 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.[014§] 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. In one variation, 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.VI. ARTICLES OF MANUFACTURE AND KU’S

[0149] 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. In certain embodiments, 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.

[0150] The present disclosure further provides 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. In one variation, 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 thetreatment of Grave’s disease, Grave’s ophthalmology (GO) / thyroid eye disease (TED), a non autoimmune thyroid disease, and / or thyroid cancer.

[0151] The 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.

[0152] 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) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[0153] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, 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).

[0154] The 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.VII. ENUMERATED EMBODIMENTS

[0155] The following enumerated embodiments are representative of some aspects of the invention.Enumerated embodiments set A

[0156] The 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 compound of formula (A):(A), or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1 ; n is an integer from 0 to 5;A\ A2, AJ, and A4are each independently -CRW~ or -N-, wherein Rwis 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 ;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;Rxis 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;R1and Rzif present, are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR1and R2are 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:1and R4are each independently H, optionally substituted C1-salkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cb-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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;R5and R° are each independently H, optionally substituted Cnealkyi, optionally substituted C1-6haloalkyl, optionally substituted Cj-ecycioalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR5and R6are 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;R8is -NHRy, -OCH3, optionally substituted Cnealkyi, optionally substituted C1- shaloalkyl, optionally substituted Cnecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; andRyis H, optionally substituted Cnealkyi, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ,A2. The compound of Embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein:A1, Az, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -OH, -NHC(O)NHCi -ealkyl, Cnealkyi, Cn ealkoxy, Cnehaloalkyl, Cnehaloalkoxyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl,X is -C(O)R8or 5-6 membered heteroaryl;Rxis independently at each occurrence halogen, -CN, C1-6alkyl, Ci-ealkoxy, Ci. ehaloalkyl, C.cecycloalkyl, or 3-8 membered heterocycloalkyl;R1and R2if present, are each independently H, Cnealkyi, Cnehaloalkyl, C3- ecycloalkyl, or 3-8 membered heterocycloalkyl, orRfand R2are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyd, or 3-8 membered heterocycloalkyl;R ’ and R4are each independently H, C1-6alkyl, C1-6haloalkyl, Cb-ecycloalkyl, or 3-6 membered heterocycloalkyl, orRJand R4are taken together with the carbon atom to which they are attached to form an C3-8cycloalkyl, or 3-8 membered heterocycloalkyl;R5and R° are each independently H, Cnealkyi, Cnehaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;Rzis H, C1-6alkyl, or C1-6haioalkyl;R8is -NHRy, -OCH3, C1-6alkyl, C1-6haloalkyl, Cmscycloalkyl, or 3-8 membered heteroaryl; andRyis H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.A3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I):or a pharmaceutically acceptable salt thereof.,A4. The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-a);or a pharmaceutically acceptable salt thereof.A5. The compound of any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-b):or a pharmaceutically acceptable salt thereof.A6. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted 3-8 membered heteroaryl.A7. The compound of any one of Embodiments 1-3 and 6, or a pharmaceutically acceptable salt thereof, wherein ringA8. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, halogen, -CN, - NHC(O)NHCi.6alkyl, or Chalky],A9. The compound of any one of Embodiments 1 -7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or halogen.A 10. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or Cl.Al l. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or -CN.A12. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or Cnsalkyl.A13. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or methyl.A14. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or -NHC(O)NHC]-salkyl.A15. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each of A!, A2, A3, and A4is -CRw-_A 16. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein each of A1, A2, A3, and A4is -CH-,A 17. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein one of A1, Az, A3, and A4is other than -CH-.A18. The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein the moiety representedA 19. The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 3.A20. The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein n is 0.A21. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence halogen, -CN, Crealkyl, or C1- ealkoxy.A22. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence F, Cl, -CN, methyl, or methoxy.A23. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence halogen or Cuealkyl.A24. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein Rxis -CN.A25. The compound of any one of Embodiments 1-2.0, or a pharmaceutically acceptable salt thereof, wherein Rxis C1-6alkoxy.A26. The compound of any one of Embodiments 1-2.0, or a pharmaceutically acceptable salt thereof, wherein the moiety represented by, is selected from the groupA27. The compound of any one of Embodiments 1 -4, and 6-23, or a pharmaceutically acceptable salt thereof, wherein m is 1 , and R1and R2are each H.A28. The compound of any one of Embodiments 1 -27, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently H or C-.^alkyl,A29. The compound of any one of Embodiments 1 -27, or a pharmaceutically acceptable salt thereof, wherein R3is H and R4is methyl.A30. The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each H.A31. The compound of any one of Embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H.A32. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R?is H.A33. The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein R8is -NHRy, 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; and3-8 membered heterocycloalkyl is not pyrrolidinyl.A34. The compound of any one of Embodiments 1 -32, or a pharmaceutically acceptable salt thereof, wherein R8is • N 1 ll\'A35. The compound of any one of Embodiments 1 -32, or a pharmaceutically acceptable salt thereof, wherein Ryis H or Cnsalkyl.A36. The compound of any one of Embodiments 1 -32, or a pharmaceutically acceptable salt thereof, wherein R8is -NHz or -NH(CHs).A37. The compound of any one of Embodiments 1 -32, or a pharmaceutically acceptable salt thereof, wherein R8is C1-6alkyl,A38. The compound of any of Embodiments 1-32, or a pharmaceutically acceptbale salt thereof, wherein R8is methyl or ethyl,A39. The compound of any one of Embodiments 1 -32, or a pharmaceutically acceptable salt thereof, wherein R8is -O( i bA40. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: n is an integer from 0 to 2;A1, A2, A3, and A4are each independently -CRW-, wherein R” is independently at each occurrence H, halogen, -CN, Cnsalkyl, or -NHC(O)NHC1-6alkyl;X is C(O)R8or 5-6 membered heteroaryl,Rxis independently at each occurrence halogen, -CN, Cnealkyl, or Ci-ealkoxy;R1and R2if present, are each H;R’ and R4are each independently H or Ci-ealkyl;R5and R6are each H;R7is H;R8is -NHRy, -OCH3, orCnsalkyl; andRyis H or C1-6alkyl.A41A. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:A41B. The compound of any one of preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (S-l):A41C. The compound of any one of preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula ( S-2):A42. A pharmaceutical composition comprising the compound of any one of Embodiments1 -41 (i.e., 1-40, 41 A, 41 B, and 41C), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.A43. A method of inhibiting a thyroid stimulation hormone receptor ( TSHR) comprising contacting the TSHR with an effective amount of the compound of any one of Embodiments 1-41, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of Embodiment 42.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.A45. The method of Embodiment 44, wherei n the disease, disorder, or condition 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.A46. 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.A47. The method of any one of Embodiments 44-46, wherein the disease, disorder, or condition is Grave’s disease.Enumerated embodiments set B

[0157] The embodiment numbers referenced in this set refer to those within set B. For example, “embodiment 1 ” recited in embodiment B2 refers to embodiment Bl.Bl. A compound of formula ( / V):(A’), or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1 ;A\ A2, AJ, and A4are each independently -CRW~ or -N-, wherein Rwis independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O)q(C1-6alkyl), -S(O)q(C3- ecycloalkyl), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted - N(Cn6alkyl)(C1-6alkyl), optionally substituted -NHC(0)NHC1-6alkyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C3- scycloalkoxy, optionally substituted C1-6haloalkyl, optionally substituted C1- shaloalkoxyl, optionally substituted C1-scycloalkyl, optionally substituted C3- shalocycloalkyl, optionally substituted -O-C1-scycloalkyl, optionally substituted - O-C4-8heterocycle, optionally substituted -NH-C1-scycloalkyl, optionally substituted -NH-C4-sheterocycle, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl;B1, B2, B3, B4and B5are each independently -CRX- or -N~, wherein Rxis independently at each occurrence H, halogen, -CN, -NO2, -NH-?, -S(O)q(C1-6alkyl), -S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(Cn6alkyl), optionally substituted -N(C1-6alkyl)(C1-6alky1), optionally substituted Cn ealkyl, optionally substituted Cj-salkoxy, optionally substituted C1-shaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted Cs^cycloalkyl, optionally substituted C3- rhalocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-waryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1, or 2;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;R1and R2if present, are each independently H, deuterium, optionally substituted Cm ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cmecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orRland R2are 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;RJand R4are each independently H, deuterium, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR3and R4are 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;R5and R6are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR5and R° 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 heterocycloal kyl ;R7is H, deuterium, optionally substituted Cnealkyl, or optionally substituted C1- shaloalkyl;R8is -NHRy, -OCHi, optionally substituted C1-6alkyl, optionally substituted C1- shaloalkyl, 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 Cusalkyl is other than tert-butyl when Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl,Ryis H, optionally substituted Cu6alkyl, optionally substituted C1-6haloalkyl, optionally substituted Cuecycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ,B2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: B1, B2, B3, B4and B' are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, halogen, -CN, -NO2, -NH2, -S(O)q(Cu6alky1), -S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(Cj . ealkyl), optionally substituted -N(Cu6alkyl)(C1-6alkyl), optionally substituted Cuealkyl, optionally substituted Cuealkoxy, optionally substituted Cuehaloalkyl, optionally substituted C1-6haloalkoxyl, optionally substituted C3-6cycloalkyl, optionally substituted C3- ehalocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl;B3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (A):(A), or a pharmaceutically acceptable salt thereof, wherein: n is an integer from 0 to 5;A!, A'4, A4, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, -GN, -OH, optionally substituted -NHC(O)NHCn ealkyl, optionally substituted Cnealkyl, optionally substituted Cnealkoxy, optionally substituted Cnehaloalkyl, optionally substituted Cnehaloalkoxyl, optionally substituted Cj-ecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl ;Rxis independently at each occurrence halogen, -CN, optionally substituted Cnealkyl, optionally substituted Cnealkoxy, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloal ky 1 ;R3and R4are each independently H, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyL or optionally substituted 3-8 membered heterocycloalkyl, orRJand R4are taken together with the carbon atom to which they are attached to form an optionally substituted Cns cycloalkyl, or optionally substituted 3-8 membered heterocycloal kyl ;R5and R6are each independently H, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted Cnecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orR5and R” are taken together with the carbon atom to which they are attached to form an optionally substituted Cnscycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl; andR7is H, optionally substituted Cnealkyl, or optionally substituted Cnehaloalkyl.B4. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:A\ A2, A3, and A4are each independently -CRW~ or -N-, wherein Rwis independently at each occurrence H, halogen, -GN, -OH, -N(C1-6alkyl)(C1-6alkyl), - NHC(O)NHC1-6alkyl, Cnealkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxyl, C3- scycloalkyl, C3-8halocycloalkyl, ~O-C3-6cycloalkyl, -O-C4-8heterocycle, -NH-C3- 6cycloalkyl, -NH-C-i-sheterocycle, or 4-8 membered heterocycloalkyl;B1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, halogen, -CN, -N(C1-6alkyl)(C]-6alkyl), Cisalkyl, C1-salkoxy, C1-6haloalkyl, C1-shaloalkoxyl, C3-6cycloalkyl, C3- 6halocycloalkyl, or 3-8 membered heterocycloalkyl;X is -C(O)R8or optionally substituted 5-6 membered heteroaryl;R1and R2if present, are each independently H, deuterium, C1-6alkyl, Cwhaloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl, orR1and R2are taken together with the carbon atom to which they are atached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R3and R4are each independently H, Cuealkyl, C1-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are atached to form an Co-scycloalkyl, or 3-8 membered heterocycloalkyl,R5and R6are each independently H, Cnsalkyl, C1-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are atached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;R7is H, C1-6alkyl, or Cj -filial oalkyl;R8is -NHRy, -OCH3, Ct-salkyl, Ci-ghaloalkyl, C3-6cycloalkyl, or 3-8 membered heteroaryl; andRyis H, C1-fialkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl.B5. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (F):or a pharmaceutically acceptable salt thereof.B6. The compound of any one of embodiments 1 -5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I’-a):or a pharmaceutically acceptable salt thereof.B7. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I’-b):or a pharmaceutically acceptable salt thereof.B8. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IF):or a pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted 3-8 membered heteroaryl.B9. The compound of any one of embodiments 1-5 and 8. or a pharmaceutically acceptable salt thereof wherein ring A isBIO, The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R'' is independently at each occurrence H, halogen, -CN, -N(Cu 6alkyl)(Cb6alkyl), -NHC(O)NI -ICnealkyl, C1-salkyl, Ci.6alkoxy, C^haloalkoxy I. C3- ecycloalkyl, or 3-8 membered heterocycloalkyl wherein the alkyl of Rwis optionally substituted with one or more -OH or C1-salkoxy, and the Cmecycloalkyl of Rwis optionally substituted with one or more halo.Bl 1. The compound of any one of embodiments 1 -9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or halogen.B12. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R" is independently at each occurrence H, Cl, or F.B13. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R" is independently at each occurrence H or -CN.B14. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or -N(methyl)2.Bl 5. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or Cnealkyi, wherein the C1- ealkyl of Rwis optionally substituted with one or more -OH or C1-6alkoxy.Bl 6. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, halogen, C1-6alkoxy, or Cn ehaloalkoxy.Bl 7. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or -NHC(0)NHC1-6alkyl.B l 8, The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or C3-6cycloalkyl, wherein the C3-6cycloalkyl of Rwis optionally substituted with one or more halo.Bl 9. The compound of any one of embodiments 1 -9, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or 3-8 membered heterocycloalkyl .B20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein each of A1, Az, A3, and A4is -CRW-.B21. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein each of A1, Az, A3, and A4is -CH-.B22. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein one of A1, A2, AJ, and A4is other than -CH-.B23. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein one of A1, A2, A3, and A4is -N-.B24. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable saltB25. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein the moiety representedB26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein each of B1, B2, B3, B4, and B5is -CRX-.B27. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein each of B1, B2, B3, B4, and B5is -CH-.B28. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein one of B1, B2, By B4, and B5is other than -CH-.B29. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein one of B1, B2, By B4, and B’ is -N-.B30. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halogen, -CN, -N(C1-6alkyl)(C1-6alkyl), C1-6aikyl, C1-6haloalkyl, C1-6haloalkoxyi, C1-6aikoxy, C3-6cycloalkoxy, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl, wherein the C1-6alkyl of Rxis optionally substituted with one or more -OH or -GN, the C1-6alkoxy of Rxis optionally substituted with one or more C3-6cycioalkyl, and the C3-6cycloalkoxy of Rxis optionally substituted with one or more -CN.B31. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halogen or C1-salkyl, wherein the C1-6alkyl of Rxis optionally substituted with one or more -OH or -CN.B32. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H or -CN,B33. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halogen, or -N(C1-6alkyl)(C1- ealkyl).B34, The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, or Cj -salkoxy, wherein the Cj, ealkoxy of Rxis optionally substituted with one or more C3-6cycloalkyl.B35. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halogen or C3.6cycloalkyl,B36. The compound of any one of embodiments 1 -25, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halogen, or 3-8 membered heterocycloalkyl .B37. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein the moiety representedselected from the groupB38. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein the moiety representedB39, The compound of any one of embodiments 1-5, and 7-38, or a pharmaceutically acceptable salt thereof, wherein m is 1 , and R1and R2are each H.B40. The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently H or C-.^alkyl,B41 , The compound of any one of embodiments 1 -39, or a pharmaceutically acceptable salt thereof, wherein R3is H and R4is methyl.B42. The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each H.B43. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H.B44. The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein R7is H.B45. The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, wherein R8is -NHRy.B46. The compound of any one of embodiments 1 -44, or a pharmaceutically acceptable salt thereof, wherein Ryis H or C1-6alkyl.B47. The compound of any one of embodiments 1 -44, or a pharmaceutically acceptable salt thereof, wherein R8is -NHz or -NHfCHi).B48. The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, wherein R8is Cnealkyl.B49. The compound of any of embodiments 1 -44, or a pharmaceutically acceptbale salt thereof, wherein R8is methyl or ethyl.B50. The compound of any one of embodiments 1 -44, or a pharmaceutically acceptable salt thereof, wherein R8is -OCH3.B51 . The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:A1, A2, A3, and A4are each independently -N- or -CRW-, wherein Rwis independently at each occurrence H, halogen, -CN, Cuealkyl, -NHC(O)NHC1-6alkyl. -N(Cu 6alkyl)(C1-6alkyl), C1-salkoxy, C1-shaloalkoxyl, Ch-ecycloalkyl, or 3-8 membered heterocycloal kyl wherein , the C1-salkyl of Rwis optionally substituted with one or more -OH or C-.^alkoxy, and the C.cecycloalkyl of Rwis optionally substituted with one or more halo;B1, B2, B3, B4, and B’ are each independently -N- or -CRX-, Rxis 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 Rxis optionally substituted with one or more -OH, and the Cnealkoxy of Rxis optionally substituted with one or more Cb-ecycloalkyl;X is C(())R8or 5-6 membered heteroaryl;Rland R2if present, are each H;RJand R4are each independently H or C1-6alkyl;R5and R6are each H;R7is H;R8is -NHRy, -OCH3, orC1-6alkyl; andRyis H or Cnealkyl.B52. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:B53. The compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (S’-l):B54. The compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (S’ -2):B55. 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.B56. A method of inhibiting a thyroid stimulation hormone receptor (TSFIR) 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.B57. A method of treating a TSHR-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effectiveamount 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.B58. The method of embodiment 57, wherein the disease, disorder, or condition 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.B59. The method of embodiment 57 or 58, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease. Grave’s ophthalmology and thyroid eye disease.B60. The method of any one of embodiments 57-59, wherein the disease, disorder, or condition is Grave’s disease.Enumerated embodiments set C

