Compounds for inhibition of thyroid stimulating hormone receptor

Abstract

The present application relates to compounds of formulae (B') and (C) and compositions thereof for inhibition of thyroid stimulating hormone receptor (TSHR) and their use in the treatment of diseases such as Grave's disease.

Description

Attorney Docket No.: 18407-20028.40COMPOUNDS FOR INHIBITION OF THYROID STIMULATING HORMONE RECEPTOR CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims priority benefit to U. S. Provisional Application No.63 / 743,974, filed January 10, 2025, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.FIELD

[0002] The present di sclosure 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 di seases. Endocrine Journal, 69(11), 1285—1293. https: / / doi.org / 10.1507 / endocrj.ej22-039I). 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 tripohosphate (IP3) and diacylglycerol (DAG), as well as the p-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, 10 / (Supplement 1), S1-S12. https: / / doi.org / 10.1210 / clinem / dgac045). TSHR belongs to the glycoprotein-hormone receptor family of GPCRs, along with lutropin receptor (LHR) and follitropin receptor (FSHR) (Nagayama et al.) (Rapoport et al.). The GPCRs possess extracellular leucine rich repeats responsible for binding their cognate hormones, eliciting a 1MF-364282035Attorney Docket No.: 18407-20028.40conformational change that 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 inPharmacology, 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 in TED, and there is evidence for a functional interaction of IGF and TSH signaling in normal thyroid and orbital fibroblast biology (Girnita et al.). Preclinical 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 phenotype (Girnita et al.). 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 indication (Girnita et al.) (Elia et al.). 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 therapies1.2MF-364282035Attorney Docket No.: 18407-20028.40Therefore, 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.

[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.

[0008] 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 (B’) or (C):or a pharmaceutically acceptable salt thereof, wherein:B is optionally substituted Ce-ioaryl, optionally substituted Ci^alkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted Cs-ehaolcycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl;— represents a single or double bond;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-oalkyl, or optionally substituted Cj-6haloalkyl;3MF-364282035Attorney Docket No.: 18407-20028.40X2is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci^alkyl, or optionally substituted Cnehaloalkyl;Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or optionally substituted Cj-6alkyl;q is 0, 1, or 2;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci-ealkyl, optionally substituted Ci-galkoxy, optionally substituted Cnehaloalkyl, optionally substituted Ci-shaioalkoxyl, optionally substituted -O-C3- 6cycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C’3-6cycloalkyl), -NH2, optionally substituted -NH(Ci^alkyl), optionally substituted -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted -NH-Cs-ecycloalkyL optionally substituted C6-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3- 6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl;either W1and W2are both -C-, or one of W1and W2is -C- and the other of W1and W2is -N-;W3is -CRy-, -NRy~, or -N-, wherein Ryis independently at each occurrence H,halogen, optionally substituted Ci-ealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6haolcycloalkyl or optionally substituted 4-8 membered heterocycloalkyl;W4and W5are each independently -CH-, -NH-, or -N-;RJand R4are each independently H, deuterium, optionally substituted Ci-6alkyl, optionally substituted Cnehaloalkyl, optionally substituted Cs-scycloalkyl, or optionally substituted 4-8 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 4-8 membered heterocycloalkyl;4MF-364282035Attorney Docket No.: 18407-20028.40R5and R6when present, are each independently H, deuterium, optionally substituted Ci- 6alkyl, optionally substituted Ci- ialoalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted Ch-scycloalkyl, or optionally substituted 4-8 membered heterocyclyl;R7when present, is H, deuterium, optionally substituted Cnealkyl, or optionally substituted Cuehaloalkyl; andR9is optionally substituted Ci-salkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cs-ecycloalkyl, optionally substituted Cri-ehalocycloalkyl, or optionally substituted 4-8 membered heterocy cloalkyl.

[0010] In one aspect, provided herein is a compound of Formula (I):(I),or a pharmaceutically acceptable salt thereof, wherein X1, Y, A1, A2, A3, B1, B2, B3, B4, B5, R5, R6, R7, and R9are as defined elsewhere herein.

[0011] In one aspect, provided herein is a compound of Formula (II):MF-364282035Attorney Docket No.: 18407-20028.40(II),or a pharmaceutically acceptable salt thereof, wherein Xf Y, A, Af A\ B, B, B, B5, W1, W2, W3, W4, W5, R5, R6, and R7are as defined elsewhere herein.

[0012] In one aspect, provided herein is a compound of Formula (III):or a phar aceutically acceptable salt thereof, wherein X1, Y, A1, A2, A3, R3, R6, R7,9, and R10are as defined elsewhere herein.

[0013] In one aspect, provided herein is a compound of Formula (IV):(IV),6MF-364282035Attorney Docket No.: 18407-20028.40or a pharmaceutically acceptable salt thereof, wherein X2, Y, A1, A2, A3, W1, W2, W3, W4, W5, R5, R6, R7, and R10are as defined elsewhere herein.

[0014] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (A), such as a compound of Formula (B’), or (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), such as a compound of Formula (B’) or (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), such as a compound of Formula (B’) or (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 dmg 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,7MF-364282035Attorney Docket No.: 18407-20028.40compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral 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, maltodextrin, 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.; disintegrants 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, microcrystalline 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] “Pharm ceutically 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., Ci-Ce 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 encompass8MF-364282035Attorney Docket No.: 18407-20028.40Ci-C6alkyl, C2-C6alkyl, C3-C6alkyl, C4-C6alkyl, C5-C6alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl.

[0024] As used herein, the term “alkenyl” refers to an unsaturated branched or straight-chain 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- 1-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 straight-chain 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 straight-chain alkyl group.

[0026] The term “cycloalkyl”, “carbocyclic”, or “carbocycle” 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. In some embodiments, “cycloalkyl” encompasses C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. In some embodiments, the term “cycloalkyl” may be further described as a “spirocycloalkyl” or a “fused cycloalkyl”. The term “spirocycloalkyl” 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 9MF-364282035Attorney Docket No.: 18407-20028.40double 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 or having no more than one double bond between ring vertices, wherein the hydrocarbon ring is attached to the rest of the molecule at two ring vertices (e.g. two carbon atoms) by two covalent bonds. 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 “heterocycioalkyl,” “heterocyclic,” or “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(lH,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycioalkyl,” “heterocyclic,” or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycioalkyl” encompasses3- to 10-membered heterocycioalkyl, 4- to 10-membered10MF-364282035Attorney Docket No.: 18407-20028.40heterocycloalkyl, 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-membered heterocycloalkyl, 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, CG-CS heterocycloalkyl, C6-C7 heterocycloalkyl, C7-C9 heterocycloalkyl, C7-C8 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 C heterocycloalkyl ring or a 4-membered heterocycloalkyl ring.