[0158] The embodiment numbers referenced in this set refer to those within set C. For example, “embodiment 1” recited in embodiment C2 refers to embodiment Cl .Cl. A compound of formula (A”-C):or a pharmaceutically acceptable salt thereof, wherein:— is absent or a bond, wherein when — is a bond, R6and R7are absent; m is 0 or 1;A!, A2, A3, and A'1are each independently CRWor N, wherein Rwis 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 oxyalkyl, optionally substituted Cusalkoxy, optionally substituted C1- ehaloalkyl, optionally substituted C1-ghaloalkoxyL optionally substituted C3- ecycloalkyl, optionally substituted Cb-ehalocycloalkyl, optionally substituted -O~ C3-6cycloalky1, optionally substituted -O-C1-6alkylene-C3-6cycloalky1, optionally substituted -O-Cb-ehalocycloalkyl, optionally substituted -O-C4-sheterocyclyl, optionally substituted -O-(5- to 10-membered heteroaryl), optionally substituted - NH-C3-6cycloalkyl, optionally substituted -NH-C3-6halocycloalkyl, optionally substituted -NH-Cnecyanoalkyl, optionally substituted -NH-Cti-sheterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Cg. loaryl, optionally substituted -O-Cg.joaryl, or optionally substituted 5-10 membered heteroaryl;B1, B2, B3, B4and B5are each independently CRSor N, wherein Rxis 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)R8, -C(S)R8, -S(O)2R9, or optionally substituted 5-6 membered heteroaryl;Rfand R2if present, are each independently H, optionally substituted Ci-ealkyl, optionally substituted C1-6haloalkyl, optionally substituted Cs-gcycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orRland R2are 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;R3and R4are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyd, orRJand R4are 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 ;R5is H, halo, optionally7substituted C1-salkyl, optionally' substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,Rb, if present, is H, optionally substituted C1-6alkyl, optionally substituted Cu 6haIoalkyl, optionally substituted Cvecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R5and R6are 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;R7, if present, is H, optionally substituted C1-6alkyl, or optionally substituted Cn ehaloalkyl ;R8is -NHRy, -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 Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;R9is optionally substituted Cnsalkyl; andRyis 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.C2. The compound of embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.C3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.C4. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, and A4are each independently CRWor N, wherein Rwis independently at each occurrence H, halo, -CN, -NO2, -NH2, -S(O)q(C1-6alkyl), -S(O)q(C3- 6cycloalkyl), -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -NHC(O)NHC1-6alkyl, - NH(C1-6haloalkyl), C1-6aikylene-C3-6 cycloalkyl, C1-6aikyl, -NH(C1-6alkylene)-C3- 6cycloalkyl, C1-6alky1ene-Ci -ealkoxy, Ci -ehydroxy alkyl, C1-6alkoxy, Ci-ehaloalkyl, C1- ehaloalkoxyi, C3-6cycloaikyl, Cti-ehalocycloalkyl, -O-C3-8cycloalkyl, -O-C1-salkylene-Cs- ecycloalkyl, -O-CAshalocycloalkyl, -O-C4-8heterocycly1, -0-5-10 membered heteroaryl, - NH-C3-6cycloalkyl, -NH-C3-6halocycloalkyl, -NH-C1-6cyanoalkyl, -NH-Ci-sheterocyclyl, 4-8 membered heterocycloalkyl, Ce-ioaryl, -O-Ce-ioaryl, or 5-10 membered heteroaryl.C5. The compound of any one of embodiments 1 -3, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, halo, -NH(C1-6alkyl), -NH(C1- ehaloalkyl), -NH(C1-3alkylene-C3-6cycloalkyl), -N(C1-6alkyl)(C1-6alkyl), C1-salkyl, C1- ealkoxy, C1-shaloalkoxyl, C3-6cycloalkyl, 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-Cuecycloalkyl, -NH-C3-6halocycloalky1, -NH- C1-6cyanoalkyl, 4-8 membered heterocycloalkyl, Cs-waryl, or 5-10 membered heteroaryl.C6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein at least one of A1, AC Ay and A4is CRWthat is not CH or CD.C7. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein each of A1, A\ A3, and A4is CRW.C8. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein each of A’1, A3, and A4is CRW; and A2is N.C9. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein each of A’1, A2, and A4is CRW; and A3is N.CIO. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein each of A1, A'4, and AJis CRW; and A4is N.Cl l. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein A1and A4are each CRW; and A2and A~’ are each N.Cl 2. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein A1and A3are each CRW; and A2and A4are each N.Cl 3. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein A3is CRWand A4is N, wherein AJis not CH or CD.C14. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein A3is N and A4is CRW, wherein A4is not CH or CD.Cl 5. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein A1is CH or C(halo); A2is CH; A3is C(C1-6alkoxy), C(C1-6haloalkoxyl), or C(C3-6cycloalkyl); and A4is N.C16, The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein A1is CH or C(halo); A2is CH; AJis N; and A4is C(C1-6alkoxy), C(C1- ehaloalkoxyl), or C(C3-6Cycloalkyl).Cl 7. The compound of any one of embodiments 1 -3, or a pharmaceutically acceptable saltC19, The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein the moiety representedC20. The compound of any one of embodiments 1 -3, or a pharmaceutically acceptable salt thereof, wherein the moiety representedC21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein B1, B2, B3, B4and B5are each independently CRXor N, wherein RKis independently at each occurrence H, halo, -CN, -NO2, -NH2, -S(O)q(C1-6alkyl), -S(O)q(C3- 6cycloalkyl), -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), Cnsalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-salkoxy, C1-6haloalkyl, C1-shaloalkoxyl, C3-6cycloalkyl, -O-C3- 6cycloalkyl, -O- C1-6alkylene-C3-6cycloalkyl, Cs-rhalocycloalkyl, 3-8 membered heterocycloalkyl, C6-10aryL or 5-10 membered heteroaryl.C22, The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halo, -NH(C1-6alky1), C1- 6alkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxy, Cuehaloalkyl, C1-6haloalkoxyl, C3- 6cycloalkyl, C3-6halocycloalkyl, or -O- C3-6cycloalkyl.C23, The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein B1, B2, B3, B4and B3are each CRX.C24, The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein B1, B2, B3, and B4are each CRX; and B5is N.C25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein B1is not CH or CD.C26. The compound of any one of embodiments 1 -24, or a pharmaceutically acceptable salt thereof, wherein B4is not CH or CD.C27. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein B1is C(halo); B2is CH or C(halo); B3is CH; B4is C(haio), C(-NH(C1- ealkyl)), C(C1-6alkyl), C(C neliy dr oxyalkyl), C(C1-6Cyanoalkyl), C(C1-6alkoxy), C(C1- ehaloalkyl), C(C1-6haloalkoxyl), C(C3-6cycloalkyl), C(C3-ehalocycloalkyl), or C(OCs- ecycloalkyl); and B3is CH or N.C28, The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein the moiety representedC29. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein the moiety representedC30. The compound of any one of embodiments 1 -20, or a pharmaceutically acceptable saltC31. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)R8.C32. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein X is -C(S)R8.C33, The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein X is -S(O)?.R9.C34. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein X is optionally substituted 5-6 membered heteroaryl.C35. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable saltC36. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)R8; R8is -NHRy; and Ryis H or C1-6alkyl.C37. The compound of embodiment 36, or a pharmaceutically acceptable salt thereof, wherein Ryis H.C38. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein R? and R2if present, are each independently H, Cnsalkyi, C1-6haloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl.C39, The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein R1and R2are taken together with the carbon atom to which they are attached to form an Cvscycloalkyl, or 3-8 membered heterocycloalkyl;C40. The compound of any one of embodiments 1 -39, or a pharmaceutically acceptable salt thereof, wherein R'' and R4are each independently H, C1-6alkyl, Cnehaloalkyl, C1- ecycloalkyl, or 3-8 membered heterocycloalkyl.C41 , The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, R3and R4are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.C42. The compound of any one of embodiments 1 -41, or a pharmaceutically acceptable salt thereof, R;’ is H, halo, Cnsalkyl, Cnehaloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl .C43. The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R’ are each independently H or D.C44. The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R' are each H.C45. The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, R6, if present, is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or 3-8 membered heterocycloalkyl.C46. The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, R5and Rbare taken together with the carbon atom to which they are attached to form an Cs-gcycloalkyl, or 3-8 membered heterocycloalkyl.C47. The compound of any one of embodiments 1 -46, or a pharmaceutically acceptable salt thereof, R7, if present, is H, C1-6alkyl, or C1-shaloalkyl.C48. The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, wherein R6and R7, if present, are each independently H or D.C49. The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt thereof, wherein R6and R7, if present, are each H.C50. The compound of any one of embodiments 1-49, or a pharmaceutically acceptable salt thereof, R8is -NHRy, -OCH3, C1-6alkyl, C1-6haloaikyl, C3-6cycloalkyl, or 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 Rxis aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl.C51, The compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt thereof, wherein R9is C1-6alkyl.C52, The compound of any one of embodiments 1-51, or a pharmaceutically acceptable salt thereof, wherein Ryis H, C1-6alkyl, C1-ghaloalkyl, Co-gcycloalkyl, or 3-8 membered heterocycloalkyl.C53. The compound of any one of embodiments 1 -52, or a pharmaceutically acceptable salt thereof, wherein — is absent.C54. The compound of any one of embodiments 1 -52, or a pharmaceutically acceptable salt thereof, wherein — is a bond.C55. The compound of any one of embodiments 1 -54, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (S’-l ):C56. The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (S’ -2):C57, The compound of embodiment 1, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof,C58, The compound of embodiment 1, wherein the compound is selected from the group consisting of the compounds 1 to 126 of Table 1, or a pharmaceutically acceptable salt thereof.C59. The compound of embodiment 1, wherein the compound is selected from the group consisting of compounds 63, 82, 97, 101, 104, 105, 106, 107, 109, 111 , 112, 113, 120, 121 , 122, 200, 201, 202, 203, 207, 21 1 , 222, 223, 225, 231, 232, 233, 234, 235, 237, 238, 239, 240, 241 , 242, 246, 247, 248, 249, 250, 251 , 254, 257, 259, 260, 261, 262, 263, 269,270, 272, 273, 284, 286, 287, 288, 289, 290, 291, 292, 293, 295, 299, 300, 309, 310, 311,312, 313, 316, 317, 320, 321, 322, 323, 324, 325, 328, 329, 334, 335, 336, 337, 338, 339,340, 341, 342, 343, 344, 345, 346, 350, 351, 352, 356, 359, 362, 363, 364, 365, 366, 367,368, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 395, 396,397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414,415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431 , 432,433, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454,455, 456, 458, 459, 460, 461, 462, 463, 464, 465, 467, 468, 469, 470, 471, 472, 477, 478,479, 480, 482, 483, 485, 486, 487, 490, 491, 494, 495, 496, 503, 508, 509, 510, 511, 512,513, 514, 515, 516, 517, 518, 519, 520, 521, and 522 of Table 1, or a pharmaceutically acceptable salt thereof.C60. The compound of any one of embodiments 1-59, or a pharmaceutically acceptable salt thereof, wherein 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-tetrahydroquinolin-3-yl)urea; l-(7-chloro-l-(5-(difluoromethyl)-2-fluorobenzyl)“ 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(7-(difluoromethyl)-l-(5- (difluoromethy l)-2-fluorobenzyl)-2-oxo- 1,2,3 ,4-tetrahydroquinolin-3 -yl)urea; 1 -(1 -(5- (difluofomethyl)-2’fluorobenzyl)’2-oxo-7-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-3- yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-2- oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(7-(difluoromethyl)-l-(2-fluoro-5- (trifluoromethoxy)benzyi)-2-oxo-l,2,3,4-tetrahydfoquinolin-3-yi)urea; l-(7- (difluoromethyl)- 1 -(2-fluoro-5-(1 ,1,1,3 ,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-2- oxo-1 ,2,3,4-tetrahydroquinolin-3-yl)urea; l-(l-(5-(difluoromethyl)-2-fluorobenzyl)-2- oxo-7-(trifluoromethyl)- 1 ,2,3,4-tetrahydroquinolin-3-yI)-3-methyIurea; 1 ~(1 -(3- methylbenzyl)-2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl)urea; l-(l-(3-cyanobenzyl)-2-oxo-1.2.3.4-tetrahydroquinoIin-3 -yl)urea; 1 -( 1 -(3 -methoxybenzyl)-2-oxo- 1 ,2,3 ,4- tetrahydroquinolin-3-yl)urea; 1 -(l-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea; 1-(1 -((2,2-difluorobenzo[d][l,3]dioxo1-4-yl)methyl)-2-oxo-1 .2.3.4-tetrahydroquinolin-3-yl)urea; l-(7-methy1-2-oxo-l-(3-(trifluoromethyl)benzyl)-1.2.3.4-tetrahydroquinolin-3-yl)urea; l-(7-methoxy-2-oxo-l-(3-(trifluoromethyl)benzyl)-1 .2.3.4-tetrahydroquinolin-3-yl)urea; l-(7-cyano-2-oxo-l-(3-(trifluoromethyl)benzyl)-1.2.3.4-tetrahydroquinolin-3-yl)urea; l-(5-fluoro-l -(2-fluoro-5-(trifluoromethy1)benzy1)- 2-oxo-l,2,3,4-tetrahydroquinohn-3-yl)urea; l-(l-(3-chloro-2-fluoro-5- (trifluoromethyl)benzyl)-7-fluoro-2-oxo-1 ,2,3,4-tetrahydroqumolin-3-yl)urea; l-(2-oxo-l- (3-(trifluoromethy1)benzy1)-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl)urea; l-(7-fluoro-l- (l-(2-fluoro-5-(trifluoroinethyl)phenyl)ethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea;1 -(2-oxo-l-phenethyl-l,2,3,4-tetrahydroquinolin-3-yl)urea; l-(2-fluoro-5-( trifluoromethy 1) benzyl)-2-oxo-3 - ureido- 1 ,2,3,4-tetrahydroquinoline-7-carboxyli c acid; 1 -(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-l,2,3,4-tetrahydroquinoline-7- carboxamide; 1 -(7-(difluoromethyl)- 1 -(2-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2- oxo-1, 2,3, 4-tetrahydroquinolin-3-yl)urea; l-(7-(difluoromethyl)-2-oxo-l-((6- (trifluoromethyl)pyridin-2-yl)methyl)-l,2,3,4-tetrahydroquinoiin-3-yl)urea; l-(8- ((dimethylamino)methyl)-l -(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea; or a pharmaceutically acceptable salt thereof.C61. A pharmaceutical composition comprising the compound of any one of embodiments 1- 60, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.C62. A method of inhibiting a thyroid stimulation hormone receptor (TSHR) comprising contacting the TSHR with an effective amount of the compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 61.C63. A method of treating a TSHR-niediated 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 -60, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 61 .C64, The method of embodiment 63, wherein the disease, disorder, or condition 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.C65. The method of embodiment 63 or 64, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease. Grave’s ophthalmology, and thyroid eye disease.C66. The method of any one of embodiments 63-65, wherein the disease, disorder, or condition is Grave’s disease.VIII. GENERAL SYNTHETIC METHODS

[0159] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0160] The intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See. e.g., Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed. 1991).

[0161] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “ Enantiomers, Racemates, and Resolutions” , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds” , Wiley-Interscience, 1994).

[0162] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures.