[0028] 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 polyhaloalkyl. For example, the term “Ci-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,” “haloalkoxyl,” or “halocycloalkyl” indicate that the alkyl, alkoxyl, or cycloalkyl is substituted with 1, 2, 3, 4, 5, or more independently selected halo groups.11MF-364282035Attorney Docket No.: 18407-20028.40

[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 Co-Cuaryl, Cs-Cuaryl, Cjo-Cuaryl, Ci2-Ci4aryl, Ce-C aryl, Cs-Cnaryl, Cio-Ci2aryl, Ce-Cio ryl, Cs-Cioaryl, or Ce-Csaryl. 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 1.2.3.4-tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, 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 quaternized. 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[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non- aromatic carbon atom) is not considered a heteroaryl group.12MF-364282035Attorney Docket No.: 18407-20028.40

[0031] Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthal aziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotri azolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyriniidinyl, pyrazolopyrimidinyl, imidazopyri dines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, 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- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9-membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8-membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl.

[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, alkoxycarbonyl, 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, a13MF-364282035Attorney Docket No.: 18407-20028.40substituted 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 amines, 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 14MF-364282035Attorney Docket No.: 18407-20028.40and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting 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, di hydrogenphosphoric, sulfuric, monohydrogensulfuric, 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 15MF-364282035Attorney Docket No.: 18407-20028.40specified 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”),3H,nC,13C,i4C,13N,15N,150,17O,1SO,32P,33P,35S,iSF,36C1,123I and!25I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled withJH or14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e..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 as13O,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 used herein, “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 di sorder, 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.16MF-364282035Attorney Docket No.: 18407-20028.40

[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 disease.

[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, (ii) attenuates, ameliorates, or eliminates 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 ceil 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 was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (z.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations 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):Z-Y -B(A),or a pharmaceutically acceptable salt thereof, wherein:17MF-364282035Attorney Docket No.: 18407-20028.40B is optionally substituted Ce-ioaryl, optionally substituted Ci-6alkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C / uecycloalkyl, optionally substituted Cs-ehaol cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl;— = represents a single or double bond;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or optionally substituted Ci-ehaloalkyl;X2is optionally substituted 5-9 membered heteroaryl or -C(0)NHRa, wherein Rais H, optionally substituted Ci^alkyl, or optionally substituted Ci-ehaloalkyl;Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or optionally substituted Cj-6alkyl;q is 0, 1, or 2;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci-6alkyl, optionally substituted Ci-galkoxy, optionally substituted Cnehaloalkyl, optionally substituted Cj-6haloalkoxyl, optionally substituted -O-C3- 6cycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C’3-6cycloalkyl), -NH2, optionally substituted -NH(Ci^alkyl), optionally substituted -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted -NH-C3-6cycloalkyl, optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3- 6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl;18MF-364282035Attorney Docket No.: 18407-20028.40either W1and W2are both -C-, or one of W1and W2is -C- and the other of W1and W2is -N-;W3is -CRy-, -NRy-, or -N-, wherein Ryis independently at each occurrence H,halogen, optionally substituted Ci-galkyl, optionally substituted Ci-6haloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted Cs-ehaol cycloalkyl or optionally substituted 4-8 membered heterocycloalkyl;W4and W5are each independently -CH-, -NH-, or -N-;R3and R4are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted Cs-ecycloalkyl, or optionally substituted 4-8 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 4-8 membered heterocycloalkyl;R5and R6when present, are each independently H, deuterium, optionally substituted Ci- 6alkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-scycloalkyl, or optionally substituted 4-8 membered heterocyclyl;R7when present, is H, deuterium, optionally substituted Ci-ealkyl, or optionally substituted Ci-ehaloalkyl; andR9is optionally substituted Ci-6alkyl, optionally substituted Cj-shaloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted Cs-shalocycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl.

[0045] In some embodiments:B is optionally substituted Cfi-ioaryl, Cnealkyl, Ci-dhaloalkyl, C3-6cycloalkyl, C3- ehaolcycloalkyl, 4-8 membered heterocycloalkyl, or 5-10 membered heteroaryl;19MF-364282035Attorney Docket No.: 18407-20028.40X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or Ci^haloalkyl;X2is 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Cnealkyl, or Ci-ehaloalkyl;Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or Ci- 6alkyl;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl, Ci^alkoxy, Ci- ehaloalkyl, optionally substituted Ci-ehaloalkoxyl, -O-C3-6cycloalkyl, - S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, -NH(Q -ealkyl), -N(Ci- 6alkyl)(Ci-6alkyl -NH-Cs-ecycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, or 4-8 membered heterocycloalkyl;W is -CRy-, -NRy-, or -N-, wherein Ryis independently at each occurrence H,halogen, Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, Cs-ehaolcycloalkyl or 4-8 membered heterocycloalkyl;W4and W3are each independently -CH-, -NH-, or -N-;R3and R4are each independently H, deuterium, optionally substituted Cnealkyl, Ci- ehaloalkyl, C3-6cycJoalkyl, or 4-8 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 4-8 membered heterocycloalkyl;R5and R6when present, are each independently H, deuterium, Ci-ealkyl, Ci-ehaloalkyl, C3- ecycloalkyl, or 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form C3- scycloalkyl, or 4-8 membered heterocyclyl;R7when present, is H, deuterium, Ci-ealkyl, or Ci-ehaloalkyl; and20MF-364282035Attorney Docket No.: 18407-20028.40R9is Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, Cs-ehalocycioalkyl, or 4-8 membered heterocycloalkyl.

[0046] In some embodiments:B is optionally substituted Co-ioaryl or optionally substituted Ci-6alkyl;X1is optionally substituted 5-6 membered heteroaryl;X2is -C(O)NHRa, wherein Rais H or optionally substituted Ci-ealkyl;Y is -O-;A1, A2, and A3are each independently -CRW-, wherein Rwis independently at each occurrence H or optionally substituted Ci-ealkyl;W1and W2are each independently -C- or -N-;W3, W4, and W5are each independently -CH- or -N-;R5and R6are each H;R7is H; andR9is optionally substituted Ci-ealkyl.

[0047] In some embodiments:B is optionally substituted C6-ioaryl or optionally substituted Ci-6alkyl;X1is 5-6 membered heteroaryl optionally substituted with NH2;X2is -C(O)NHRa, wherein Rais H or Ci-6alkyl;Y i s -O-;A1, A2, and A3are each independently -CRW~, wherein Rwis independently at each occurrence H or Cnealkyl;W3, W4, and W5are each independently -CH- or -N-;21MF-364282035Attorney Docket No.: 18407-20028.40R5and R6are each H;R7is H; andR9is Ci-6alkyl.

[0049] In some embodiments, the compound is a compound of Formula (B’) or (C ):

[0050] or a pharmaceutically acceptable salt thereof, wherein X1, X2, Y, A1, A2, A, B, W1, W2, W3, W4, W5, R5, R6, R', and R9are as defined elsewhere herein. In some embodiments, the compound is a compound of Formula (B’). In some embodiments, the compound is a compound of Formula (C).

[0051] In some embodiments, the compound is a compound of Formula (B) or (C):22MF-364282035Attorney Docket No.: 18407-20028.40(Q or a pharmaceutically acceptable salt thereof, wherein X1, X2, Y, A1, A2, AJ, B, W1, W2, W3, W4, W5, R5, R6, R7, and R9are as defined elsewhere herein. In some embodiments, the compound is a compound of Formula (B). In some embodiments, the compound is a compound of Formula (C).

[0052] In some embodiments, B is optionally substituted Ce-ioaryl, optionally substituted Ci- 6alkyl, optionally substituted Ci-ehaloalkyl, optionally substituted Cs-ecycloalkyl, optionally substituted C -ehaol cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, B is optionally substituted Ce-ioaryl, Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, Cs-ehaolcycloalkyl, 4-8 membered heterocycloalkyl, or 5-10 membered heteroaryl. In some embodiments, B is phenyl optionally substituted with one or more halo. In some embodiments, B is phenyl substituted with halo.B1=B2

[0053] In some embodiments, B isB B, wherein B1, B, BJ, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci-salkyl, optionally substituted Ci-ealkoxy, optionally substituted Ci-dhaloalkyl, optionally substituted Ci-ohaloalkoxyl, -S(O)q(Cj -ealkyl), -S(O)q(C3-6cycloalkyl), -NH2, optionally substituted -NH(Ci-ealkyl), optionally substituted -N(Ci-ealkyl)(Ci-ealkyl), optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally- substituted C3-6cycloalkyl, optionally substituted CN-ehaolcycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, B1, B2, BJ, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci- ealkyl, Cnealkoxy, Cnehaloalkyl, Ci-ehaloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), - NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)(Ci-6alkyl), Ce-ioaryl, 5-10 membered heteroaryl, C3- ecycloalkyl, Ch-ehaolcycloalkyl, or 4-8 membered heterocycloalkyl. In some embodiments, B1,23MF-364282035Attorney Docket No.: 18407-20028.40B2, B3, B4and B5are each independently -CRX-, wherein Rxis independently at each occurrence H or halogen.B1~B2

[0054] In some embodiments, B isB B andat ieast fourof B1, B2, B3, B4, and B5B1=B2are -CRX- In some embodiments, B isB Ban(jaleast four of B1, B, BJ, B4, and B5are -C wherein R is at each occurrence halogen, Ci-ealkyl, Ci-ehaloalkoxyl, or C3-6cycloalkyl. In some embodiments, B is phenyl or pyridyl optionally substituted with one or more halogen, Ci- alkyl, Ci-ehaloalkoxyl, or C3-6cycloalkyl. In some embodiments, B is phenyl or pyridyl optionally substituted with one or more Ci, F, methyl, isopropyl, -OCHF2, or

[0055] In some embodiments, the compound is a compound of Formula (I):, B3B2" B4II Ior a pharmaceutically acceptable salt thereof, wherein X1, Y, A1, A2, A3, B1, B2, B3, B4, B5, R5, R6, R7, and R9are as defined elsewhere herein.MF-364282035Attorney Docket No.: 18407-20028.40

[0056] In some embodiments, the compound is a compound of Formula (I-A):»3B2' ^B4li ior a pharmaceutically acceptable salt thereof, wherein X1, A1, A2, A3, Bl, B2, B3, B4, B5, R5, R6, R7, and R9are defined elsewhere herein.

[0057] In some embodiments, the compound is a compound of Formula (I-A):„NHX1(I-Al),or a pharmaceutically acceptable salt thereof, wherein X1, Y, R5, R6, R7, R9, and Rxare defined elsewhere herein, and n is an integer from 0 to 5.

[0058] In some embodiments, X1is optionally substituted 5-6 membered heteroaryl. In some embodiments, X1is 5-6 membered heteroaryl. In some embodiments, X1is 5-6 membered heteroaryl optionally substituted with one or more -NH2, -NHfCi- alkyl), or -N(Ci-6alkyl)2. InMF-364282035Attorney Docket No.: 18407-20028.40

[0059] In some embodiments, X1is optionally substituted 5-9 membered heteroaryl. In some embodiments, X1is 5-9 membered heteroaryl optionally substituted with one or more -NH2, - NH(Ci^alkyl), or -N(Ci-6 lkyl)2. In some embodiments, X1is 5-9 membered heteroaryl optionally substituted with one or more -NH2 or -NIICH3. In some embodiments, X1is 5-6 membered heteroaryl optionally substituted with one or more -NH2 or -NHCH3. In some

[0060] In some embodiments, X1is -C(O)NHRa, wherein Rais H, optionally substituted Ci- ealkyl, or optionally substituted Cnehaloalkyl. In some embodiments, X1is -C(O)NHRa, wherein H H H H H. ’ NyRais H, or Ci-salkyl. In some embodiments, X1is °, °, or OHH2N NIn some embodiments, X1is OMF-364282035Attorney Docket No.: 18407-20028.40

[0061] In some embodiments, the compound is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X2, Y, A1, A2, A3, B1, B2, BJ, B4, B5, W1, W2, W3, W4, W5, R5, R6, R', and R9are as defined elsewhere herein.

[0062] In some embodiments, the compound is a compound of Formula (II-A) or (II-B):or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, R3, R6, R7, and Raare as defined elsewhere herein and ring A is an optionally substituted 5-9 membered heteroaryl. In some embodiments, the compound is a compound of Formula (II-A). In some embodiments, the compound is a compound of Formula (II-B).

[0063] In some embodiments, the compound is a compound of Formula (II-A1):27MF-364282035Attorney Docket No.: 18407-20028.40or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, B1, Bz, BJ, B4, B5, W1, W2, WJ, W4, W3, R5, R°, R7, and Raare as defined elsewhere herein; ring A is an optionally substituted 5-9 membered heteroaryl; n is an integer from 0 to 5; and p is an integer from 0 to 3. In some embodiments, the compound is a compound of Formula (II-A1). In some embodiments, the compound is a compound of Formula (II-BI).