[0163] Compounds of Formula (I), Formula (I- A), Formula (I-a), or Formula (I-b), can be prepared according to Scheme A, Scheme B, Scheme C, and Scheme D, wherein of m, n, A1, A2, AJ, A4, X, R1, R2, R3, R4, R5, R6, R', Rs, Rw, Rx, and Ry, are as defined for Formula (I), or any applicable variation or subformulae thereof as detailed herein.Scheme A

[0164] As shown in Scheme A, wherein RAis a leaving group, RBis alkyl, and PG is a protecting group (such as Boe), compounds of formula A-a are reacted with compounds of formula A-b, over one or more steps, to provide compounds of formula A-c. In some embodiments, compounds of formula A-a are coupled with compounds of formula A-b, in a Negishi-type coupling reaction, e.g. where compounds of formula A-b form organometallic compounds with metals such as Zn, and the organometallic compound is coupled with compounds of formula A-a, e.g. in the presence of a catalyst such as a palladium catalyst (e.g. Pd(OAc)2, XPhos). Compounds of formula A-c are coupled with compounds of formula A-d, in the presence of a base such as CS2CO3 to give compounds of formula A-e.Compounds of formula A-e are then deprotected, e.g. in the presence of an acid such as HC1, to afford amine compounds of formula A-f.Scheme B

[0165] As shown in Scheme B, wherein RAis a leaving group, compounds of formula B- a are reacted with compounds of formula B-h. to provide compounds of formula A-f. In some embodiments, RAis halo, and compounds of formula B-a are coupled with compounds of formula B-h. in the presence of a base such as Nall. In some embodiments, the RAis hydroxyl, and compounds of formula B-a are coupled with compounds of formula B-b, in a Mitsunobu-type reaction, e.g. with a coupling reagent such as CMBP.Scheme C

[0166] As shown in Scheme C, compounds of formula A-f are reacted e.g., with an isocyanate compound such as isocyanatotrimethylsilane in the presence of a base such as TEA, to provide compounds of formula C-a.Scheme D

[0167] As shown in Scheme D, wherein RAis a leaving group such as halo, compounds of formula A-f are reacted with compound of formula D-a, for example in the presence of a base such as pyridine, to provide compounds of formula D-b.Scheme E

[0168] As shown in Scheme E, wherein RAis a leaving group such as halo, compounds of formula A-f are reacted with compound of formula E-a, for example in the presence of a base such as pyridine, to provide compounds of formula E-b.EXAMPLES

[0169] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0170] Abbreviations used in the Examples include the following: ACM: acetonitrile;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;fH 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; and THF: tetrahydrofuran.IX. SYNTHETIC EXAMPLESExample 1: l-[(3-chlorophenyl)methytf-2-oxo-3,4-dihydroqitinolin-3-ylurea (Compound 1)Step 1: Synthesis of 3-amino-l-[(3-chlorophenyl)methyl]-3,4”dihydroquiiiolin-2-oiie

[0171] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (700.2 mg, 4.32 mmol) in DMF (10.0 mL) was added NaH (172.6 mg, 60%) at 0 °C under NT The mixture was stirred at 0 °C for 0.5 h. To the above mixture was added 1 -chlor o-3 -(chlor omethyl)benzene (695.3 mg, 4.32 mmol) at 0 °C under Ni. The resulting mixture was stirred at room temperature for additional 2 h under N?. After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (93 / 7, v / v) to afford 3 -amino- 1- [(3- chlorophenyl)methyl]-3,4-dihydroquinolin-2-one (400.0 mg, 29%) as a brown oil. LCMS (ESI, m / z): 1 N I 111 = 287.1.Step 2: Synthesis of l-[(3-chJorophenyl)methyl]-2-oxo~3,4"dihydroqiiinolm~3-ylurea(Compound 1)

[0172] To a solution of 3-atnino-l-[(3-chlorophenyi)methyi]-3,4-dihydroqumolin-2-one (200.8 mg, 0.70 mmol) in THF (6.0 mL) was added isocyanatotrimethyisilane (160.5 mg, 1.39 mmol) and TEA (282.7 mg, 2.79 mmol) at room temperature. The resulting mixture wTas stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 99, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 42% B in 10 min; Wave Length: 254 / 220 nm) to afford l-[(3-chlorophenyl)methyl]-2-oxo-3,4-dihydroqmnolin-3-ylurea (Compound 1) (35,5 mg, 15%) as a white solid. LCMS (ESI, m / z): [M+H] ' = 330.1.5 7.39 - 7.27 (m, 4H), 7.22 - 7.18 (m, 2H), 7.04 - 6.98 (m, 2H), 6.46 (d, J= 6.4 Hz, 1H), 5.81 (s, 2H), 5.26 - 5.22 (m, 1H), 5.14 - 5.10 (m, 1H), 4.47 - 4.41 (m, 1H), 3.21 - 3.16 (m, 1 H), 2.94 - 2.87 (m, 1 H).Example 2: Synthesis of l-[(2-chlorophenyl)methyl / ~2~axo~3,4-dihydroquinolin~3~ylurea (Compound 2)Step 1: Synthesis of 3-ammo~l~[(2~chIoropheuyi)methyi]-3,4-dihydroquinolm~2~one

[0173] To a solution of 3-amino-3,4-dihydro-1H-quinolin-2-one (500,3 mg, 3,09 mmol) in DMF (10.0 mL) was added NaH (123.3 mg, 60%) at 0 °C under N?. The mixture wasstirred at 0 °C for 0.5 h. Then l-chloro-2-(chloromethyl)benzene (496.7 mg, 3.09 mmol) was added to the mixture at 0 °C under N?. The resulting mixture was stirred at room temperature for additional 2 h under N?. After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / 'MeOH (97 / 3, v / v) to afford 3 -amino- 1- [(2- chlorophenyl)methyl]-3,4-dihydroquinolm~2~one (200.0 mg, 19%) as a brown oil. LCMS (ESI, m / z): I M ■ H | = 287.1 .Step 2: l-[(2-chiorophenyl)methyl]~2~oxo~3,4"dihydroqiiinolin~3~ylurea (Compound 2)Compound 2

[0174] To a solution of 3-aniino-l-[(2-chlorophenyl)methyl]-3,4-dihydroquinolin-2-one (100.1 mg, 0.35 mmol) in THF (6.0 mL) was added isocyanatotrimethylsilane (80.8 mg, 0.70 mmol) and TEA (141.3 mg, 1.40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCMZMeOH (95 / 5, v / v) and then purified by Prep-HPLC with the following conditions: (Column: Xselect CSH Cl 8 OBD Column 30x150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACM; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 10% B to 28% B in 15 min; Wave Length: 254 / 220 ran) to afford l-[(2- chlorophenyl)methyl]-2-oxo-3,4~dihydroquinolin-3-ylurea (Compound 2) (12.1 mg, 10%) as a white solid. LCMS (ESI, m / z): [M+Hp - 330.1.:H NMR (400 MHz, DMS()-c / 6): 8 7.53 - 7.50 (m, III), 7.32 - 7.24 (rn, 3H), 7.21 - 7.17 (rn, 1H), 7.05 - 7.01 (m, 2H), 6.77 (d, 8.0 Hz, HI), 6.45 (d, ■ / 6.8 Hz, 1 H), 5.82 (s, 2H), 5.33 - 5.28 (m, HI), 5.02 - 4.98 (rn, 1H), 4.52 - 4.46 (m, H I). 3.25 - 3.20 (m, i l l). 2.99 - 2.92 (m, 1 H).Step 1: Synthesis of 3-amino-l-[(4-chIorophenyl)methyl]-3,4-dihydroquinoIin-2-one

[0175] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.0 mg, 3.08 mmol) in DMF (10.0 mL) was added NaH (185.0 mg, 60%) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 30 min under N2. Then I -chloro-4-(chloromethyl)benzene (744.6 mg, 4.62 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h under N?. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 10, v / v) to afford 3-amino-l-[(4- chlorophenyl)methyl]-3,4-dihydroquinolin-2-one (400.0 mg, 45%) as a yellow solid. LCMS (ESI, m / z): [M+I If = 287.1.Step 2: l-[(4-chiorophenyI)methyl]~2~oxo~3,4"dihydroquinolm~3~ylurea (Compound 3)Compound 3

[0176] To a solution of 3-aniino-l-[(4-chlorophenyl)niethyl]-3,4-dihydroquinolin-2-one (200.0 mg, 0.69 mmol) in THF (5.0 tnL) were added isocyanatotrimethylsilane (160.7 nig, 1.39 mmol) and TEA (211.7 nig, 2.09 mmol) at room temperature. The resulting mixture wasstirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 10, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mniol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / mm; Gradient: 34% B to 44% B in 10 min; Wave Length: 254 / 220 nm) to afford l-[(4-chlorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 3) (17.9 mg, 7%) as a white solid. LCMS (ESI, m / z): [M+H]4= 330.1.7.37 (d, J = 8.4 Hz, 2H), 7.28 - 7.26 (m, 3H), 7.20 - 7.16 (m, 1H), 7.03 - 6.96 (m, 2H), 6.45 (d, J = 6.8 Hz, 1H), 5.82 (s, 2H), 5.25 - 5.21 (m, 1H), 5.12 - 5.07 (m, 1H), 4.45 - 4.39 (m, 1H), 3.21 - 3.16 (m, 1H), 2.93 - 2.86 (m, 1H).Example 4: Synthesis of 2-axo-l-(2-phenylethyl)-3,4-ddtydroquinolin-3-ylurea (Conqpound 4)Step 1: Synthesis of 3~ammo"l~(2~phenylethyl)~3,4~dihydroqumoim~2~rme

[0177] 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 (123.4 mg, 60%) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. To the above mixture was added (2~brornoethyl)benzene (570.7 mg, 3.08 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for additional 2 h under N?„ After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (95 / 5, v / v) to afford 3-amino-1 -(2-phenylethyl)-3,4- dihydroquinohn-2-one (189.0 mg, 20%) as a brown solid. LCMS (ESI, m / z): [MHI] ' ~ 267.1.Step 2: 2~oxo-l-(2-phenyIethyi)“33"dihydroqumoiisi“3~ylurea (Compound 4)

[0178] To a solution of 3-amino- 1 -(2-phenylethyl)-3,4-dihydroqumolin-2-one (110.2 mg, 0.41 mmol) m THF (6.0 mL) was added isocyanatotrimethylsilane (95.3 mg, 0.83 mmol) and TEA (167.1 mg, 1.65 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with I-fcO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (96 / 4, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 y.111; Mobile Phase A: Water (10 nimol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / mm; Gradient: 33% B to 48% B in 12 mm; Wave Length: 2.54 / 22011111) to afford 2-oxo-l-(2-phenylethyl)-3,4- dihydroquinolin-3-ylurea (Compound 4) (47.5 mg, 37%) as a white solid. LCMS (ESI, m / z): | \-l 111 = 310.1. ’H NMR (400 MHz, DMSOM’6): 5 7.32 - 7.11 (m, 8H), 7.07 - 7.04 (m, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.78 (s, 2H), 4.22 - 4.07 (m, 3H), 3.18 - 3.06 (m, 1H), 2.93 - 2.83 (m, 2H), 2.68 - 2.58 (m, 1H).Example 5: Synthesis of l-(l-(3-chloro-2-fluorobenzyl)-2-oxo-l,2,3,4-tetrahydroqiiinolin- 3-yl)urea (Compound 5)Step 1: Synthesis of 3-amino-l-(3-€htoro-2-fluorobenzyl)-3,4-dihydroqumoIm-2(lH)-ooe

[0179] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (500.2 mg, 3.08 mmol) in DMF (5.0 mL) were added NaH (123.3 mg, 60%) at 0 °C under Ns. The resulting mixture was stirred at 0 °C for 30 minutes under N?. To the above mixture was added 1-(bromomethyl)-3-chloro-2-fluorobenzene (689.1 mg, 3,08 mmol) at 0 °C under N?. The resulting mixture was stirred at room temperature for additional 2 h. After die reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / m ethanol (75 / 15, v / v) to afford 3-amino-l-(3-chloro-2-fluorobenzyl)-3,4-dihydroquinolin-2(IH)-one (650.2 mg, 69%) as a white solid. LCMS (ESI, m / z): [M + H i === 305.1.Step 2: l-(l"(3~chlorO"2-fluorobenzy8)-2-oxO"1,233"tefrahydroquinoIin~3~yI)urea (Compound 5)

[0180] To a solution of 3-amino-l-(3-chloro-2-fluorobenzyl)-3,4’dihydroquinolin-2(lH)- one (400.3 nig, 1.31 mmol) in THF (5.0 niL) were added isocyanatotrimethylsilane (301.1 mg, 2.61 mmol) and TEA (530.3 mg, 5.24 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture wasdiluted with HzO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (5 / 1, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 45% B in 10 min, 45% B to 45% B in 20 min; Wave Length: 254 nm) to afford 1 - (l-(3-chloro-2-fluorobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 5) (16.4 mg, 4%) as a white solid. LCMS (ESI, m / z): [M+H]+= 348.1.!H NMR (300 MHz, DMSO-tie): 5 7.51 - 7.46 (m, 1H), 7.31 - 7.28 (m, 1H), 7.24 - 7.14 (m, 1H), 7.11 - 7.04 (m, 3H), 7.01 - 6.96 (m, 1H), 6.45 (d, J = 6.6 Hz, 1H), 5.81 (s, 2H), 5.33 - 5.11 (m, 2H), 4.50 - 4,41 (m, 1H), 3.24 - 3.17 (m. 1H), 2.96 - 2.86 (m. 1H).Step 1: Synthesis of 3-amino-l~(3~chloro-4-fluorobenzyI)-3,4~dihydroqiiinoIin”2(lH)~one

[0181] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (300.0 mg, 1.85 mmol) in DMF (6.0 ml.,) was added NaH (74.0 mg, 60% purity) at 0 °C under Nz. The resulting mixture was stirred at 0 °C for 30 mm under N?„ To the above mixture was added 4- (bromornethyl)-2-chloro-l -fluorobenzene (413.3 mg, 1.85 mmol) at 0 °C under Nz. The resulting mixture was stirred at room temperature for additional 1 h under Nz. After the reaction was completed, the reaction mixture was quenched with NH4CI (aq.) at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHzCh / MeOH (90 / 10, v / v) to afford 3 -amino- 1 -(3-chloro-4-fluorobenzyl)-3,4-dihydroquinolin-2(lH)-one (200.2 mg, 32%) as a yellow solid..Step 2: Synthesis of l-(l-(3-chJorO”4-fliwrobenzyI)~2”Oxo-l,2,3,4~tetrahydroq«molin-3- yl)urea (Compound 6)Compound S

[0182] To a solution of 3-amino-l-(3-chloro-4-fluorobenzyl)-3,4-dihydroquinolin-2(lH)- one (180.0 mg, 0,63 mmol) in THF (5.0 mL) was added TEA (237.8 mg, 2.35 mmol) and isocyanatotrimethylsilane (134.7 mg, 1.17 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 99, v / v) and then purified by Prep- HPLC with the following conditions (Column: XBndge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 49% B in 10 min; Wave Length: 254 / 220 nm) to afford 1 -(1 -(3-chloro-4-fluorobenzyl)-2-oxo-1 ,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 6) (22.6 mg, 10%) as a white solid. LCMS (ESI, m / z): i X I i 1 ] === 348.1 .VH NMR (400 MHz, DMSO-r / e): 8 7.51 - 7.49 (m, 1H), 7.37 - 7.18 (m, 4H), 7.03 - 6.99 (m, 2H), 6.45 (d, J --- 6.4 Hz, 1H), 5.81 (s, 2H), 5.23 - 5.08 (m, 2H), 4.47 - 4.41 (m, 1H), 3.20 - 3.15 (m, HI), 2.94 - 2.87 (m, 1H).Step 1: Synthesis of 3-amino-l-[(5-€hioro-2-fluorophenyi)methyi]-3,4-dihydroquinoiin-2-one

[0183] To a solution of 3-ammo-3,4-dihydro-lH-qumolin-2-one (500.0 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 room temperature for 0.5 h under N?. To the above mixture was added 2- (bromomethyl)-4-chloro-l -fluorobenzene (688.9 mg, 3.08 mmol) at 0 °C under N2. The mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the resulting mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CELCh / MeOH (95 / 5, v / v) to afford 3 -amino- 1- [(5- chloro-2-fluorophenyl)niethyl]-3,4-dihydroquinolin-2-one (653.2 mg, 66%) as a yellow- solid. LCMS (ESI, m / z): | M H j = 305.1.Step 2: Syn thesis of l~[(5”€hIoro-2-flnoropheiiyI)methyI]”2”Oxo-3,4~dihydroqiiiiioIin-3- ylurea (Compound 7)

[0184] To a solution of 3-amino- l-[(5-chloro-2-fluorophenyl)methyl]-3,4- dihydroquinolin-2-one (300.0 mg, 0.98 mmol) in THF (10.0 mL) was added isocyanatotrimetihylsilane (453.7 mg, 3.94 mmol) and TEA (796.9 mg, 7.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purifiedby flash column chromatography with CEfoCh / MeOH (95 / 5, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 niL / min; Gradient: 32% B to 42% B in 10 min; Wave Length: 254 / 220 nm) to afford l-[(5-chloro-2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-yiurea (Compound 7) (151.9 mg, 44%) as a white solid. LCMS (ESI, m / z): [M+H]4= 348.1.JH NMR (400 MHz, DMSO-cfe): d 7.39 - 7.35 (m, 1H), 7.31 - 7.20 (m, 3H), 7.15 - 7.13 (m, 1H), 7.06 - 7.02 (m, H I). 6.96 (d, J= 8.0 Hz. 1H), 6.48 (d. . / 6.8 Hz, 1 H), 5.81 (s. 2H), 5.24 - 5.09 (m, 2H), 4.49 - 4,43 (m, H I). 3.19 - 3.14 (m. H i). 2.92 - 2.85 (m, 1 H).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

[0185] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.4 mg, 3.09 mmol) in DMF (10.0 mL) was added NaH (123.4 mg, 60% purity) at 0 °C under Nj. The resulting mixture was stirred at 0 °C for 30 min. Then l-chloro-3-(l-chloroethyl)benzene (540.1 mg, 3.09 mmol) and Nal (92.5 mg, 0.62 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at room temperature for additional 2 h under N2. .After the reaction was completed, the resulting mixture was quenched with water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CI-hCh / MeOH (83 / 17, v / v) to afford 3-amino-l-|T-(3-chlorophenyl)ethyr|-3,4-dihydroquinolin-2-one (120.2 mg, 13%) as a brown oil. LCMS (ESI, m / z): [M+H]+ ::::301.1.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-CempsusKS 8 Campou s'sd 0

[0186] To a solution of 3-amino-l-[l-(3-chlorophenyl)ethyi]-3,4-dihydroquinoiin-2-one (70.4 mg, 0.23 mmol) in THF (5.0 mL) was added with EtsN (71.1 mg, 0.70 mmol) and TMSNCO (53.9 nig, 0.47 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHiCh / MeOH (92 / 8, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 niL / min; Gradient: 35% B to 45% B in 10 min, 45% B to 45% B in 20 min; Wave Length: 254 / 220 nm; RTl(min): 12,0 RT2(min): 12.8) to afford cis- l-(l-(l-(3-chlorophenyI)ethyI)-2-oxo-l,2,3?4-tetrahydroquinoUn-3- yl)urea (Compound 8) (assumed, 2.8 mg, 3%) as a white solid and trans- l-(l-(l-(3- chIorophenyl)ethyl)~2-oxo-l,23i>4~tetrahydroquinolin-3-yI)urea (Compound 9) (assumed, 4.8 mg, 6%) as a white solid.

[0187] cis- l-(l-(l~(3~chIorophenyi)ethyl)~2~oxo-l,2,3,4~tetrahydroquinolin-3-yl)urea (Compound 8): RTl(min): 12.0; LC MS (ESI, m / z): [ M H ; = 344. 1. fll NMR (400 MHz, D.MSO-W): 5 7.35 - 7.22 (m, 5H), 7.12 - 7.08 (m, 1H), 7.00 - 6.96 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.39 id. . / 6.8 Hz, 1H), 5.91 - 5.86 (m, 1 H), 5.79 (s, 2H), 4.30 - 4.23 (m, 1H), 3.13 - 3.08 (m, 1H), 2.93 - 2.86 (m, 1H), 1.83 (d, .7 = 7.2 Hz, 3H).