[0064] In some embodiments, B is Ci-calkyl. In some embodiments, B is Ci-salkyl, In some embodiments, B is isopropyl.

[0065] In some embodiments, B is optionally substituted Ci-salkyl, optionally substituted Ci-ehaloalkyl, or optionally substituted C3-6cycloalkyl. In some embodiments, B is Ci^alkyl, Ci-ohaloalkyl, or Ca-ocycloalkyl. In some embodiments, B is Cj-salkyl, Ci-shaloalkyl, or cyclopropyl. / CF3In some embodiments, Bis

[0066] In some embodiments, the compound is a compound of Formula (III):MF-364282035Attorney Docket No.: 18407-20028.40or a pharmaceutically acceptable salt thereof, wherein X1, Y, A1, A2, A3, B1, B2, BJ, B4, B3, R5, R6, R7, and R9are as defined elsewhere herein, and R10is Ci-6alkyl, Ci-ehaloalkyl, or C3-6cycloalkyl.

[0067] In som e embodiments, the compound is a compound of Formula (IV):(IV),or a phar ceutically acceptable salt thereof, wherein X2, Y, A1, A2, A3, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, R5, R6, R', and R9are as defined elsewhere herein, and R!0is Ci-6alkyl, Ci- ehaloalkyl, or Cj^cycloalkyl.

[0068] In some embodiments, the compound is a compound of Formula (IV- A) or (IV-B):or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, R5, R6, R7, and Raare defined elsewhere herein; ring A is an optionally substituted 5-9 membered heteroaryl; and R10is Ci-ealkyl, Ci-shaloalkyl, or C3-6cycloalkyl. In some embodiments, the compound is a compound of Formula (IV-A), In some embodiments, the compound is a compound of Formula (IV-B).MF-364282035Attorney Docket No.: 18407-20028.40

[0069] In some embodiments, R10is Ci-salkyl, Ci-ehaloalkyl, or Cs-ecycloalkyl. In someembodiments, R10is Cj-salkyl, Cnshaloalkyl, or cyclopropyl. In some embodiments, R10is

[0070] In some embodiments, the compound is a compound of Formula (IV-A1) or Formula (IV-BI):or a pharmaceutically acceptable salt thereof, wherein W1, W2, W3, W4, W5, R3, R6, R7, and Rware defined as elsewhere herein; ring A is an optionally substituted 5-9 membered heteroaryl; and p is an integer from 0 to 3. In some embodiments, the compound is a compound of Formula (IV-A1), In some embodiments, the compound is a compound of Formula (IV-BI).

[0071] In some embodiments, X2is ring A. In some embodiments X2is optionally substituted 5-6 membered heteroaryl. In some embodiments, X2is 5-6 membered heteroaryl. In some embodiments, X2is 5-6 membered heteroaryl optionally substituted with one or more -NH2, -NH(Ci-6alkyl), or -N(Ci-6alkyl)2. In some embodiments, X2is

[0072] In some embodiments, X2is optionally substituted 5-9 membered heteroaryl. In some embodiments, X2is optionally substituted 5-6 membered heteroaryl. In some embodiments, X2is 5-9 membered heteroaryl optionally substituted with one or more -NH2, -NHfCi- alkyl), or - 30MF-364282035Attorney Docket No.: 18407-20028.40N(Ci-6alkyl)2. In some embodiments, X2is 5-9 membered heteroaiyl optionally substituted with one or more -NH2 or -NHCH3. In some embodiments, X2is 5-6 membered heteroaryl optionally substituted with one or more -NII2 or -NHCH3 In some embodiments, X2is 5-6 memberedheteroaiyl. In some embodiments, X2is

[0073] In some embodiments, X2is -C(O)NHRa, wherein Rais H, optionally substituted Ci- ealkyl, or optionally substituted Ci-ehaloalkyl. In some embodiments, X2is -C(O)NHRa, wherein HRais H, or Ci-ealkyl. In some embodiments, X2isO

[0074] In some embodiments, X2is -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or optionally substituted Ci-ehaloalkyl. In some embodiments, X2is -C(O)NHRa, wherein Rais H, Ci-ealkyl, or Ci-ehaloalkyl. In some embodiments, X2is -C(O)NH2. In some embodiments, X2is -C(O)NH(Ci-ealkyl). In some embodiments, X2is -C(O)NH(Cll3). In some embodiments, X2is -C(O)NH(CH2CH3).

[0075] In some embodiments, X2is -C(O)NHRa, wherein Rais H or optionally substituted Ci-ealkyl. In some embodiments, X2is -C(O)NHRa, wherein Rais H or Ci-ealkyl. In some embodiments, X2is -C(O)NH2 In some embodiments, X2is -C(O)NH(Ci -ealkyl). In some embodiments, X2is -C(O)NH(CH3). In some embodiments, X2is -C(O)NH(CH2CH3).

[0076] In some embodiments, or a pharmaceutically acceptable salt thereof, either W1and W2are both -C-, or one of W1and W2is -C- and the other of W1and W2is -N-; and W3, W4, and W5are each independently -CH-, -NH-, or -N-. In some embodiments, one or more of W!and31MF-364282035Attorney Docket No.: 18407-20028.40W2, W3, W4, and W5is -N-. In some embodiments, at least two of W1and W2, W3, W4, and W5is -N-. In some embodiments, at least three of W1and W2, W3, W4, and W5is -N-.

[0077] In some embodiments, or a pharmaceutically acceptable salt thereof, the moiety A9AVW2A3r. 'w4represented by v ' w5, is

[0078] In some embodiments, or a pharmaceutically acceptable salt thereof, the moietyrepresented byor N=N

[0079] In some embodiments, Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or optionally substituted Ci- alkyl. In some embodiments, Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or Ci-ealkyl. In some embodiments, Y is -O-, -NH-, or -S-. In some embodiments, Y is -O-.

[0080] In some embodiments, A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci-ealkyl, optionally substituted Cnealkoxy, optionally substituted Ci-ehaloalkyl, optionally substituted Cj-ehaloalkoxyl, optionally substituted -O-Cs-scycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, optionally substituted -NH(C j. ealkyl), optionally substituted -N(Ci- 6alkyl)(Ci-6alkyl), optionally substituted -NH-C / uecycloalkyl, optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted Cs-ecycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl, Cnealkoxy, Cj-ehaloalkyl, Ci-ehaloalkoxyl, -O-CAcycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C -6cycloalkyl), -NH2, -NH(C^alkyl), -N(Ci-6alkyl)(Ci-6alkyl -NH-C3- 6cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, or 4-8 membered32MF-364282035Attorney Docket No.: 18407-20028.40heterocycloalkyl. In some embodiments, A1, A2, AJ, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halo, or Ci^alkyl. In some embodiments, A1, A2, A3, and A4are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, Cl, F, or methyl.