[0188] trans- l-(l~(l-(3-chlorophenyl)ethy?)-2-oxo-l,2,3,4-tetrahydroqumoIin~3~ yl)urea (Compound 9): RT2(mm): 12.8; LCMS (ESI, m / z): [M+H];= 344.1. H NMR (400 MHz, DMSOWe): 5 7.49 - 7.25 (m, 5H), 7.16 - 7.12 (m, 1H), 7.05 - 7.01 (m, 1H), 6.71 (d, J =8.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.18 - 6.13 (m, 1H), 5.81 (s, 2H), 4.38 - 4.32 (m, 1H), 3.15 - 3.10 (m, 1H), 2.86 - 2.79 (m, 1H), 1.68 (d, . / 6.8 Hz, 3H)Step 1: Synthesis of l-(l-(3-chlorobenzyl)"2"Oxo-l,2,3,4-tetrahydroquinoiin-3“yi)-3- methylnrea (Compound 10)Compound 16

[0189] To a solution of 3-amino-l-(3-chlorobenzy1)-3,4-dihydroquinolin-2(lH)-one (100.0 mg, 0.35 mmol) m pyridine (2.0 mL) were added methylcarbamic chloride (100.0 mg, 1 .07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (20 / 80, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 inL / min; Gradient: 58% B to 68% B in 10 min; Wave Length: 254 nm) to afford 1 -(l-(3-chlorobenzyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-methylurea (Compound 10) (47.3 mg, 39%) as a white solid.I. ('MS (ESI, m / z): [ M H ! =344.2.lH NMR (400 MHz, DMSOM’6): 8 7.40 - 7.26 (m, 4H), 7.21 - 7.17 (m, 2H), 7.03 - 6.97 (m, 2.H), 6.38 (d, J = 6.8 Hz, 1H), 6.22 - 6.18 (m, 1H), 5.25 - 5.09 (m, 2H), 4.50 - 4.43 (m, 1H), 3.19 - 3.13 (m, 1H), 2.96 2.88 (m, 1 H), 2.59 (d, J 4.4 Hz, 3H).Example 10; Synthesis of l-(l-(4-chlorophenethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- y I) urea (Compound 11)Step 1: Synthesis of 3-amino-l-(4-chlorophenethy8)-3,4-dihydroquino8in-2( lH)-one

[0190] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (200.0 mg, 1.23 mmol) in toluene (8.0 mL) was added 2-(4-chlorophenyl)ethan-l-ol (193.1 mg, 1.23 mmol) and CMBP (595.2 mg, 2.46 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 4 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (64 / 36, v / v) to afford 3-amino-l-(4- chlorophenethyl)-3,4-dihydroquinolin-2(lH)-one (130.2 mg, 32%) as a colorless oil. LCMS (ESI, m / z): [M+Hf - 301.1.Step 2: Synthesis of l-(l-(4"ChIoropheiiethyl)-2-oxo-l,2,354-tetrahydroquinolin-3-yI)urea(Compound 11)Compound It

[0191] To a solution of 3-amino- 1 -(4-chlorophenethyl)-3,4-dihydroquinolin-2(lH)-one (110.0 mg, 0.36 mmol) in THF (5.0 mL) was added isocyanatotrimethylsilane (84.3 mg, 0.73 mmol) and TEA (111.0 mg, 1.09 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19x250 mm,5 pm; Mobile Phase A: Water (10 nimol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 31% B to 41% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(l-(4- chlorophenethyl)~2-oxo-l,2,3,44etrahydroquinolin-3-yl)urea (Compound 11) (18.8 mg, 15%) as a white solid. LCMS (ESI, m / z): [M+H]+= 344.1.]H NMR (400 MHz, DMSO- cL): 57.34 - 7.19 (m, 7H), 7.07 - 7.03 (m, 1H), 6.32 (d, J = 6.4 Hz, 1H), 5.78 (s, 2H), 4.23 - 4.06 (m, 3H), 3.12 - 3.07 (m, 1H), 2.86 - 2.82 (m, 2H), 2.68 - 2.57 (m, 1H).Step 1: Synthesis of 3-amino-l-(3-chtorophesiefhyI)-3,4-dihydroqumoim-2(lH)-osie

[0192] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (500.0 mg, 3.08 mmol) in toluene (20.0 mL) was added 2-(3-chlorophenyl)ethan-l-ol (480.0 mg, 3.06 mmol) and CMBP (1.5 g, 6.21 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 5 h under N2. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-amino-l-(3-chlorophenethyl)-3,4- dihydroquinoiin-2(lH)“One (160.1 mg, 17%) as an orange solid. LCMS (ESI, ni / z): [M+H]+= 301.1.Step 2: Synthesis of l-(l-(3"drlorophenethyI)~2~o:TOM,23ylTetrahydroqsHnolm-3-yl)urea(Compound 12)Compound 'll

[0193] To a solution of 3-amino- l-[2-(3-chlorophenyl)ethyi’|-3,4-dihydroquinoiin-2-one (140.0 mg, 0.46 mmol) m THF (2.0 mL) was added TEA (140.0 mg, 1 .38 mmol), TMSNCO (112.0 mg, 0.97 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column 30x150 mm; Mobile Phase A: Water (10 nnnol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 23% B to 43% B in 15 nun; Wave Length: 2.54 / 220 nm) to afford l-(l-(3-chlorophenethyl)-2- oxo-1 , 2,3, 4-tetrahydroquinolin-3-yl)urea (Compound 12) (46.6 mg, 29%) as a white solid.I . CMS (ESI, m / z): [ M i l l = 344. 1.fH NMR (400 MHz, DMSO-cL): 8 7.37 - 7.25 (m, 6H), 7.14 (d, J= 6.4 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.31 (d, J= 5.2 Hz, 1H), 5.78 (s, 2H), 4.19 - 4.08 (m, 3H), 3.13 - 3.07 (m, 1H), 2.87 - 2.84 (m, 2H), 2.65 - 2.57 (m, 1H).Step 1: Synthesis of 3-amino-l~[2~(2~chlorophenyI)ethyl]~3,4"dihydroquinolin~2~one

[0194] To a solution of 3-aminO’3,4-dihydro-lH-quinolin-2-one (502.1 mg, 3.10 mmol) in toluene (10.0 ml..) was added 2-(2-chlorophenyl)ethanol (484.8 mg, 3.10 mmol) and C.MIsP (1.5 g, 6,22 mmol) at room temperature tinder Ns. The resulting mixture was stirred at 110 °C for 16 h under Nj, After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na?SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (31 / 69, v / v) to afford 3-amino-l-[2-(2-chloropheny1)ethyl]-3,4- dihydroquinolin-2-one (200.5 mg, 20%) as a yellow solid. LCMS (ESI, m / z): [M-f-Hj ':::301.1.Step 2: Synthesis of l-[2-(2-chIorophenyi)ethyI]-2-oxo~3,4-dihydroquinoIin~3~yIurea(Compound 13)

[0195] To a solution of 3-amino- l-[2-(2-chlorophenyl)ethyl]-3,4-dihydroquinolin-2-one (181.2 mg, 0.60 mmol) in THF (10.0 ml...) was added isocyanatotrimethylsilane (138.8 mg, 1 .21 mmol) and TEA (243.8 mg, 2.41 mmol) at 0 °C under Nj. The resulting mixture was stirred at room temperature for 16 h under N2. .After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na?S()4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash columnchromatography with petroleum ether / ethyl acetate (1 / 99, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column 30x150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 30% B to 50% B in 15 min; Wave Length: 254 / 220 nm) to afford l-[2-(2-chlorophenyl)ethyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 13) (72.4 mg, 34%) as a white solid. LCMS (ESI, m / z): | \i ■ l l j = 344.1.NAIR (400 MHz, DMSO-tfc): $ 7-42 - 7.21 (m, 7H), 7.07 - 7.03 (m, 1H), 6.33 (d, J= 6.0 Hz, 1H), 5.78 (s, 2H), 4.27 - 4.10 (m. 3H), 3.13 - 3.08 (m, H I). 3.04 - 2.92 (m, 2H), 2.68 - 2.60 (m, 1H).Example 13; Synthesis l-[(2,5-dichlorophenyl)methylJ-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 14)Step 1: Synthesis of 3-ammo-l-[(2,5~dichloropheiiyI)methyl]”3,4-dihydroquinolm~2~oiie

[0196] To a solution of 3-amino-3,4~dihydro~l H-quinolm-2-one (500.4 mg, 3.09 mmol) in DMF (10.0 mL) was added NaH (123.4 mg, 60%) at 0 °C under Ns. The resulting mixture was stirred at 0 °C for 1 h under Ns. To the above mixture was added 2-(br oniomethyl)-! ,4- dichlorobenzene (740.2 mg, 3.09 mmol) at 0 °C under Ns. The resulting mixture was stirred at room temperature for additional 1 h under Ns. After the reaction was completed, the reaction mixture was quenched with FLO at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CITaCh / MeOH (92 / 8, v / v) to afford 3 -amino- 1 -[(2,5- dich1orophenyl)methyl]-3,4-dihydroquinolin-2-one (268.0 mg, 27%) as a yellow solid. LCMS (ESI, m / z): | \L H I - 321.0.Step 2: Synthesis of l-[(2,5-dichIorophenyJ)methyi]-2-oxo-3,4-dihydroquinoHn-3-yiurea(Compound 14)Compound 14

[0197] To a solution of 3-amino- l-[(2,5-dichlorophenyI)methyl’|-3,4-dihydroquinoIin-2- one (220.5 nig, 0.69 mmol) in THF (5.0 niL) was added TEA (208.4 mg, 2.06 mmol) and TMSNCO (158.2 mg, 1.37 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHiCk / MeOH (92 / 8, v / v) and then purified by Prep-HI’LC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 38% B to 58% B in 14 min; Wave Length: 254 nm) to afford l-[(2,5-dichlorophenyl)methyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 14) (11.9 mg, 5%) as a white solid. LCMS (ESI, m / z): | V= U J = 364.0. ’H NMR (400 \IHz. DMSO-de): 5 7.56 (d. J= 8.4 Hz, 1 H ), 7.42 - 7.38 (m, 1H), 7.32 (d, 7.2 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.08 - 7.04 (m, 2H), 6.81 (d, 8.0 Hz,1H), 6.45 (d, J= 6.8 Hz, 1H), 5.80 (s, 2H), 5.29 - 5.25 (m, 1H), 5.01 - 4.96 (m, 1H), 4.57 - 4.50 (m, H I). 3.24 - 3.18 (m, 1H), 2.99 - 2.92 (m, 1H).Example 14: Synthesis of l-[(5-chloro-2-methylphenyl)methylj-2-oxo-3,- 4-dihydroquinalin- 3-yhtrea (Compound 15)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 110c:'C for 16 li under N2. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACNZH2O (65 / 35, v / v) to afford 3-amino-l-[(5-chloro-2- methylphenyl)methyl]-3,4-dihydroquinolin-2-one (360.5 mg, 39%) as a yellow oil. LCMS (ESI, m / z): [M+H] = 301.1.Step 2: Synthesis of l-[(5-chJorO”2~methyIpheiiyl)methyl]-2~oxo~3,4"dihydroqiimoliii~3~ yhirea (Compound 15)Compound 15

[0199] To a solution of 3-aminO’l-[(5-chloro-2-methylphenyi)methyl]-3,4- dihydroquinolin-2-one (100.5 nig, 0.33 mmol) in THF (4.0 niL) was added TEA (101.4 mg, 1.00 mmol) and TMSNCO (77.1 mg, 0.67 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H?O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHzClj / MeOH (93 / 7, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow' rate: 20 mL / min; Gradient: 32% B to 42% B in 10 min; Wave Length: 254 ran) to afford 1 -[(5- chloro-2-methylphenyl)methyl]-2-oxo-3 ,4-dihy droquinolin-3-ylurea (Compound 15) (19.3 mg, 13%) as a white solid. LCMS (ESI, m / z): [ M H i - 344.1.1H NMR (400 MHz, DMSO- J6): 8 7.33 - 7.18 (m, 4H), 7.06 - 7.02 (m, 1 H), 6.82 - 6.79 (m, 2H) 6.46 (d, ■ / 6.8 Hz, 1 H),5.80 (s, 2H), 5.22 - 5.17 (m, IH), 4.96 - 4.91 (m, 1H), 4.52 - 4.45 (m, 1H), 3.25 - 3.21 (m, 1H), 2.97 - 2.90 (m, If I), 2.35 (s, 3H).Step 1: Synthesis of 3-amino-l-(2-chIoro-5-fluorobenzyl)-3,4-dihydroqninoIin-2(lH)-one

[0200] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (200.0 mg, 1.23 mmol) in DMF (5.0 mL) was added NaH (48.0 mg, 60%) at 0 °C under Nz. The resulting mixture was stirred at 0 °C for 1 h under Nz. To the above mixture was added 2-(bromomethyl)-l- chloro-4-fluorobenzene (270.0 mg, 1.20 mmol) at 0 °C under Nft. The resulting mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the reaction mixture was quenched with HjO at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-amino- 1-(2-chloro-5-fluorobenzyl)-3,4-dihydroquinolin-2(lH)-one (240.0 mg, 64%) as a light yellow' solid. LCMS (ESI, m / z): [MH 1 11 305.1 .Step 2: Synthesis of l-(l-(2"cMoro-5"fluorobenzyi)-2-oxO"1,233-tet*’ahydroqninoIm~3~ yi)urea (Compound 16)

[0201] To a solution of 3-amino-l-(2-chloro-5-fluorobenzyl)-3,4-dihydroquinolin-2(lH)- one (220.0 mg, 0.72 mmol) in THF (5.0 mL) was added TEA (220.0 mg, 2.17 mmol) and TMSNCO (176.0 mg, 1.52 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHjCh / MeOH (10 / 1, v / v) and then purified by Prep-HPLC with the following conditions : (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 64% B in 14 mm; Wave Length: 254 / 220 nm) to afford l-(l-(2-chloro-5~fluorobenzyl)-2-oxo- l,2,3,4-tetrahydroquino1in-3-yl)urea (Compound 16) (64.9 mg, 25%) as a white solid.I..CMS (ESI, m / z): [ M + H j = 348.1.lH NMR (400 MHz, DMSCM6): 5 7.59 - 7.55 (m, 1H), 7.31 (d, .7 = 7.6 Hz, 1H), 7.22 - 7. 16 (m, 2H), 7.07 - 7.03 (m, 1H), 6.93 - 6.90 (m, 1H), 6.77 (d, .7 = 8.0 Hz, 1H), 6.43 (d, J = 6.8 Hz, 1H), 5.81 (s, 2H), 5.29 - 5.24 (m, 1H), 4.99 - 4.95 (m, 1H), 4.59 - 4.52 (m, 1H), 3.24 - 3.18 (m, 1H), 3.00 - 2.93 (m, HI).Example 16: Synthesis of l-(l-(3-cyanobemyl)-2-cxo-l,2,3,4-tetrahydroquinolin-3~yl)urea (Compound 17)Step 1: Synthesis of 3-((3-amino-2-oxo-3,4-dihydroquinolin-l(2H)~ yl)methyi)benzonitriie

[0202] To a solution of 3-amino-3,4~dihydroqumolin-2(lH)-one (400.1 mg, 2.47 mmol) in toluene (5.0 mL) were added 3-(hydroxymethyl)benzonitrile (328.4 mg, 2.47 mmol) and CMBP (1.2 g, 4,93 mmol) at room temperature under Ns. The resulting mixture was stirred at 110 °C for 4 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (90 / 10, v / v) to afford 3-((3-amino-2-oxo- 3,4-dihydroquinolin-l(2H)-yl)methyl)benzonitrile (550.1 mg, 90%) as a yellow oil. LCMS (ESI, m / z): i \l 1 I | 278. LStep 2: Synthesis of l-(l-(3-cyanobenzyl)-2~oxo~1434-tefrahydroquinoIin-3-yI)urea(Compound 17)Compound 17

[0203] To a solution of 3-((3-amino-2-oxo-3,4-dihydroquinolin-l(2H)- yl)methyl)benzonitrile (200.1 mg, 0.72 mmol) in THF (5.0 mL) were added TMSNCO (166.2 mg, 1.44 mmol) and TEA (291.3 mg, 2.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. I'he residue was purified by flash column chromatography with dichloromethane / methanol (95 / 5, v.A) and then purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep Cl 8 OBD Column, 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 24% B to 34% B in 10 min; Wave Length: 254 nm) to afford 1 -(l-(3- cyanobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolm-3-yl)urea (Compound 17) (14.5 mg, 6%) as

[0204] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (400.1 mg, 2.47 mmol) in toluene (5.0 mL) were added (3-fluorophenyl)niethanol (311.1 mg, 2.47 mmol) and CA1BP (1.2 g, 4.93 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 4 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (85 / 15, v / v) to afford 3-amino-l -(3~fluorobenzyl)-3,4- dihydroquinolin-2(lH)-one (500.1 mg, 75%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=271.1.Step 2: Synthesis of l-(l-(3-fluorobenzyJ)-2-oxo-l,2,3,4-tetrahydroqumoIin~3-yl)iirea(Compound 18)Compound 1§

[0205] To a solution of 3-amino-l-(3-fluorobenzyl)-3,4-dihydroquinolin-2(lH)"One (200.1 mg, 0.74 mmol) in THF (5.0 mL) were added TMSNCO (170.5 mg, 1.48 mmol) and TEA (299.6 mg, 2.96 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (95 / 5, v,A) and then purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic Wave Length: 254 nm) to afford l-(l-(3-fluorobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 18) (32.8 mg, 14%) as a white solid. LCMS (ESI, m / z): [M+Hp = 314.1.NAIR (300 MHz, DMSOW6): 5 7.54 - 7.33 (m, 1H), 7.29 - 7.21 (m, 1H), 7.19 - 7.16 (m, 1H), 7.10 - 7.04 (m, 3H), 7.03 - 6.89 (m, 2H), 6.47 (d, J= 6.6 Hz, 1H), 5.82 (s, 2H), 5.38 - 5.10 (m, 2H), 4.50 - 4.42 (m, 1 H), 3.24 - 3.17 (m, 1H), 2.97 - 2.88 (m, 1H).Example 18: Synthesis of l-[(3-methylphenyl) methylf2-axo-3,4-dihydroquinolin-3-ylurea (Compound 19)Step 1: Synthesis of 3-amino-l-[(3-methyiphenyi) methyi]-3,4-dihydroquinoiin-2-osie

[0206] To a solution of 3-amino-3,4-dihydro-1H-quinolin-2-one (500.0 mg, 3.08 mmol) in DMF (10.0 mL) was added sodium hydride (122.0 mg, 60%) at 0 °C under Nj. The resulting mixture was stirred at room temperature for 1 h under Nz. To the above mixture was added l-(bromomethyl)-3-methylbenzene (570.5 mg, 3.08 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h under N?. After the reaction was completed, the resulting mixture was quenched with water at room temperature and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CHzCIz / MeOH (92 / 8, v / v) to afford 3-amino-l-[(3-methy1phenyl) methyl]-3,4-dihydroqumolin-2-one (600.0 mg, 73%) as a light yellow solid. LCMS (ESI, m / z): [M+H]4 :::267.1 .Step 2: Synthesis of l-[(3-methy8phenyi) rnethyd]”2”Oxo-3,4-dihydroqninotin-3-yhirea(Compound 19)Compound 10

[0207] To a solution of 3-amino-l-[(3-methylphenyl) methyl]-3,4-dihydroqumolin- 2-one(100.0 mg, 0.37 mmol) in THF (5.0 mL) was added isocyanatotrimethylsilane (86.1 mg, 0.75mmol) and EtjN (113.9 mg, 1.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (74 / 26, vA) and then purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 62% B in 14 min; Wave Length: 254 / 220 nm) to afford 1- [(3 -methylphenyl) methyl]-2-oxo-3,4-dihydroquinoIin-3-ylurea (Compound 19) (48.4 mg, 41%) as a white solid. LCMS (ESI, m / z): [M+H]+= 310.3.JH NMR (400 MHz, DMSO-Ai): H),[G2G8] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)~one (200.0 mg, 1.23 mmol) in DMF (5.0 mL) was added NaH (48.0 mg, 60%) at 0 °C under Nz. The resulting mixture was stirred at 0 °C for 1 h under N2. To the above mixture was added l,3-dichloro-5- (chloromethyl)benzene (241.0 mg, 1.23 mmol) at 0CC under N2. The resuiting mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-amino- l-(3,5-dichlorobenzyl)-3,4-dihydroquinolin-2(lH)-one (300. 1 mg, 75%) as a yellow solid. I .CMS (ESI, m / z): [ M H ; = 321 .0.Step 2: Synthesis of l-(l-(3,5~dichIorobeiizyl)-2~oxo~l,2,3>4-tetrahydroqnmoIiB-3- yl)urea (Compound 20)Compound 20[0209| To a solution of 3-amino-l-[(3,5-dichlorophenyi)methyl]-3,4-dihydroquinoiin-2- one (100.0 mg. 0.31 mmol) in THE (5.0 mL) was added TEA (95.0 mg, 0.93 mmol) and TMSNCO (74.0 mg, 0.64 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBndge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 64% B in 14 min; Wave Length: 254 / 220 nm) to afford l-[(3,5-dichlorophenyl)methyl]- 2-oxo-3,4-dihydroquino1in-3-ylurea (Compound 20) (45.5 mg, 40%) as a white solid. LCMS (ESI, m / z): IM ■ H | = 364.1 .lH NMR (400 MHz. DMSO-de): 5 7.49 (s, 1H), 7.32 - 7.19 (m, 4H), 7.05 - 6.97 (m, 2H), 6.45 (d, J= 6.8 Hz, 1H), 5.80 (s, 2H), 5.25 - 5.08 (m, 2H), 4.51 - 4.44 (m, H I). 3.21 - 3.15 (m, H I).. 2.96 - 2.88 (m, 1H).Example 20: Synthesis oflf(2,5-difluorophenyl)methylf2-oxo-3,4-dihydroqHinolin-3- ylurea (Compound 21)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?. The resulting mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the resulting mixture was quenched with H?O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 99, v / v) to afford 3-amino-l-[(2,5- difluorophenyl)methyl]-3,4-dihydroqumolin~2-one (230.0 mg, 25%) as a yellow solid. LCMS (ESI, m / z): i M ■ 11 | = 289.1 .Step 2: Synthesis of l-[(2,5-difl«oropheiiyI)methy?]-2-oxo-3,4-dihydroquinoIin-3-yhjrea (Compound 21)Compound 21

[0211] To a solution of 3-amino4-[(2,5-difluorophenyl)methyl]~3,4-dihydroquinolin-2- one (200.2 mg, 0.69 mmol) in THF (5.0 mL) was added isocyanatotrimethylsilane (159.2 mg, 1.38 mmol) and TEA (280,4 mg, 2.77 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h After the reaction wras completed, the resulting mixture was diluted with HjO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (60 / 40, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 prn; Mobile Phase A; Water (10.0 mmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL / min; Gradient: 28% B to 38% B in 10 min; Wave Length: 254 / 220 nm) to afford 1 - [(2, 5 -difluoropheny 1 )m ethyl ] -2-oxo-3 ,4-dihydroquinoli n-3 -y 1 urea (Compound 21)(92.9 mg, 40%) as a white solid. LCMS (ESI, m / z): [M+H]+= 332.1.!H NMR (400 MHz, DMSO-ifc): 5 7.32 - 7.30 (m, 2H), 7.28 - 7.12 (m, 2H), 7.06 - 7.02 (m, 1H), 6.98 - 6.93 (m, 2H), 6.44 (d, J= 6.8 Hz, 1H), 5.81 (s, 2H), 5.26 - 5.21 (m, 1H), 5.12 - 5.08 (m, 1H), 4.52 - 4.45 (m, 1H), 3.21 - 3.16 (m, 1H), 2.95 - 2.88 (m, 1 H).Ex / unple 21: Synthesis of l-(8-chloro-l-(5-chloro-2-fluorobenz^'l)-2-aKO-l, 2,3,4- teh‘ahydroqiih'udin-3-yl)urea (Conypound 22)Step 1: Synthesis of tert-butyl (8-chIoro-2-oxo-l,2,3,4”ietrahydroquinoIin-3- yl)carbamate

[0212] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.1 g, 12.46 mmol) in DMF (20.0 mL) was added Zinc (1.5 g, 22.94 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 h under N2. To the above mixture was added a solution of 2-bromo-6-chloroaniline (2.0 g, 9.69 mmol) in DMF (2.0 mL), Pd(OAc)2 (109.4 mg, 0.49 mmol) and XPhos (461.2 mg, 0.97 mmol) at room temperature. The resulting mixture was stirred at 40 °C for additional 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. The mixture was filtered. The filtrate was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (22 / 78, v / v) to afford tert-butyl (8-chloro-2-oxo-l,2,3,4-tetrahydroqumolin-3-yl)carbamate (2.4 g, 82%) as a white solid.I .CMS (ESI, m / z): [ M H ; = 297.1.Step 2: Synthesis of tert-butyl (8-chIoro-l-(5-chloro-2-fluorobenzyl)-2-oxo-1^23,4- tetrahydroquinolin-3~yl)carbamate

[0213] To a solution of tert-butyl (8-chloro-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)carbamate (814.2 mg, 2.74 mmol) in DMF (10.0 mL) was added 2-(bromomethyl)-4- chloro-1 -fluorobenzene (607.5 mg, 2.72 mmol) and CS2CO3 (2.3 g, 7.06 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (16 / 84, v / v) to afford tert-butyl (8-chloro-l-(5-chloro-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroqumolin-3-yl)carbamate (1.2 g, 99%) as a white solid. LCMS (ESI, m / z): [M+H]!- 439.1.Step 3: Synthesis of 3-amino-8-ch?oro~l~(5-chIoro-2-fluorobenzyl)-3,4-dihydroquinoIiii- 2(lH)-one

[0214] A solution of tert-butyl (8-chloro- l-(5-chloro-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate (1.1 g, 2.50 mmol) in HCl / dioxane (10.0 mL, 4.0 mol / L) was stirred at room temperature for 4 h. After the reaction was completed, the pH value of the mixture was adjusted the to 7.0 with NaHCCfi (aq.) at 0 °C. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 3-amino-S- chloro-l-(5-chloro-2~fluorobenzyl)~3,4-dihydroquinolin-2(lH)-one (811.4 mg, crude) as a light yellow oil.= 339,0.Step 4: Synthesis of l-(8-chlorO”l”(5-chIoro-2~fluorobenzyl)-2-oxo~l,2,3>4- tetrahydroquinolin-3-yl)nrea (Compound 22)Compound 22[0215j To a solution of 3-amino-8-chloro-l-(5-chloro-2-fluorobenzyl)-3,4- dihydroquinolin-2(lH)-one (196.8 mg, 0.58 mmol) in THF (7.0 mL) was added isocyanatotrimethylsilane (134.5 nig, 1.17 mmol) and TEA (235.3 mg, 2.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH3OFI / CH2CI2 (7 / 93, v / v) and then purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD Cl 8 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 69 niL / min; Gradient: 38% B to 58% B in 14 min; Wave Length: 254 / 220 nm) to afford l-(8-chloro-l-(5-chloro-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea ( Compound 22) (28.8 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H]+= 382.2.!H NMR (400 MHz, DMSO-J6): 57.38 - 7.29 (m, 4H), 7.20 - 7.11 (m, 2H), 6.45 (d, J = 6.4 Hz, 1H), 5.80 (s, 2H), 5.25 - 5.11 (m, 2H), 4.36 - 4.30 (m, 1H), 3.10 - 3.05 (m, 1H), 2.75 - 2.68 (m, 1H).Ex / unple 22: Synthesis of l-(l-(5-chloro-2-fluorobenzyl)-7-niethyl-2-oxo-l, 2,3,4- teh‘ahydroqiih'udin-3-yl)urea (Conypound 23)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?. To the above mixture was added 2-bronio-5-inethylamline (1.0 g, 5.37 mmol), Pd(OAc)2 (60.0 nig, 0.26 mmol) and XPhos (256.0 mg, 0.53 mmol) at room temperature under N?. The resulting mixture was stirred at 40 °C for additional 4 h under N2. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford tert-butyl (7-methyl-2-oxo-l,2,3,4~tetrahydroquinolin-3-yl)carbamate (900.0 mg, 60%) as a white solid, i .('.MS (ESI, m / z): [M- + H i = 277.1.Step 2: Synthesis of tert-butyl (l-(5-chloro-2-fluorobenzyl)-7-methyl-2-oxo-l,2,3»4- tetrahydroquinolin-3~yl)carbamate

[0217] To a solution of tert-butyl (7-methyl-2-oxo-3,4-dihydro-lH-quinolin-3- yl)carbamate (820.0 mg, 2.96 mmol) in DMF (10.0 mL) was added 2-(bromomethyl)-4- chloro-1 -fluorobenzene (656.5 mg, 2.93 mmol) and CS2CO3 (2.4 g, 7.36 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer w'as washed with brine, dried over anhydrous Na?.SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1 , v / v) to afford tert-butyl (l-(5-chloro-2-fluorobenzyl)-7-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.1 g, 88%) as a white solid. LCMS (ESI, m / z): [M+H]+= 419.1.Step 3: Synthesis of 3-amino-l~(5~chloro-2-fluorobenzyI)-7-methyI-3,4-dihydroqiiinoIin” 2(lH)-one

[0218] A solution of tert-butyl (l-(5-chloro-2-fluorobenzyl)-7-niethyl-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate (1.0 g, 2.38 mmol) in HCl / l,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 7 with NaHCCh (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-amino- l-(5-chloro-2-fluorobenzyl)-7-methyl-3,4-dihydroquinolin-2(lH)-one (800.0 mg, crude) as a light yellow solid. I., CMS (ESI, m / z): |\H l i = 319. 1.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)Compound 23

[0219] To a solution of 3-amino-l-(5-chloro-2-fluorobenzyl)-7-methyl-3,4- dihydroquinolin-2(lH)-one (200.0 mg, crude) in THE (5.0 mL) was added TEA (188.0 mg, 1.85 mmol) and TMSNCO (146.0 mg, 1.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column 30x150 mm; Mobile Phase A: Water (10 nimol / L NH1HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / nnn; Gradient: 5% B to 5% B in 2 min, 30% B to 50% B in 15 min; Wave Length: 254 / 22011m) to afford l-(l-(5-chloro-2-fluorobenzyl)-7-methyl-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea (Compound 23) (57.3 nig, 25%) as a white solid. LCMS (ESI, m / z): [M+H]4' = 362.2.!H NMR (400 MHz, DMSO-Y): 87.40 - 7.29 (m, 2H), 7.18 - 7.13 (ni, 2H), 6.87 - 6.83 (m, 2H), 6.44 (d, J = 6.8 Hz, 1H), 5.80 (s, 2H), 5.22 - 5.08 (m, 2H), 4.45 - 4.38 (n:. H I). 3.16 - 3.10 (m, 1H), 2.84 - 2.77 (m, 1 H), 2.23 (s, 3H).Example 23: Synthesis of lf(5-chloro-2-fluorophenyl)niethyll-6-niethyl-2-oxo-3,4- dihydro^unolm-3-yhirea (Compound 24)Step 1: Synthesis of tert-butyl N-(6-methyl-2-oxo-3,4-dihydro-lH-qumoIm-3- yl)carbamate

[0220] To a solution of methyl 2-[(tert.-butoxycarbonyl)amino]-3-iodopropanoate (2.3 g. 6.99 mmol) in DMF (15.0 m.L) wras added Zn (843.4 mg, 12.90 mmol) at room temperature under N?„ The mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 2-bromo~4-methylaniline (1.0 g, 5.38 mmol), XPhos (256.2 mg, 0.54 mmol) and Pd(OAc)?. (60.3 mg, 0.27 mmol) at room temperature under N?„ The resulting mixture was stirred at 40 °C for additional 4 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (65 / 35, v / v) to afford tert-butyl N-(6- methyl-2-oxo-3,4-dihydro-1 H-qumolin-3-yl)carbarnate (1.1 g, 74%) as a yellow oil. LCMS277.1 .Step 2: Synthesis of tert-butyl N-{1"[(5-cMoro-2-fluorophenyl)methyI]-6-methyi-2-oxo-3,4”dihydroquinoIm-3-y!}carbamate

[0221] To a solution of tert-butyl N-(6-methyl-2-oxo-3,4-dihydro-lH-quinolin-3- yljcarbamate (1.0 g, 3.62 mmol) in DMF (15.0 mL) was added 2-(bromomethy l)-4-chl oro-1- fluorobenzene (808.6 mg, 3.62 mmol) and CS2CO3 (3.5 g, 10.86 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified byflash column chromatography with petroleum ether / ethyl acetate (89 / 11 , v / v) to afford tertbutyl N-{l-[(5-chloro-2-fluorophenyl)methyl]-6-methyl-2-oxo-3,4-dihydroquinohn-3- yl} carbamate (1.0 g, 67%) as a white solid. LCMS (ESI, m / z): [M+H] ’ = 419.1.Step 3: Synthesis of 3-ammo~l~[(5~chIoro-2-fluorophenyi)methyl]-6-methyl~3,4" dihyd roquino! in -2-one

[0222] A solution of tert-butyl ]\-{1 -[(5-chloro-2-fluorophenyl)methyl]-6-methyl-2-oxo- 3,4-dihydroquinolin-3-yl}carbamate (490.0 mg, 1.17 mmol) in HCl / l,4-dioxane (4.0 mL, 4 mol / L) was stirred at room temperature for 0,5 h. After the reaction was completed, the pH value of the mixture was adjusted to 8 with NaHCOs (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3- ammo-1 -[(5-chloro-2-fluorophenyl)methyl]-6-methyl-3,4-dihydroquinolin-2-one (450.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+Hp::::319.1.Step 4: Synthesis of l-[(5-chloro-2-f8uorophenyI)methyI]-6-methyI-2-oxo~3,4- dihydroqisinoIin-3-yhsrea (Compound 24)Compound 24

[0223] To a mixture of 3-amino-l-[(5-chloro-2-fluorophenyl)methyl]-6-methyl-3,4- dihydroquinolin-2-one (430,0 mg, 1.35 mmol) and isocyanatotrimethylsilane (312,4 mg, 2,71 mmol) in THF (5.0 mL) was added TEA (546.1 mg, 5.40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with HjO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (96 / 4, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD CIS Column 30x150 mm; Mobile PhaseWater (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 26% B to 46% B in 10 min; Wave Length: 254 / 220 nm) to afford 1 - [(5-chl oro-2-fl uorophenyl)methyl] -6-methy l-2-oxo-3 ,4-di hydroquin otin-3 -y lurea (Compound 24) (41.8 mg, 8%) as a white solid. LCMS (ESI, m / z): [M+H]T ::::362.1, ’ll NMR (400 MHz DMSO- ch): 5 7.39 - 7.36 (m, 1 H), 7.31 - 7.26 (m, 1 H), 7.14 - 7. 10 (m, 2H), 7.02 (d. • / 8.4 Hz, 1H), 6.87 (d, ■ / 8.0 Hz, 1H), 6.45 (d. . / 6.8 Hz, 1 H ), 5.80 (s, 2H), 5.21 - 5.09 (m, 2H), 4.46 - 4.39 (m, 1H), 3.15 - 3.10 (m, 1H), 2.88 - 2.80 (m, 1H), 2.24 (s, 3H).Example 24: Synthesis of l-(l-(5-chloro-2-fluorobenzyl)~7-cyano~2~oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea (Compound 25)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. To the above mixture was added a solution of 3 -amino-4-br oniobenzonitrile (2.0 g, 10.15 mmol) in DMF (5.0 mL), XPhos (483.9 mg, 1.01 mmol) and Pd(OAc)2 (113.9 mg, 0.51 mmol) at room temperature. The resulting mixture was stirred at 40 °C for additional 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. The mixture was filtered. The filtrate was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (22 / 78, v / v) to afford tert-butyl (7-cyano-2-oxo-l ,2,3,4-tetrahydroquinolm-3~yl)carbamate (1.7 g, 52%) as a white solid.I .CMS (ESI, m / z): | M ■ H j = 288.1.Step 2: Synthesis of tert-butyi (l-(5-chIoro-2-fluorobenzyi)~7-cyano-2-oxo-l,2,3?4- tetrahydroqMiiioiin-3-yi)carbainate