[0081] In some embodiments, Rwis independently at each occurrence H, halogen, optionally substituted Cnealkyl, optionally substituted Cnealkoxy, optionally substituted Ci-ehaloalkyl, optionally substituted Ci-ehaloalkoxyl, optionally substituted Cs-ecycloalkyl, or optionally- substituted 4-8 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, optionally substituted Ci-salkyl, optionally substituted Ci-salkoxy, optionally substituted Cnshaloalkyl, optionally substituted Cs-ecycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, Ci-salkyl, Cj-ealkoxy, Ci-ehaloalkyl, Cj-ehaloalkoxyl, Cs-scycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H, halogen, Cnsalkyl, Ci-salkoxy, Ci-shaloalkyl, C3-6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, Rwis independently at each occurrence H or halogen. In some embodiments, Rwis independently at each occurrence H. In some embodiments, Rwis independently at each occurrence II or Ci-salkyl. In some embodiments, Rwis independently at each occurrence H or Ci-salkyl. In some embodiments, Rwis independently at each occurrence H or methyl. In some embodiments, Rwis independently at each occurrence FI, halo, or Ci-salkyl. In some embodiments, Rwis independently at each occurrence H, Cl, F, or methyl.

[0082] In some embodiments, A1, A2, and A3are each independently -CRW- or -N-. In some embodiments, each of A1, A2, and A3is -CRW-. In some embodiments, each of A1, A2, and A3is - CFI-. In some embodiments one of A1, A2, and A3is other than -CFI-.

[0083] In some embodiments, one of A1, A2, A3is -N-.33MF-364282035Attorney Docket No.: 18407-20028.40

[0084] In some embodiments, the moiety represented by is an optionallysubstituted Ce-ioaryl. In some embodiments, the moiety represented by

[0086] In some embodiments, each of B1, B2, B3, B4, and B5is -CRN. In some embodiments, each of Bl, B2, B3, B4, and B5is -CH-. In some embodiments, at least one of B1, B2, B3, B4, and B5is other than -CH-. In some embodiments, one of B1, B2, B3, B4, and B5is -N-.

[0087] In some embodiments, Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Cj-6alkyl, optionally substituted Cj-ealkoxy, optionally substituted Ci- haloalkyl, optionally substituted Cnehaloalkoxyl, -S(O)q(Cj -ealkyl), -S(O)q(C3-ecycloalkyl), - NH2, optionally substituted -NH(Ci-ealkyl), optionally substituted -N(Ci-ealkyl)(Ci-ealkyl),34MF-364282035Attorney Docket No.: 18407-20028.40optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C^cycloalkyl, optionally substituted Cs-ehaolcycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, -CN, -NO2, -NH2, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -OH, - NH(Ci^alkyl), -N(Ci^,alkyl)(Ci-6alkyl), Ci-ealkyl, Ci-ealkoxy, Ci-ehaloalkyl, Ci-bhaloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, -NH(Ci-6alkyl), -N(Ci^alkyl)(Ci-balkyl), Cb- waryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, Cs-ehalocycloalkyl, or 4-8 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen or Ci-balkyl. In some embodiments, Rxis independently at each occurrence H or -CN. In some embodiments, Rxis independently at each occurrence H, halogen, or -N(Ci-6alkyl)(Ci-6alkyl). In some embodiments, wherein Rxis independently at each occurrence H, or Ci-salkoxy. In some embodiments, Rxis independently at each occurrence H, halogen or C3-6cycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen or 4-8 membered heterocycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen, Ci-ealkyl, Ci-bhaloalkoxyl, or C3-6cycloalkyl. In some embodiments, Rxis independently at each occurrence H, halogen, Ci-3alkyl, C]-3haloalkoxyl, or cyclopropyl. In some embodiments, Rxis independently at each occurrence H, Cl, F, methyl, isopropyl, -OCHF2, or cyclopropyl.B 12 - 1 D14 „BVBS^Ac,

[0088] In some embodiments, the moiety represented by -1~ is —L35MF-364282035Attorney Docket No.: 18407-20028.40

[0090] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0091] In some embodiments, RJand R4are each independently H, deuterium, optionally substituted Cuealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 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 4-8 membered heterocycloalkyl. In some embodiments, R3and R4are each independently H or Ci- alkyl, or R3and R4are taken together with the carbon atom to which they are attached to form C3-8 cycloalkyl or 4-8 membered heterocycloalkyl.

[0092] In some embodiments, R3and R4are each independently II, deuterium, optionally substituted Ci-ealkyl, optionally substituted Cncdialoai yl, optionally substituted C.3-6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, R3and R4are each independently H or optionally substituted Cj-ealkyl. In some embodiments, R3and R4are each independently H or Cnealkyl.

[0093] In some embodiments, RJand R4are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 4-8 membered heterocycloal yl. In some embodiments, R3and R4are taken together with the carbon atom to which they are attached to form C3-8 cycloalkyl or 4-8 membered heterocycloalkyl.36MF-364282035Attorney Docket No.: 18407-20028.40

[0094] In some embodiments, R5and R6are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted C / necycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl, or R5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, R3and R6are each independently H, deuterium, Cnealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, or 4-8 membered heterocycloalkyl, or R5and R6are taken together with the carbon atom to which they are attached to form C3-8 cycloalkyl or 4-8 membered heterocycloalkyl.

[0095] In some embodiments, R5and R6are each independently H deuterium, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted Cb-ecycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, R3and R6are each independently H or optionally substituted Cnealkyl. In some embodiments, R5and R° are each independently H or Cnealkyl. In some embodiments, R5and R6are each independently H.

[0096] In some embodiments, R5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted C3-8 cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, R3and R6are taken together with the carbon atom to which they are attached to form C3-8 cycloalkyl or 4-8 membered heterocycloalkyl.

[0097] In some embodiments, R7is H, deuterium, optionally substituted Cnealkyl, or Cn ehaloalkyl. In some embodiments, R7is H or Cnealkyl. In some embodiments, R'' is H. In some embodiments, R7is Cnealkyl.

[0098] In some embodiments, R9is optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted Cs-ecycloalkyl, optionally substituted Cs-ehalocycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl. In some embodiments, R9is Cnealkyl, Cn ehaloalkyl, Cs-ecycloalkyl, Cs-ehalocycloalkyl, or 4-8 membered heterocycloalkyl. In some embodiments, R9is Cnealkyl. In some embodiments, R9is methyl, ethyl, or isopropyl. In some embodiments, R9is methyl.

[0099] In some embodiments:37MF-364282035Attorney Docket No.: 18407-20028.40B1~B2M\5B isB Bor optionally substituted Ci-ealkyl;X!is 5-6 membered heteroaryl optionally substituted with one or more -NH2, - NH(Ci-ealkyl), or N(Ci-6alkyl)2;X2is -C(O)NHRa, wherein Rais H or optionally substituted Ci-ealkyl;Y is -O-;A1, A2, and A3are each independently -CRW-, wherein Rwis independently at each occurrence H, halogen, or optionally substituted Ci-ealkyl;B1, B2, B3, B4and B5are each independently -CRX-, wherein Rxis independently at each occurrence H or halogen;W1and W2are each independently -C- or -N-;W3, W4, and W5are each independently -CH- or -N-;R5and R° are each H;R7is H; andR9is optionally substituted Ci-ealkyl.

[0100] In some embodiments:B1=B2H L3B isB B, Ci-ealkyl, Cnehaloalkyl, or C’3-6cycloalkyl;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H;38MF-364282035Attorney Docket No.: 18407-20028.40X2is 5-6 membered heteroaryl or -C(O)NHRa, wherein Rais H or optionally substituted Ci-ealkyl;Y is -O-, -NH-, or -S-;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, or optionally substituted Ci-ealkyl;B1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, halogen, Ci-calkyl, Cj-ehaloalkoxyl, or Ca-ecycloalkyl;W1and W2are each independently -C- or -N-;W3is -CRy-, -NRy-, or -N-, wherein Ryis independently at each occurrence H, Cn 6alkyl, or Cs-ecycloalkyl;W4and W5are each independently -CH- or -N-;R5and R6when present, are each H;R7when present, is H; andR9is optionally substituted Ci-ealkyl.

[0101] In some embodiments, the compound of formula (A’), or a pharmaceutically acceptable salt thereof, the compound is a compound of formula (B-Sl), (B-S2), (C-Sl), or (C-S2):MF-364282035Attorney Docket No.: 18407-20028.40(C-S2). In some embodiments, the compound is a compound of formula (B- SI). In some embodiments, the compound is a compound of formula (B-S2). In some embodiments, the compound is a compound of formula (C-Sl). In some embodiments, the compound is a compound of formula (C-S2).

[0102] In some embodiments, the compound of formula (A’), or a pharmaceutically acceptable salt thereof, the compound is a compound of formula (I-Sl), (I-S2), (II-S 1), (II-S2), (III-S1), (III-S2), (1V-S1), or (IV-S2):40MF-364282035Attorney Docket No.: 18407-20028.40SI). In some embodiments, the compound is a compound of formula (I-S2). In some embodiments, the compound is a compound of formula (II-S1). In some embodiments, the compound is a compound of formula (II-S2). In some embodiments, the compound is a compound of formula (III-S 1). In some embodiments, the compound is a compound of formula (I II-S2). In some embodiments, the compound is a compound of formula (IV-SI). In some embodiments, the compound is a compound of formula (IV-S2).