[0225] To a solution of tert-butyl (7-cyano-2-oxo- 1,2,3, 4-tetrahydroquinolin-3- yl)carbamate (800,0 mg, 2,78 mmol) in DMF (10.0 mL) was added 2-(bromomethyl)-4- chloro-1 -fluorobenzene (622,2 mg, 2, 78 mmol) and CssCOs (2.3 g, 6.96 mmol) at room temperature under N?. The resulting mixture was stirred at room temperature for 2 h under Nj. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (19 / 81, v / v) to afford tert-butyl (l-(5-chloro-2-fluorobenzyl)-7-cyano-2-oxo-l ,2,3,4- tetrahydroquinolm-3-yl)carbamate (700.2 mg, 53%) as a white solid. LCMS (ESI, m / z): [M-;-H]+- 430.1.Step 3: Synthesis of 3-amino-l~(5~chloro-2-fluorobenzyI)-2-oxo-l, 2,3,4- tetrahydroquinoiine-7-carbonitrile hydrochloride

[0226] A solution of tert-butyl (l-(5-chloro-2-fluorobenzyl)-7-cyano-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate (560.0 mg, 1.30 mmol) in HCl / l,4-dioxane (6.0 mL, 4.0 mol / L) was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford 3-amino-l-(5-chloro-2- fluorobenzyl)-2-oxo-l ,2,3,4-tetrahydroquinoline-7-carbonitrile hydrochloride (350.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 330.1.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)Compound 25

[0227] To a mixture of 3-amino-l-(5-chloro-2-fluorobenzjd)-2-oxo-l, 2,3,4- tetrahydroquinoline-7-carbonitrile hydrochloride (330.0 mg, crude) and isocyanatotrimethylsilane (103.8 mg, 0.90 mmol) in THF (10.0 mL) were added TEA (273.6 mg, 2.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h, After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (40 / 60, v / v) and then purified by Prep-HPLC with the following conditions (Column: XselectCSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: isocratic 27-37; Wave Length: 254 nm / 220 nm) to afford l-(l-(5-chloro-2-fluorobenzyl)-7-cyano-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea (Compound 25) (8.2 mg, 2%) as a white solid. LCMS (ESI, m / z): [M+H]+= 373.1.SH NMR (400 MHz, DMSO- d6): 57.52 - 7.50 (m, 3H), 7.41 - 7.37 (m, 1H), 7.31 - 7.22 (m, 2H), 6.47 (d, .7 = 7.2 Hz, 1H), 5.81 (s, 2H), 5.25 - 5.20 (m, 2H), 4.57 - 4.50 (m, 1H), 3.30 - 3.25 (m, 1H), 3.03 - 2.96 (m, 1H).Step 1: Synthesis of 3-ammo-l-(3,5~difluorobenzyl)-3,4-dihydroquinolm-2(lH)-one[0228| To a solution of 3-amino-3,4-dihydro-l H-quinolin-2-one (200.0 mg, 1.23 mmol) in DMF (5.0 mL) was added NaH (47.0 mg, 60%) at 0 °C under N?. The resulting mixture was stirred at 0 °C for 1 h under N2. To the above mixture was added l-(bromomethyl)-3,5- difluorobenzene (255.0 mg, 1 .23 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for additional 2 li under M2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-amino- l-(3,5-difluorobenzyl)-3,4-dihydroquinolin-2(lH)-one (365.0 mg, 92%) as a yellow oil. LCMS (ESI, m / z): [ M + H j = 289.1.Step 2: Synthesis of l-(l~(3,5-difliiorobenzyi)-2-oxo-l,2,3?4"tetrahydroqninoIin”3-yI)nrea (Compound 26)Compound 26

[0229] To a solution of 3-amino- l-[(3,5-difluorophenyl)methyl]-3,4-dihydroquinolin-2- one (150.0 nig, 0.52 mmol) in THF (5.0 niL) was added TEA (159.0 mg, 1.57 mmol) and TMSNCO (123.0 mg, 1.06 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MaiSOi and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column 30x150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow' rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 20% B to 40% B in 15 min; Wave Length: 254 / 220 nm) to afford 1 -(1 -(3,5-difluorobenzyl)- 2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 26) (26.8 mg, 15%) as a white solid, LCMS (ESI, m / z): [Mi I U - 332. 1. ' l l NAIR (400 MHz, DMSO-rL): 5 7.29 - 7.27 (m, 1 H), 7.22 - 7.18 (m, 1H), 7.14 - 7.08 (m, 1H), 7.04 - 6.94 (m, 4H), 6.43 (d, J= 6.8 Hz, 1H), 5.81 (s, 2H), 5.27 - 5.22 (m, H I) 5.13 - 5.08 (m, H I). 4.51 - 4.44 (m, H i). 3.21 - 3.16 (m, H I ). 2.98 - 2.91 (rn, 1H).Example 26: Synthesis of l-(l-(3-ehloro-5-methylbenzyl)-2-oxo-],2,3,4- tetrahydroquinolin-3-yl)urea (Compound 27)Step 1: Synthesis of 3-amino-l-(3-chIoro~5-methyiI>enzyl)~3,4"dihydroquinoiin~2(lH)- one

[0230] To a solution of 3-aminO’3,4-dihydro-lH-quinolin-2-one (300.0 mg, 1.85 mmol) in toluene (5.0 mL) was added (3-chloro-5-methylphenyl)methanol (300.0 mg, 1.91 mmol) and CMBP (892.0 mg, 3.69 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 2 h under N2. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHzClz / MeOH (10 / 1, v / v) to afford 3-amino-l-(3-chloro-5- methylbenzyl)-3,4-dihydroquinolin-2(lH)-one (110.0 mg, 19%) as a brown solid. LCMS (ESI, m / z): [M+H] = 301.1.Step 2: Synthesis of l-(l-(3-chJoro-5-methyIbenzyI)~2”Oxo-l,2,3,4"tetrahydroqiimoliii~3~ yl)urea (Compound 27)Compound 27

[0231] To a solution of 3-amino-l-[(3-chloro-5-methylphenyl)methyl]-3,4- dihydroquinolin-2-one (100,0 mg, 0.33 mmol) in THE (3,0 mL) was added TEA (100.0 mg, 0.98 mmol) and TMSNCO (76.6 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous NazSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C l 8 Column 30x150 mm; Mobile Phase A: Water (10 mrnol / L NH4HCO3), Mobile Phase B; ACN, Flow rate: 60 rnL / min; Gradient: 5% B to 5% B in 2 mm, 40% B to 60% B in 10 mm, Wave Length: 254 / 220 nm) to afford 1- (l-(3-chloro-5-methylbenzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 27) (43.8 mg, 38%) as a white solid. LCMS (ESI, m / z): iM H | 344.1. H NMR (400 MHz, DMSO-rL): 5 7.28 (d, J ------ 7.2 Hz, IH), 7.22 - 7.18 (rn, IH), 7.14 - 7.09 (rn, 2H), 7.04 - 6.96 (m, 3H), 6.46 id. 7 6.4 Hz, 1 H), 5.81 (s, 2H), 5.23 - 5.18 (m, H i). 5.07 - 5.02 (m, IH), 4.48 - 4.41 (m, H I). 3.22 - 3.16 (m, H i). 2.95 - 2.86 (m, IH), 2.27 (s, 3H).Example Synthesis of l-[(3fluoro-5-methylphenyl)methyl]-2‘<vco-3,4-dihydroquinolin-3-ylurea (Compound 28)Step 1: Synthesis of 3-amino-l-[(3-fIs.ioro-5-snethyiphenyi)nsethyl]-3,4-dihydroquhsoIm- 2-one

[0232] To a solution of 3-atnino-3,4-dihydro-lH-quinolin-2-one (500.6 mg, 3.09 mmol) in toluene (10.0 niL) was added (3-fluoro-5-methylphenyl)methanol (432.6 mg, 3.09 mmol) and CMBP (1.5 g, 6.22 mmol) at room temperature under N?. The resulting mixture was stirred at 110 °C for 4 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN / H2O (66 / 34 v / v) to afford 3-amino-1-[(3-fluoro-5-metihylpheny1)methy1]-3,4- dihydroquinolin-2-one (720.0 mg, 82%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 285.1.Step 2: Synthesis of l-[(3-flHoro-5-methyipheiiyI)methyI]~2~oxO”3,4~dihydroquiBoIin”3” yhirea (Compound 28)

[0233] To a solution of 3-amino-l-[(3-fluoro-5-methylphenyl)methyl]-3,4- dihydroquinoIm-2-one (250,4 mg, 0.88 mmol) in THF (5,0 mL) was added TEA (267.4 mg,2.64 mmol) and TMSNCO (202.9 mg, 1.76 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 li. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHzClz / MeOH (80 / 20, v / v) and then purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 33-43; Wave Length: 254nm) to afford l-[(3-fluoro-5-methylphenyl)methyl]-2-oxo- 3,4-dihydroquino1in-3-ylurea (Compound 28) (35.7 mg, 12%) as a white solid. LCMS (ESI, m / z): ( M ■ 11 | = 328. 1. TI NMR (400 MHz, DMSO-tL,): 8 7.27 (d, .7 = 7.6 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.03 - 6.95 (m, 2H), 6.91 - 6.84 (m, 3H), 6.45 (d, J= 6.4 Hz, 1H), 5.81 (s, 2H), 5.23 - 5,19 (m, 1H), 5.07 - 5.02 (m, 1H), 4.48 - 4.41 (m, 1H), 3.22 - 3.17 (m, 1H), 2.94 - 2.87 (m, 1H), 2.28 (s, 3H).Example 28: Synthesis of lf(3-methaxyphenyl)methyl]-2-oxo-3y$-dihydroquinolin-3- ylurea (Compound 29)Step 1: Synthesis of 3"amino~l~[(3~methoxyphenyi)methyI]-3,4"dihydroquinoIin-2-one

[0234] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.7 mg, 3.09 mmol) in DMF (10.0 mL) was added NaH (148.2 mg, 60%) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. To the above mixture was added l-(bromomethyl)-3- meth oxybenzone (620.7 mg, 3.09 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for additional 1 h under N?, After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified byflash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford 3-amino-l-[(3-methoxyphenyl)methyl]-3,4-dihydroquinolin-2-one (340.5 nig, 39%) as a brown oil. LCMS (ESI, ni / z): j XI 111 = 283.1.Step 2: Synthesis of l-[(3-methoxypheny8)methyl|-2-oxo-3,4”dihydroquino8in-3-ylurea(Compound 29)[0235| To a solution of 3-atnino-l-[(3-niethoxyphenyl)methyl’|-3,4-dihydroquinolin-2- one (150.4 mg, 0.53 mmol) in THF (5.0 mL) was added TEA (53.9 mg, 0.53 mmol) and TMSNCO (122.2 mg, 1.06 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHiCh / MeOH (90 / 10, v / v) and then purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 22- 42; Wave Length: 254 nm) to afford l-[(3-methoxyphenyl)methyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 29) (38.0 mg, 22%) as a white solid. LCMS (ESI, m / z): [M+H]+= 326. 1.SH NMR (400 MHz, DMSO-tfc): 8 7.28 - 7.16 (m, 3H), 7.02 - 6.98 (m, 2H), 6.81 - 6.77 (m, 3H), 6.46 (d, .7 = 6.8 Hz, 1H), 5.81 (s, 2H), 5.22 - 5.06 (m, 2H), 4.44 - 4.37 (m, 1H), 3.72 (s, 3H), 3.21 - 3.16 (m, 1H), 2.92 - 2.85 (m, 1H).Example 29: Synthesis of (3S)-l-[(5-chloro~2~fluorophenyl)fnethylJ-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 30) & (3R)-l-[(5-ehloFo-2-fl.uoi-'ophenyl)methylJ~2- oxo-3,4-dihydroquinolin-3-ylurea ( Compound 31 )Step 1: Synthesis of (3S)-l-[(5-ch8oro-2-fluorophenyl)methyI]-2-oxo~3,4- dihydroqninolin~3~yhirea (Compound 30) & (3R)~l”[(5-chIoro-2~fluorophenyi)methyi|-2-oxo-3,4~dihydroquino8in-3-ylurea (Compound 31)

[0236] The racemic product of 1 -[(5-chloro-2-fluorophenyl)methyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 7) (146,0 mg, 0.42 mmol) was separated by Prep- Chiral -HPLC with the following conditions: (Column: CHIRALPAK IC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.3% IP AMIN), Mobile Phase B: EtOH: DCM= =1 : 1-HPLC; Flow rate: 20 mL / mm, Gradient: 25% B to 25% B in 16 min; Wave Length: 220 / 254 nm;RTl(min): 11.44; RT2(min): 14.27) to afford (3S)-l-[(5-chloro-2-fluorophenyl)methyl]-2- oxo-3 ,4-dihydroquinolin-3-ylurea (Compound 30) (26.1 mg, 35%) as a light yellow solid and (3R)-l-[(5-chloro-2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 31) (23.9 mg, 32%) as a light yellow solid.

[0237] (3S)-l-[(5-chIoro~2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 30): RTl(min): 11.44, LCMS (ESI, m / z): [ M + H i - 348.0.JH NMR (400 MHz, DMSO-40: 5 7.40 - 7.36 (m, HI), 7.31 - 7.21 (m, 3H), 7.17 - 7.15 (m, 1H), 7.06 - 7.02 (m, 1H), 6.97 (d, . / 8.0 Hz, HI), 6.46 (d, J- 6.4 Hz, HI), 5.80 (s, 211), 5.25 - 5.20 (m, 1 H), 5.13- 5.08 (m, 1H), 4.50 - 4.44 (m, 1H), 3.21 - 3.16 (m, HI), 2.93 - 2.85 (m, HI).

[0238] (3R)-l-[(5-chIoro-2-fiuorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 31): RT2(min): 14.27; LCMS (ESI, m / z): | M H i === 348.0.(400 MHz, DMSOW6): 5 7.39 - 7.36 (m, 1H), 7.32 - 7.14 (m, 4H), 7.06 - 7.02 (m, 1H), 6.97 (d, J ------ 8.0 Hz, 1H), 6.45 (d, J --- 6.8 Hz, I II), 5.80 (s, 2H), 5.25 - 5.09 (m, 2H), 4.50 - 4.44 (m, 1H), 3.21- 3.16 (m, HI), 2.93 - 2.85 (m, 1 H).Example 30: Synthesis of ]-[(3<Woro-5-fluorophenyl)methyl]-2-oxo-3,4-dihydroqumolin~ 3-ylurea (Compound 32)Step 1: Synthesis of 3-amino-l-[(3-chIoro-5-fiuorophenyl)methyl]-3,4-dihydroquinoIin-2-one

[0239] To a solution of 3-amino-3,4-dihydro-lH-quinoIin-2-one (500.2 mg, 3.08 mmol) in DMF (6.0 mL) was added NaH (120.8 mg, 60%) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then l-(bromomethyl)-3-chloro-5~fluorobenzene (689,2 mg, 3,08 mmol) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (96 / 4, v / v) to afford 3-amino-1 -[(3-chloro-5- fluorophenyl)methyl]-3,4-dihydroquinolin-2-one (530.0 mg, 56%) as a yellow oil. LCMS (ESI, m / z); [M+Hf - 305.1.Step 2: Synthesis of l-[(3"Chioro-5-fliiorophenyI)methyI]"2"Oxo-3,4-dihydroquinoIin-3- yiurea (Compound 32)Csmpoimd 32

[0240] To a mixture of 3-amino-l-[(3-chloro-5-fluorophenyl)methylj-3,4- dihydroquinolin-2-one (260,1 mg, 0.85 mmol) and isocyanatotrimethylsilane (196.6 mg, 1 ,71 mmol) in THF (5.0 mL) was added TEA (345.4 mg, 3.41 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with I-fiO and extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / 'MeOH (94 / 6, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column30xl 50 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 niL / min; Gradient: 5% B to 5% B in 2 min, 29% B to 49 % B in 10 mm; Wave Length: 254 / 220 nm) to afford 1- [(3-chloro-5-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-ylurea (Compound 32) (88.5 mg, 30%) as a white solid. LCMS (ESI, m / z): [M+H]4= 348.1.SH NMR (400 MHz, DMSO- c / e): 5 7.32 - 7.27 (m, 2H), 7.23 - 7.18 (m, 2H), 7.10 (d, J= 9.2 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 6.4 Hz, 1H), 5.81 (s, 2H), 5.26 - 5.09 (m, 2H), 4.51 - 4.44 (m, 1H), 3.21 - 3.15 (m, 1H), 2.97 - 2.90 (m, H I).Example 31: Synthesis of l-(tert-butyl)-3-(l-(5-chloro-2-fluoroben^l)-2-axo-3-ureido- l,2,3,4-tetrahydroquinolin-6~yl)urea (Compound 33)Step 1: Syn thesis of tert-butyl (2-oxo-l,2,3,4-tetrahydroqumoIin-3-yl)carbamate

[0241] To a solution of 3-amino-3,4-dihydroquinolin-2(lH)-one (3.0 g, 18.49 mmol) in DCM (40.0 mL) were added BOC2O (8.1 g, 37. 11 mmol) and TEA (5.6 g, 55.34 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (90 / 10, v / v) to afford tert-butyl (2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (4.0 g, 82%) as a brown solid. LCMS (ESI, m / z): [M+H]4=263.1.Step 2: Synthesis of tert-butyi (6-bronio-2-oxo-l,23,4-tetrahydroquinoiin-3- yijcarbamate

[0242] To a solution of tert-butyl (2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl)carbamate (2,5 g, 9.53 mmol) in methanol (20.0 mL) were added NBS (2.0 g, 1 1.24 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (85 / 15, v / v) to afford tertbutyl (6-bromo-2-oxo-l ,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.8 g, 86%) as a yellow solid. LCMS (ESI, m / z): I M H j -341.0.Step 3: Synthesis of tert-butyl (6-bromo-1-(5-chloro-2-fluorobmzyI)-2-oxo-l,2,394- tetrahydroquiiiolin-3-yl)carbamate

[0243] To a solution of tert-butyl (6-bromo-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)carbamate (2,8 g, 8.21 mmol) in DMF (30.0 mL) were added 2-(bromomethyl)-4-chloro-l- fluorobenzene (1.8 g, 8.06 mmol) and CS2CO3 (8.0 g, 24.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H?O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (88 / 12, v / v) to afford tert-butyl (6-bromo- l-(5-chloro-2-fluorobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.8 g, 71%) as a white solid. LCMS (ESI, m / z): [ M -HE Ip 483.0.Step 4: Synthesis of tert-butyl (6~(3~(tert"biityI)ureido)~l~(5-chIoro-2-fliiorobenzyl)-2- oxo- 1 ,2,3,4- tetrahyd roquinolin-3-yI)car hamate

[0244] To a solution of tert-butyl (6-bromo-l-(5-chloro-2-fluorobenzyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)carbamate (200.0 mg, 0.41 mmol) in dioxane (6.0 mL) were added 1- (tert-butyl)urea (48.0 mg, 0.41 mmol), Pdsldba)?, (41.7 mg, 0.05 mmol), XantPhos (47.9 mg, 0.08 mmol) and CS2CO3 (404.2 mg, 1 .24 mmol) at room temperature under N?. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (70 / 30, v / v) to afford tert-butyl (6-(3- (tert-butyl)ureido)-l-(5-chloro-2-fiuorobenzyl)-2-oxo-l,2,3,4-tetrahydroquinolm-3- yl)carbamate (150.0 mg, 70%) as a green solid. LCMS (ESI, m / z): [M+H];=519.2.Step 5: Synthesis of l-(3-amino~l~(5~chlorO"2-fluorobeiizyJ)-2-oxo-l, 2,3,4- tetrahyd roquinolin-6-yl)-3-( tert-butyl )nrea

[0245] A solution of tert-butyl (6-(3-(tert-butyl)ureido)~l-(5-chloro-2-fluorobenzyl)-2- oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (110.0 mg, 0.21 mmol) in HCl / dioxane (4.0 mL, 4.0 mol / L) was stirred at room temperature for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCCh (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 1- (3-amino-l-(5-chloro~2-fluorobenzyl)-2-oxo-l,2,3,4-tetrahydroqumolin-6-yl)-3-(tert- butyl)urea (100.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=419.2.Step 6: Syn thesis of l~(tert-biityl)~3”(l”(5-chloro~2~fluorobenzyl)-2~oxo~3~iireido~l,2,3>4" tetrahydroqumoIin-6-yI)iirea (Compound 33)

[0246] To a solution of l-(3-amino-l-(5-chloro-2-fluorobenzyl)-2-oxo-l, 2,3,4- tetrahydroquinolin-6-yl)-3-(tert-butyl)urea (90.0 mg, 0.22 mmol) in THF (2.0 mL) was added TMSNCO (49.5 mg, 0.43 mmol) and TEA (90.0 mg, 0.89 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 6 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (75 / 25, v / v) and then purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBI) Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 41% B in 14 min; Wave Length: 254 nm) to afford 1- (tert-butyl)-3-(l-(5-chloro-2-fluorobenz.yl)-2-oxo-3-ureido-l ,2,3,4-tetrahydroqumolin-6- yl)urea (Compound 33) (18.3 mg, 18%) as a white solid. LCMS (ESI, rn / z): [M+H]+=462.2. T-I NAIR (400 MHz, DMSO-d6): 5 8.19 (s, 1H), 7.36 - 7.26 (m, 3H), 7.13 - 7.1 1 (m, 2H), 6.84 (d, ■ / 8.4 Hz, 11 -I), 6.43 id. , / 6.4 Hz, 1 H), 5.96 (s, 1H), 5.79 (s, 2H), 5.17 - 5.07 (rn, 2H), 4.43 - 4.37 (m, 1 H), 3.12 - 3.02 (m, 1H), 2.85 - 2.78 (m, 1H), 1.27 (s, 9H).Example 32: Synthesis ofN-{l ~[(5~chloro~2~fhi(.irophenyl)methyl]~2~oxo~3,4~ dihydroquinolin-3-yl^propanamide ( Compound 34)Step 1: Synthesis of N-{l-[(5-chIoro-2-fIuorophenyl)methyJ]-2-oxo-3,4"djhydroqumolin-3-yI}propenamide (Compound 34)

[0247] To a solution of 3-amino-l-[(5-chioro-2-fluorophenyl)methyl]-3,4- dihydroquinolin-2-one (100.0 mg, 0.32 mmol) in DCM (3.0 mL) were added propanoyl chloride (50.1 mg, 0.54 mmol) and TEA (99.6 mg, 0.98 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XB ridge Prep OBD CT 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10,0 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 68 mL / mm; Gradient: 39% B to 59% B in 14 min; Wave Length: 254 / 220 nm) to afford N~ { 1 -[(5-chloro-2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3- yl}propanamide (Compound 34) (23.4 mg, 20%) as a white solid. LCMS (ESI, m / z):| M T | - 361 .1. 4-1 NMR (400 MHz, DMSO-r / s): 6 8.22 (d, J 8.0 Hz, 1 H), 7.40 - 6.97 (m, 7H), 5.24 - 5.10 (m, 2H), 4.74 - 4.67 (m, 1H), 3. 10 - 2.95 (m, 2H), 2.24 - 2.18 (m, 2H), 1.06 - 1 .03 (m, 3H).Example 33: Synthesis of methyl N-{l-[(5^hloro-2~fluof'ophenyl)methyl]-2-oxo-3,4- dihydroquinolin-3-yl}carbamate (Compound 35)Step 1: Synthesis of methyl N~{l-[(5-ch?oro~2~flnorophenyl)methyl]-2-oxo-3,4- dihydroquinolm~3yyl}carbamate (Compound 35)Compound 35[024§] To a solution of 3-amino- 1 -f(5-chloro-2-fluorophenyl)methyi]-3,4- dihydroquinolin-2-one (100.3 mg, 0.33 mmol) in CH2Q2 (10.0 mL) was added methyl chloroformate (31.1 mg, 0.33 mmol) and 4-methylmorpholine (166.5 mg, 1.65 mmol) at 0 °C under N2. The mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous NaaSOr and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHjCh / MeOH (95 / 5, v / v) and then purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 61 mL / min; Gradient: 42% B to 62% B in 14 min; Wave Length: 254 / 220 nm) to afford methyl N-{l-[(5-chloro~2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3-yl} carbamate (Compound 35) (61.3 mg, 51%) as a white solid. LCMS (ESI, m / z): [M+H]" = 363.1.NMR (400 MHz, DMSOvL): <5 7.54 (d, .7 = 8.0 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.32 - 7.28 (m, 2H), 7.25 - 7.21 (m, 1 H), 7.12 - 7.10 (m, 1H), 7.06 - 7.02 (m, 1H), 6.96 (d, J 8.4 Hz, 1H), 5.24 - 5.09 (m, 2H), 4.47 - 4.40 (m, HI), 3.59 (s, 3H), 3. 14 - 3.02 (m, 2H).Example 34: Synthesis of N-(l-(5-chloro-2-fluoroben?yl)-2-oxo-l, 2,3,4- tetrahydmqmnolbi-3-yl)acetimiide (Componnd 36)Step 1: Synthesis of N-(l-(5-chIoro-2-fluorobenzyl)~2~oxo-l,2,394~tetrahydroquinoIin-3- yl)acetamide (Compound 36)Compound 36

[0249] To a solution of 3-amino-l-(5-chloro-2-fluorobenzyl)-3,4-dihydroquinolin-2(lH)- one (100.0 mg, 0.32 mmol) in DCM (2.0 niL) was added acetyd chloride (28.0 mg, 0.35 mmol) and TEA (100.0 mg, 0.98 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with HbO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 65% B in 14 mm; Wave Length: 254 / 220 nm) to afford N-(l -(5-chloro-2-fl uorobenzy l)-2-oxo- l,2,3,4-tetrahydroquino1in-3-yl)acetamide (Compound 36) (59.7 mg, 52%) as a white solid. LCMS (ESI, m / z): [M+H]+= 347.1.8 8.32 (d, J= 8.0 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.32 - 7.21 (m, 3H), 7.15 - 7.12 (m, 1H), 7.06 - 7.02 (m, 1 H), 6.98 (d, J === 8.0 Hz, 1H), 5.24 - 5.10 (m, 2H), 4.73 - 4.65 (m, 1H), 3. 10 - 2.94 (m, 2H), 1.93 (s, 3H).Example 35: Synthesis of l-[(5~chloro~2~fhiorophenyl)fnethyll-3-(lH~imidazol-2-ylanuno)~ 3,4-dihydroquinolin-2-one (Compound 37)Step 1: Synthesis of tert-butyl 2-({l-[(5-chloro-2-fluorophenyI)methyI]-2-oxo-3,4- dihyd roquinol in -3-y?}amino)imidazol e- l~carboxylate

[0250] To a solution of 3-amino-l-[(5-chloro-2-fluorophenyl)methyl]-3,4- dihydroquinolin-2-one (480,1 mg, 1.58 mmol) in toluene (6.0 mL) was added tert-butyl 2- bromoimidazole-l-carboxylate (1.2 g, 4.71 mmol), CS2CO3 (1.0 g, 1.35 mmol) and (SP-4-1)- [l,3-bis[2,6~bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol~2- ylidene]dichloro(2-methylpyridine)palladium (132.4 mg, 0.16 mmol) at room temperature under Nz. The resulting mixture was stirred at 120 °C for 16 h under Nz. After the reaction was completed, the resulting mixture was diluted with HzO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford tertbutyl 2-({l-[(5-chloro-2-fluorophenyl)methyl]-2-oxo-3,4-dihydroquinolin-3- yl}amino)imidazole-l -carboxylate (50.0 mg, 7%) as a yellow solid. LCMS (ESI,m / z);] XI W J 471.2.Step 2: Synthesis of l-[(5"Chioro-2-fliiorophenyI)niethyI]"3-(lH-imidazoJ-2-yIamiiio)-3,4- dihydrnquinolin~2~one (Compound 37)Compound 37

[0251] To a solution of tert-butyl 2-({l-[(5-chloro~2-fluorophenyl)methy1]-2-oxo-3,4- dihydroquinolin-3-y1}amino)imidazole-l -carboxylate (40.0 mg, 0.09 mmol) in DCM (1.0mL) was added IT A (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCCh (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30x150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 niL / min; Gradient: 5% B to 5% B in 2 min, 35% B to 55% B in 10 min; Wave Length: 254 / 220 nm) to afford 1- [(5-chloro-2-fluorophenyl)methyl]-3-(lH-imidazol-2-y1amino)-3,4-dihydroquinolin-2-one (Compound 37) (7.7 mg, 24%) as a white solid. LCMS (ESI, m / z): [M+H]" = 371.1.NMR (400 MHz, DMSO- d6): 8 10.39 (s, 1H), 7.39 - 7.18 (m, 5H), 7.08 - 7.04 (m, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.60 - 6.44 (m, 2H), 6.00 (d, J = 5.2 Hz, 1H), 5.28 - 5. 12 (m, 2H), 4.51 - 4.47 (m, 1H), 3.48 - 3.43 (m, 1H), 3.03 - 2.96 (m, 1H).Example 36: Synthesis of cis-l-(l-( l-(5-chloro-2-fluorophenyl)ethyl)-2-axo-l, 2,3,4- tetrahydroqmnolin-3~yl)urea (Compound 38) & trans-]-(l-(l~(5~chloi-'o-2- fluorophenyl)ethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)iirea (Compound 39)Step 1: Synthesis of 3-amino-l-(l-(5-chIoro-2-fluorophenyI)ethyl)-3,4-dihydroquinoIin- 2(lH)-one[0252| To a mixture of 3-amino-3,4-dihydroquinolin-2(lH)-one (300.0 mg, 1.85 mmol) and l-(5-chloro-2-fluorophenyl)ethanol (322,9 mg, 1.84 mmol) in toluene (8.0 mL) was added CMBP (892.8 mg, 3.69 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 4 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (25 / 75, vA) to afford 3-amino-l-(l-(5- chloro-2-fluorophenyl)ethyl)-3,4-dihydroquinolin-2(lH)~one (290.3 mg, 44%) as a brown oil. LCMS (ESI, m / z): [ M ■ H i = 319.1.Step 2: Synthesis of cis-l-(l-(l-(5-chJoro~2-fluorophenyl)ethyi)-2-oxo-l,2,3?4” tetrahydroquinoiin-3~yi)urea (Compound 38) and trans-l-(l~(l~(5~chloro-2- fluorophenyI)ethyl)~2~oxo~l,234-tetrahydroqnmoIin-3-yI)urea (Compound 39)cistrans¬Compound 38 Compound 39

[0253] To a solution of 3-amino-l-(l-(5-chloro-2-fluorophenyl)ethyl)-3,4- dihydroquinolin-2(lH)-one (250.0 mg, 0.78 mmol) in methanol (10.0 mL) was added isocyanatotrimethylsilane (90.3 nig, 0.78 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (40 / 60, v / v) and then purified by Prep- HPLC with the following conditions (Column: XSelect CSH Prep Cl 8 OBD Column, 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 36% B to 46% B in 10 min; Wave Length: 254 / 220 nm;RTl(min): 12.23; RT2(min): 15.01 ) to afford cis-l-(l-(l-(5-chloro-2-fluorophenyl)ethyl)-2- oxo-1, 2,3, 4-tetrahydroquinolin-3-yl)urea (Compound 38) (assumed, 32.3 mg, 23%) as a white solid and trans-l-(l-(l-(5-chloro-2-fluorophenyl)ethyl)-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 39) (assumed, 36.3 mg, 26%) as a white solid.

[0254] cis~l”(l”(l-(5-chIoro~2~flnorophenyl)ethyJ)-2-oxo-l,2,3!>4-tetrahydroquinolm~ 3-yI)urea (Compound 38): RTl(min): 12.23; LCMS (ESI, m / z): [M+H]+= 362.1. >HNMR (400 MHz, DMSO4): 5 7.67 - 7.65 (in, 1H), 7.36 - 7.32 (m, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.12 - 7.07 (in, 3H), 6.97 - 6.93 (m, 1H), 6.49 (d, 7 = 3.6 Hz, 1H), 6.12 - 6.06 (m, 1H), 5.79 (s, 2H), 4.23 - 4.17 (m, 1H), 3.08 - 3.03 (m, 1H), 2.74 - 5.67 (m, 1H), 1.83 (d, J= 7.2 Hz, 3H).