[0103] In some embodiments, provided is a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, provided is a compound selected from41MF-364282035Attorney Docket No.: 18407-20028.40compounds 1-23 of Table 1, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, provided is a compound selected from compounds 1-115 of Table 1, or pharmaceutically acceptable salt, solvate, hydrate,IEor co-crystal thereof, Z or a mixture of any of the foregoing.Z ZLTable 1Cmpd. No. Struc hture NameOl-(9-(2-chloro-5- O Tl - — fluorophenoxy)-4, 5 - 1di hy droimi dazo [1,2- Q LL — — u. —a]quinolin-4-yl)ureao Ol-(9-(2-chl oro-5 - y z — 'o \ / = \=== \ / —fluorophenoxy)-4,5-dihydro- 2ZI [1,2,4] triazolo [4,3 -a]< °= quinolin-4-yl) urea ^.,0 Z 2:3-((l,3,4-oxadiazol-2- yl)amino)-8-(2-chloro-5- 3fluorophenoxy)- 1 -methyl-3,4- dihy droquinolin-2( 1 H)-oneFl-(9-(2-chl oro-5 - fluorophen oxy )-4, 5 - 4 0dihydroimidazo[l,2- \ Jk / -k N Clu u V. / / a]quinolin-4-yl)-3-methylureaMF-364282035Attorney Docket No.: 18407-20028.40 l-(9-(2-chl oro-5 - fl uorophenoxy )-4, 5 - 5di hydroimi dazo[ 1,2-a]quinolin-4-yl)-3 -ethylureaCZZ \F\ ~ / — Z%.J \ * y. _ _ _ / \ \ Z*\ *?a>1 | °AV / (“^Gil-(9-(2-chl oro-5 - Tl fluorophenoxy)-8-methyl-4,5- 6di hydroimi dazo [1,2- a]quinolin-4-yl)urea0<yNH o u_ — —NH2oF_ 3-((l,3,4-thiadiazol-2- yl)amino)-8-(2-chloro-5- 7 N-NS£T""fluorophenoxy)- 1 -methyl-3,4- V^^ o= X^ cidihydroquinolin-2(l H)-oneHs8-(2-chloro-5- fluorophenoxy)- 1 -methyl -3- 8(pyrimidin-2-ylamino)-3,4- di hy droquin olin-2( 1 H)-oneMF-364282035Attorney Docket No.: 18407-20028.40ci-^y 8-(2-chloro-5- fluorophenoxy)- 1 -methyl-3 - 9(pyridazin-3 -ylamino)-3,4- dihydroquinolin-2-oneL Z. NNcr' Y^ 8-(2-chloro-5- fl uorophenoxy)- 1 -m ethyl-3 - 10 IL. (pyri din-3 -ylamino)-3,4- y^ / \v O z#>x- — o dihy droqui nolin-2-one\ / \ \ / \ / V / \ - f / \ \HZ- 'NZ- / 7 / r \ / A / / O\ / (3R)-8-(2-chloro-5- fluorophenoxy)- 1 -ni ethyl-3 - 11(pyridazin-3 -ylamino)-3, 4- dihydroquinolin-2-oneCI-^Y (3S)-8-(2-chloro-5- fluorophenoxy)- 1 -methyl -3 - 12(pyridazin-3 -ylamino)-3, 4- i ^0dihydroqui nol in-2-NMF-364282035Attorney Docket No.: 18407-20028.40F3-((5-amino-l,3,4-tliiadiazol- 2-yl)amino)-8-(2-chloro-5- 13 N -N^ 7^0HZN-Y II 1 1 1 fluorophenoxy)- 1 -methyl-3,4- S'^N / V'N\Cdihy droquinolin-2( 1 H)-oneH0IZF(R)-3-((l,3,4"thiadiazol-2- yl)amino)-8-(2-chloro-5- 14 N-NK II 1 o ' fluorophenoxy)- 1 -methyl-3,4-Cldihydroquinolin-2(lH)-oneH^ oTl—-- 0(S)-3-((l,3,4-thiadiazol-2- yl)amino)-8-(2-chloro-5- 15fluorophenoxy)- 1 -methyl-3,4- dihydroquinolin-2(l H)-oneCl F1 -(7-chloro-9-(2-chloro-5- fluorophenoxy)-4, 5 - 16 0dihydroimidazo[l,2- H2NANY\CLH a]quinolin-4-yl)ureaF3-((lH-l,2,3-triazol-5- yl)amino)-8-(2-chloro-5- 17 Nfluorophenoxy)- 1 -methyl-3,4- N'^'N'^YNXCIdihydroquinolin-2(lH)-oneH HMF-364282035Attorney Docket No.: 18407-20028.40cr y 8-(2-chloro-5-,0fluorophenoxy)- 1 -methyl-3 - 18(pyrimidin-4-ylamino)-3,4- y x)Z \ v z; n —. - — dihydroquinolin-2-oneY / A / / i, 2 ( ) ( M — — - 1.N^NJ°\ ’i~\ ANz(R)-8-(2-chloro-5- fluorophenoxy )- 1 -methyl-3 - 19( Of Li--- — ((5-(methylamino)-l,3,4- thiadiazol-2-yl)amino)-3,4- Odihydroquinolin-2(l H)-one(S)-8-(2-chloro-5- ^O== Ffluorophenoxy)- 1 -methyl-3 - z:x:20 \ / ZN^^ 2^N=7 ((5-(methylamino)-l,3,4~HNAbA,1 1 aN \ thiadiazoi-2-yl)amino)-3,4-H6 dihydroquinolin-2(lH)-oneF\Ci y ^JI1 -( 8-chloro-9-(2-chloro-5- J^Ofluorophenoxy)-4, 5 - 21dihydroimidazo[l,2- y 'Xa]quinolin-4-yl)ureaO^NHNH21 -( 8-fluoro-9-i sopropoxy-4, 5 - 22 dihy droimidazo[ 1,2- a]quinolin-4-yl)urea46MF-364282035Attorney Docket No.: 18407-20028.40l-(9-(2-chloro-5- ' 32 '^ —, s fluorophenoxy)- 1 -methyl-4, 5 - 23 1££ t 1 --—~^J= di hy droimi dazo [1,2- z i L 'L 2a]quinolin-4-yl)urea°<yNH(( oo= / ===\^\ / 2) Z G — / NH H / / Az / / zYzZ / 24 O O (S)-3-((lH-l,2,3-triazol-5- yl)amino)-8-(2-chloro-5- Q O n — —~fluorophenoxy)- 1 -methyl-3,4- dihydro- 1,7-naphthyridin-2( 1H)- one25 F (R)-3-(( 1H- 1,2,3 -triazoi-5- rf'^N yl)amino)-8-(2-chloro-5- fluorophenoxy)-! -methyl-3,4- N' H f r i\, Nk A N Cl dihydro- 1,7-naphthyridin-2( 1H)- N N A \H H II one26 (R)-3-((lH-l,2,3-triazol-5- 1F[A yl)amino)-8-(2-chloro-5- fluorophenoxy)- 1,6-dimethyl- N 1 1 N Ci 3,4-dihydro- 1,7 -naphthyridin- N" Y''' AfN\CH Ho 2(lH)-one27 (S)-3-(( 1H- 1,2,3 -triazol-5 - yl)amino)-8-(2-chloro-5- fluorophenoxy)- 1,6-dimethyl- 3,4-d ihydro- 1, 7 -naphthyridin- 2(lH)-oneMF-364282035Attorney Docket No.: 18407-20028.4028 l-(9-(2-chloro-5- fluorophenoxy)-8-tluoro-4,5- Fdihydroimidazo [ 1, 2-a] quinolin- 4-yl)ureaO^NHNH229 N-(9-(2-chloro-5- fluorophenoxy) -4,5- dihydroimidazo [ 1, 2-a] quinolin- 4-yl)- 1,3,4-thiadiazoI-2-amineLL LL, / \z—\ / T \ / t _ f b " '30 9-(2-chloro-5-fluorophenoxy)- N-(pyridazin-3-yl)-4,5- dihydroimidazo [ 1,2-a] quinolin- 4-amine31 F (R)-3 -((5 -amino- 1,3,4- thiadiazol-2-yl)amino)-8-(2- n drX N r 0 N chloro-4,5-difluorophenoxy)- 1 - H, N— '< II i 1 12 XSAN-VN^CImethyl-3,4-dihydroquinolin-H62( lH)-oneMF-364282035Attorney