[0255] trans-l-( l-( l-(5-chJorO”2-fliiorophenyl)ethyi)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)urea (Compound 39): RT2(min): 15.01; LCMS (ESI, m / z): [M+H]+= 362.1.JH NMR (400 MHz, DMSO-J6): 57.57 - 7.55 (m, 1H), 7.39 - 7.07 (m, 6H), 6.34 - 6.32 (m, 1H), 5.71 - 5.66 (m, 3H), 4.16 - 4.09 (m, 1H), 3.08 - 3.03 (m, 1H), 2.67 - 2.56 (HI, 1H), 1.81 (d, J = 7.2 Hz, 3H).Example 37; Synthesis of 1 -[(2-fluoro-5-methylph&iyl)ntethyl(-2-oxo-3, 4-dihydroquinolin- 3-ylurea (Compound 40)Step 1: Synthesis of 3-ammo-l-[(2-fluoro-5-methyIphenyl)methyl]-3,4-dihydroquinolin- 2-one

[0256] To a solution of 3-amino-3,4-dihydro-lH-qumoIin-2-one (500.1 mg, 3.08 mmol) in toluene (5,0 mL) was added (2-fluoro-5-methylphenyl)methanoI (432.2 mg, 3.08 mmol) and CMBP (1.5 g, 6. 17 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 5 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCMZMeOH (97 / 3, v / v) and then purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150 mm, 5umn, Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min, Gradient: isocratic 10—18, Wave Length: 254 nm / 220 nm) to afford 3-arnino-l-[(2-fluoro-5-methylphenyl)methyl]-3,4- dihydroquinolin-2-one (150.0 rng, 17% ) as a white solid. LCMS (ESI, m / z); [M+H]+- 285.1.Step 2: Synthesis of l-[(2-fluoro-5-methylphmyl)methyi]-2-oxo-3,4-dihydroquin(din-3- ylurea (Compound 40)Compound 40

[0257] To a solution of 3-aniino-l-[(2-fluoro-5-methylphenyl)methyl]“3,4- dihydroquinolin-2-one (65.0 nig, 0.23 mmol) in methanol (3.0 mL) was added isocyanatotrimethylsilane (34.1 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: isocratic 27-47; Wave Length: 254 nm / 220 nm) to afford l-[(2-fluoro-5- methylphenyl)methyl]-2~oxo-3,4-dihydroqumolin~3-ylurea (Compound 40) (21.4 mg, 29%) as a white solid, i .('.MS (ESI, m / z): | M • H I = 328.2.1H NMR (400 MHz. DMSO- cL): 5 7.30 - 7.28 (m, 1 H). 7.23 - 7.19 (m, 1H), 7.13 - 7.08 (m, 2H), 7.05 - 7.01 (m, 1H), 6.93 - 6.88 (m, 2H), 6.47 (d, J ------ 6.4 Hz. 1H), 5.82 (s, 2H), 5.25 - 5.20 (m, 1H), 5.07 - 5.02 (m, 1H), 4.48 - 4.41 (m, H I). 3.23 - 3.18 (m, H I). 2.92 - 2.84 (m, 1 H), 2.19 (s, 3H).Example 38: Synthesis of lf(3,5~dimethylphenyl)methyl]~2~oxo-3,4~dihydroqubu>lin~3~ ylurea (Compound 41)Step 1: Synthesis of 3-amino-l-[(3,5~dimethyiphenyI)methyI]-3,4-dihydroquinoIin-2-one

[0258] To a solution of 3-amino-3,4-dihydro-lH-quinolin-2-one (500.0 mg, 3.08 mmol) in DMF (10.0 mL) was added NaH (138.1 mg, 60%) at 0 °C under N2. The resulting mixturewas stirred at 0 °C for 30 min under N2. To the above mixture was added 1 -(bromomethyl)- 3,5-dimethylbenzene (613.8 nig, 3.08 mmol) at 0 °C under N?. The resulting mixture was stirred at room temperature for additional 2 h under N2. After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-amino- l-[(3,5-dimethylphenyl)methyl]~3,4-dihydroquinolin-2-one (150.0 mg, 17%) as a light yellow solid. LCMS (ESI, m / z): [M + H] = 281.2.Step 2: Syn thesis of l-[(3,5-dimethylphenyI)methyI]”2-oxo-3,4~dihydroqnmoIm-3-yInrea (Compound 41)Compound 41

[0259] To a solution of 3-amino-l-[(3,5-dimethylphenyl)methyl]-3,4-dihydroquinoiin-2- one (110.0 mg, 0.39 mmol) in methanol (5.0 mL) were added isocyanatotrimethylsilane (58.8 mg, 0.51 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column 30x150 mm; Mobile Phase A: Water (10.0 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 30% B to 50 % B in 10 mm, Wave Length: 254 / 220 nm) to afford l-[(3,5-dimethylphenyl)methyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 41) (51.7 mg, 41%) as a white solid. LCMS (ESI, m / z): [M+H]+= 324.2.SH NAIR (400 MHz, DMSO-de): 5 7.26 (d, J= 7.6 Hz, 1H), 7.20 - 7.16 (m, 1H), 7.02 - 6.95 (m, 2H), 6.86 - 6.82 (m, 31 I), 6.48 (d, J = 6.4 Hz, 1 H ), 5.82 (s, 2H), 5.21 - 5.16 (m, 1H), 5.00 - 4.95 (m, 1H), 4.45 - 4.38 (m, 1H), 3.23 - 3.18 (m, 1H), 2.91 - 2.83 (m, 1H), 2.22 (s, 6H).Ex / unple 39: Synthesis of l-(l-(3,5-dichloro-2-fluorobenz^'l)-2-aKO-l, 2,3,4- teh‘ahydroqidnolm-3-yl)urea (Conypound 42)Step 1: Synthesis of 3-amino-l-(3,5-dichioro-2-fluorobeHzyi)-3,4-dihydroquinoiin-2(lH)“ one[0260| To a solution of 3-amino-3,4-dihydroquinoiin-2(1H)-one (500.0 mg, 3.08 mmol) in toluene (5.0 mL) were added (3,5-dichloro-2-fluorophenyl)methanol (601.2 mg, 3.08 mmol) and CMBP (1 .5 g, 6.17 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (94 / 6, v / v) to afford 3-amino-l-(3,5~ dichloro-2-fluorobenzyl)-3,4-dihydroquinolin-2(lH)-one (400.0 mg, 38%) as a yellow solid. LCMS (ESI, m / z): [ M i l l =339.0.Step 2: Synthesis of l-(l-(3,5~dichIoro-2~fliiorobenzyl)-2-oxo~l,2,3>4-teti’ahydroqninoIin- 3~yl)urea (Compound 42)Compsnnd 42

[0261] To a solution of 3-aniino-l-(3,5~dichloro-2-fluorobenzyl)-3,4~dihydroquinolin- 2( 1 H)-one (80.0 nig, 0.24 mmol) in methanol (2.0 tnL) were added TMSNCO (35.4 mg, 0.31 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 li. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydro...

Claims

1.CLAIMSWhat is claimed is:C laim 1. A compound of formul a ( A ” ) :(A”), or a pharmaceutically acceptable salt thereof, wherein:— is absent or a bond, wherein when — is a bond, R(;and R7are absent;A!and A2are CRW;A3is CRWand A4is N, or A3is N and A4is CRW; wherein at least one of A1, A2, A3, and A4is CRWthat is not CH or CD;Rwis independently at each occurrence H, halo, -CN, -NO?., -NH?, -S(O)q(C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(C1-6a1kyl), optionally substituted -N(Ci -6alkyl)(Cu6alkyl), optionally substituted -NHC(O)NHCn6alkyl, optionally substituted -NH(C]-6haloalkyl), optionally substituted C1-salkylene-Cs-b cycloalkyl, optionally substituted C1-salkyl, optionally substituted -NH(Cu 6alkylene)-C3-6cycloalkyl, optionally substituted C1-6alky1ene-Cu6alkoxy, optionally substituted Cu6hydroxyalkyl, optionally substituted Cuealkoxy, optionally substituted Cnehaloalkyl, optionally substituted Cnehaloalkoxyl, optionally substituted Ca-ecycloalkyl, optionally substituted Cuehalocycloalkyl, optionally substituted -O-C.uecycloalkyl, optionally substituted -O-C1-6alkylene- C3-6cycloalkyl, optionally substituted -O-C3-6halocycloalkyl, optionally substituted -O-Cugheterocyclyl, optionally substituted -0-5-10 membered heteroaryl, optionally substituted -NH-C3-6cycloalkyl, optionally substituted -NH-C3- shalocycloalkyl, optionally substituted -NH-Cuecyanoalkyl, optionally substituted -NH-Ca-gheterocyclyl, optionally substituted 4-8 membered heterocycloalkyl,optionally substituted Cg-toaryl, optionally substituted -O-Ce-ioaryl, or optionally substituted 5-10 membered heteroaryl, wherein at least one Rwis notH or D;B1, B2, B3, B ' and B5are each independently CRXor N;Rxis independently at each occurrence H, halo, -CN, -NO2, -NH2, -S(O)q(C1-6alkyl), - S(O)q(C3-6cycloalkyl), -OH, optionally substituted -NH(Cn6alkyl), optionally substituted -N(Ci-6alkyl)(Cb6alkyl), optionally substituted C1-6alkyl, optionally substituted Ci-ehydroxyalkyl, optionally substituted C1-6cyanoalkyl, optionally- substituted Cuealkoxy, optionally substituted Cuehaloalkyl, optionally substituted Cuehaloalkoxyl, optionally substituted Cs.gcycloalkyl, optionally substituted -O- C3-6cycloalkyl, optionally substituted -O-C1-salkylene-Ca-scycloalkyl, optionally substituted Cwshalocycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted Cs-ioaryl, or optionally substituted 5-10 membered heteroaryl; q is 0, 1, or 2;X is -C(O)R8, -C(S)Rs, -S(O)2R9, or optionally substituted 5-6 membered heteroaryl;R3and R" are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloaikyl, or optionally substituted 3-8 membered heterocycloalkyl, orRJand R4are 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 ky I ;R5is H, halo, optionally substituted C1-salkyl, optionally substituted C1-6haloalkyl, optionally substituted Cs-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl,Rb, if present, is H, optionally substituted Cnsalkyl, optionally substituted Cu shaloalkyl, optionally substituted Cs-ficycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R5and R6are taken together with the carbon atom to which they are atached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;R7, if present, is H, optionally substituted Cnealkyl, or optionally substituted Cn ehaloalkyl ;R8is -NHRy, -OCH3, optionally substituted C1-salkyl, optionally substituted Cu shaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, wherein the Cusalkyl is unsubstituted or is substituted with 1, 2, 3, 4, or 5 instances of independently selected halo, and wherein the Cusalkyl is other than tert-butyl when Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;R9is optionally substituted Cusalkyl; andRyis H, optionally substituted C1-salkyl, optionally substituted Cushaloalkyl, optionally substituted Ca-scycloalkyl, 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.Claim 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, halo, -NH(Cusalkyl), -NH(Ci- shaloalkyl), -NH(C1-3alkylene)-C3-6cycloalkyl, -N(C1-6alkyl)(C1-salkyl), C1-salkyl, C1- ealkoxy, Cushaloalkoxyl, Gb-scycloalkyl, Cushalocycloalkyl, -O-Cti-ecycloalkyl, -O-Ci. 3alkylene-C3-6cycloalkyl, -O-Cr-ehalocycloalkyl, -O-Cti-sheterocyclyl, -O-(5- to 10- membered heteroaryl), -O-Cs-ioaryl, -NH-Cb-scycloalkyl, -NH-C1-shalocycloalkyl, -NH- C1-scyanoalkyl, 4-8 membered heterocycloalkyl, Cs-ioaryl, or 5-10 membered heteroaryl.Claim 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A3is CRWand A4is N, wherein A3is not CH or CD.Claim 4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A3is N and A4is CRW, wherein A4is not CH or CD.Claim 5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A’1is CH or C(halo); A2is CH; A4is CtCnsalkoxy), C(C1-shaloaikoxyl), or C(C: scycloalkyl); and .A4is N.Claim 6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof wherein A1is CH or C(halo); A2is CH; A3is N; and A1is C(Ci<, alkoxy), C(Cu ehaloalkoxy i). or C(C3-ecycloalkyl),Claim 7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the moiety representedClaim 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Rxis independently at each occurrence H, halo, -NH(Ci -ealkyl), C1- ealkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxy, Cuehaloalkyl, C1-6haloalkoxyl, C3. ecycloalkyl, C3-6halocycloalkyl, or -O-C3.6cycloalk.yl.Claim 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein B1, B2, B3, B4and B5are each CRX.Claim 10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein B1, B2; By and are each CR ._ and B5is N.Claim 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B1is C(halo); B2is CH or C(halo); B3is CH; B4is C(halo), C(-NH(C1-6alky1)), C(C1-6alkyl), C(C1-6hydroxyalkyl), C(C1-6cyanoalkyl), C(C1-6alkoxyj,C(C1-6haloalkyl), C(Ci -ethal oalkoxyl), C(C3-6cycloalkyl), C(C3-6halocycloalkyl), or C(()C3- ecycloalkyl); and B5is CH or N.Claim 12. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the moiety representedsi-6164996Claim 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein X is -C(O)R8; R8is -NHRy; and Ryis H or C1-salkyl.Claim 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Ryis H.Claim 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R' are each independently H or D.Claim 16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R5are each H.Claim 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R6and R?, if present, are each independently H or D.Claim 18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R6and R?, if present, are each H.Claim 19. The compound of any one of claims 1 to 18, wherein the compound is a compound of Formula (pharmaceutically acceptable salt thereof.Claim 20. The compound of any one of claims 1 to 18, wherein the compound is a compound of Formula (pharmaceutically acceptable salt thereof.Claim 21. The compound of claim 1. selected from the group consisting of compounds 63, 82, 97, 101 , 104, 105, 106, 107, 109, 111, 112, 113, 120, 121, 122, 200, 201 , 202, 203, 207, 211, 222, 223, 225, 231 , 232, 233, 234, 235, 237, 238, 239, 240, 241, 242, 246, 247, 248, 249, 250, 251, 254, 257, 259, 260, 261 , 262, 263, 269, 270, 272, 273, 284, 286, 287, 288, 289, 290, 291, 292, 293, 295, 299, 300, 309, 310, 311 , 312, 313, 316, 317, 320,321, 322, 323, 324, 325, 328, 329, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344,345, 346, 350, 351, 352, 356, 359, 362, 363, 364, 365, 366, 367, 368, 378, 379, 380, 381,382, 383, 384, 385, 386, 387, 388, 389, 390, 391 , 392, 395, 396, 397, 398, 399, 400, 401,402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419,420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 438, 439, 440, 441,442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 458, 459, 460,461, 462, 463, 464, 465, 467, 468, 469, 470, 471, 472, 477, 478, 479, 480, 482, 483, 485,486, 487, 490, 491, 494, 495, 496, 503, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517,518, 519, 520, 521, and 522 of Table 1, or a pharmaceutically acceptable salt thereof.501 si-6164996Claim 22. A compound of formula (A’):(A’), or a pharmaceutically acceptable salt thereof, wherein:— is absent or a bond, wherein when — is a bond, R6and R7are absent; m is 0 or 1 ; A3, and A4are each independently CRWor N, wherein Rwis independently at each occurrence H, halo, -CM, -NO?, -NH-?, -S(O)q(C1-6alkyl), -S(O)q(Cs. ecycloalkyl), -OH, optionally substituted -NH(Cb6alkyl), optionally substituted - N(Cu6alkyl)(C1-6alkyl), optionally substituted -NHC(O)NHCj -salkyl, optionally substituted -NH(Ci-6haloalkyl), optionally substituted Cnealkylene-C3-6 cycloalkyl, optionally substituted C1-6alkyl, optionally substituted -NH(Ct-6alkylene)-C3- ecycloalkyl, optionally substituted C1-6alkylene-C1-6alkoxy, optionally substituted Cuehy dr oxyalkyl, optionally substituted Ci-salkoxy, optionally substituted C1- ehaloalkyl, optionally substituted C1-shaloalkoxyl, optionally substituted C3- gcycloalkyl, optionally substituted C3.6halocycloalk.yl, optionally substituted -()- Cj-ecycloalkyl, optionally substituted -O-C1-6alkyiene-Cj-ecycioalkyl, optionally substituted -O-C3-8halocycloalkyl, optionally substituted -O-Ch-sheterocyclyl, optionally substituted -O-(5- to 10-membered heteroaryl), optionally substituted - NH-C3-6cycloalkyl, optionally substituted -NH-Cs^halocycloalkyl, optionally substituted -NH-Cnecyanoalkyl, optionally substituted -NH-C-i-gheterocyclyl, optionally substituted 4-8 membered heterocycloalkyl, optionally substituted Ce- waryl, optionally substituted -O-Cs-ioaryl, or optionally substituted 5-10 membered heteroaryl;Bl, B2, B3, B4and B5are each independently CRXor N, wherein Rxis independently at each occurrence H, halo, -CN, -NOz, -NHc, -S(O)q(C1-6alkyl), -S(O)q(C3-502 si-61649966cyc1oalky1), -OH, optionally substituted -NH(C1-6alkyl), optionally substituted - N(C1-6alkyl)(C1-6alky1), optionally substituted Cnealkyl, optionally substituted Cn 6hydroxyalkyl, optionally substituted Cu6cyanoalkyl, optionally substituted C1- ealkoxy, optionally substituted C1-6haloalkyl, optionally substituted Cn ehaloalkoxyl, optionally substituted (X-ecycloalkyl, optionally substituted -O-C3- ecycloalkyl, optionally substituted -O-C1-6alkylene-C3-6cycloalkyl, optionally- substituted CXshalocycloalkyl, 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(())R8, -C(S)R8, -S(O)2R9, or optionally substituted 5-6 membered heteroaryl; R1and R2if present, are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, orRfand R2are taken together with the carbon atom to which they are attached to form an optionally substituted CXscycloalkyl, or optionally substituted 3-8 membered heterocy cloalky 1 ;R and R" are each independently H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted Ch-ecy cloalky 1, or optionally substituted 3-8 membered heterocycloalkyl, orRJand R4are 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 ;R5is H, halo, optionally substituted C1-6alkyl, optionally substituted C nehaloalkyl, optionally substituted C3-6cycloalky1, or optionally substituted 3-8 membered heterocycloalkyl,Rb, if present, is H, optionally substituted Cnsalkyl, optionally substituted Cu 6haloalkyl, optionally substituted (Xecycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl, or R5and R6are taken together with the carbon atom to which they are atached to form an optionally substituted C3-8cycloalkyl, or optionally substituted 3-8 membered heterocycloalkyl;R7, if present, is H, optionally substituted Cj-ealkyl, or optionally substituted Cn ehaloalkyl ;R8is -NHRy, -OCTI;;, 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 Cnealkyl is other than tert-butyl when Rxis optionally substituted aryl, and the 3-8 membered heterocycloalkyl is not pyrrolidinyl;R9is optionally substituted Cnsalkyl; andR' is H, optionally substituted C1-6alkyl, optionally substituted Cnehaloalkyl, optionally substituted (Aecycloalkyl, 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.Claim 23. The compound of claim 22, selected from the group consisting of the compounds of I able 1, or a pharmaceutically acceptable salt thereof.Claim 24. .A pharmaceutical composition comprising the compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.Claim 25. A method of inhibiting a thyroid stimulation hormone receptor (TSHR) comprising contacting the TSHR with an effective amount of the compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 24.Claim 26. 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 claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 24.Claim 27. The method of claim 26. wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease. Grave’s ophthalmology (G()) / thyroid eye disease (TED), a non-autoimmune thyroid disease, and thyroid cancer.Claim 28. The method of claim 26 or 27, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease, Grave’s ophthalmology and thyroid eye disease.Claim 29. The method of any one of claims 26 to 28, wherein the disease, disorder, or condition is Grave’s disease.

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