Docket No.: 18407-20028.40 32 F (S)-3-((5-amino-l,3,4- thiadiazol-2-yl)amino)-8-(2-NXI XX T X' -N r -r o T chloro -4,5 -di fluorophenoxy) - 1 - H2MN z C JI N Clmethyl-3,4-dihydroquinolin- ^X CZ / H02( lH)-one33 F (R)-3-((5-amino-l,3,4- 4$ / \ O TZ, _ _thiadiazol-2-yl)amino)-8-(2- M J Hp \ / =\j oX>=N-.NJ oz-- / chl oro-5 -fluorophenoxy )- 1 - X x J \xo ' ( —.xH2NXA NJ i, methyl-3,4-dihydroquinolin- mbN n X o H 2(lH)-one 0O "n — —34 (S)-3-((5-amino-l,3,4- thiadiazol-2-yl)amino)-8-(2- chl oro-5 -fluorophenoxy)- 1 - m ethyl-3,4-dihydroquinolin- 2(lH)-one35 8-(2-chloro-5-fluorophenoxy)- 1 - methyl-3-(pyridin-2-ylamino)- CI'^Y3,4-dihydroquinoIin-2(lH)-one y x)L^S-N36 8-(2-chloro-5-fluorophenoxy)- 1 - methyl-3-(pyridin-2- ylamino)quinolin-2(lH)-oneMF-364282035Attorney Docket No.: 18407-20028.4037 8-(2-chloro-5-fluorophenoxy)- 1 - methyl-3 -((5,6,7,8-tetrahydro- [ 1,2,4]tri azolo [4,3 -ajpyri midin- " TZ 3-yl)amino)-3,4- '" y \ zJ dihydroquinolin-2( 1 H)-one38 3-((l,3,4-thiadiazol-2- / \ o= - > yl)amino)-8-((6- 42 Z— / i sopropy lpyridin-2 -yl)oxy )- 1 - c methyl-3, 4-dihydroquinolin- o — 2(lH)-oneX / \P / z' —\ / \ \ / y <o4 _ z-- 39 T / ) ) Z A Z > — - — F (R)-3 -(( 1H- 1.2,3 -triazol-5 - ( HC V ~~-7yl)amino)-8-(2-chloro-5- fluorophenoxy)- 1 -methyl-3,4-N'NJL V'^SL-N Cl dihydroquinolin-2( 1 H)-oneH K r040 F (S)-3 -(( 1H- 1,2,3 -triazol-5 - yl)amino)-8-(2-chloro-5- fluorophenoxy)-! -methyl-3,4- J'SCI dihy droq uinolin-2( lH)-oneH S T 'o41 F (R)-3-((lH-l,2,3-triazol-5- yl)amino)-8-(2-ch!oro-4,5- difluorophenoxy )- 1 -methy 1-3,4- Cl dihydroquinolin-2( lH)-oneN N X X H H IIOMF-364282035Attorney Docket No.: 18407-20028.4042 (S)-3-((lH-l,2,3-triazol-5- yl)amino)-8-(2-chioro-4,5- difluorophenoxy)- 1 -methyl -3,4- xzvz dihydroquinolin-2( 1 H)-one43 F\xYy (S)-l-(8-chloro-9-(2-chloro-5- / □=""" / X>;4 h z — fluorophenoxy)-! -methyl-4,5- cidihy droimidazo [ 1,2-a] quinolin- J^o o4-yl)ureao n — —nH2N^NHY044 F-X -'Y. (R)- 1 -(8-chloro-9-(2-chloro-5- fluorophenoxy)- 1 -methyl -4,5- CIdihydroimidazo [ 1,2-a] quinolin- J^O4-yl)ureavdH2N^NH045 ci "y" 1 -(8-chloro-9-isopropoxy- 1 - J^o methyl-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)ureaI L3>NANO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40 46FY^ l-(9-(2-chloro-5- fluorophenoxy)- 1 -cyclopropyl- Y ^^4,5-dihydroimidazo[l,2- rx° F a] quinol in-4-yl)ureaI L?H2N^NH047 (S)- 1 -(9-(2-chloro-5- fluorophenoxy)- 1 -methyl -4,5- y^cidihydroimidazo [ 1, 2-a] quinolin- YY°4-yI)ureaOY^Nz \° r —O^NH\ / A z:°z~©zi" \ \ / = / —NH2\ / yz= — —~48 >F^ XY (R)- 1 -(9-(2-chloro-5 - fluorophenoxy)- 1 -methyl -4,5- y^C!dihydroimidazo [ 1,2-a] quinolin- YY°4-yl)ureaT nY^NO^NHNH249 (R)-3-((l,3,4-thiadiazol-2- yl)amino)-8-(2-chloro-5- fluorophenoxy)-l,7-dimethyl- 3,4-dihy droq uinolin-2( lH)-oneMF-364282035Attorney Docket No.: 18407-20028.4050 (R)-3-((l,3.4-thiadiazol-2- yl)amino)-8-(2-chloro-5- fluorophenoxy)-7 -fluoro- 1 - methyl-3,4-dihydroquinolin- n: Mz 2( lH)-one— / <.K Ox ZZZ 0 ) ( I31‘1- ■.51 Fx. h1(R)-3-((l,3.4-thiadiazol-2- Q yl)amino)-7-chloro-8-(2-chloro- ci Q Y ci / L,o 5 -fluorophenoxy)- 1 -methyl-3,4- dihydroquinolin-2( 1 H)-oneXXkoS^. NHN- p ^2. N== LL LL #— - *52 (R)-3 -((5 -amino- 1,3,4”thiadiazol-2-yi)amino)-7-chloro- 8 -( 2-ch] oro-5 -fluorophenoxy) - 1 - methyl-3,4-dihy droquinolin- 2(lH)-one53Fx^x l-(9-(2-chloro-5-Ffluorophenoxy)-8 -fluoro- 1 - methyl-4,5-dihydroimidazo[l,2- x^xx0a]quinolin-4-yl)urea1 x O'0=?NO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40 54 l-(8-chloro-9-(3- fluorophenoxy)- 1 -methyl -4, 5 - CIdibydroimidazo [ 1, 2-a] quinolin- 4-yl)ureaOz O / = =xO < Z \< z 71yv — —\ ’z / \ / A— —. / / T. / \ / / T V / s _( (_ z: )N M - - - s y, HL “n v ' * O A / / / NH24 Vr:■ 0z- p < A55 Q l-(9-(2-chloro-5- fluorophenoxy)- 1 -methyl -4, 5 - dihydroimidazo[l,2- a] [ 1,6]naphthyridin-4-yl)urea56 l-(9-(2-chloro-5- fluorophenoxy)- 1 -methyl -4, 5 - Y^C!dihydroimidazo[l,2- YW'0a] [ 1,5]naphthyridin-4-yl)ureaI0< Y'NHNH257 l-(l-methyl-9-((6- methylpyridin-2-yl)oxy)-4,5- dihydroimidazo [ 1,2-a] quinolin- 4-yl)ureaMF-364282035Attorney Docket No.: 18407-20028.4058 l-(l-methyl-9-((3- methylpyridin-2-yi)oxy)-4,5- dihydroimidazo [ 1, 2-a] quinolin- 4-yl)urea59 3-((2H-l,2,3-triazol-4- yl)amino)-8-((6- VNA NxM / isopropylpyridin-2-yl)oxy )- 1 - H 7 CH methyl-3,4-dihydroquinolin- 2(lH)-one60 z - / l-(8-((2-chloro-5- ( yo z4 <—- fluorophenyl)aniino)- 1 -methyl - 5 } z — / / / \ A 32 Y^ayy(^NH 2 -oxo-1, 2,3,4- \ y —Q=J \tetrahydroquinolin -3 -yl)ureay^oO<yNHNH261 l-(9-((2-chloro-5- Cl J* fluorophenyl)animo)- 1 -methyl - 4,5 -dihy droim idazo [1,2-. NHLX a]quinolin-4-yl)ureaAT '-y- U NO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.4062 l-(l-((2-chloro-5- fluorophenyl)aniino)-9-methyi- 5,6-dihydroimidazo[l,2- a] [ 1,7]naphthyridin-6-yl)nrea( -n — / ' / — / ? ( Z / 1\ — r=b1y --z-—63 Q (S)-l-(9-(2-chloro-5- fluorophenoxy) -1,8 -dimethyl - 4,5-dihydroimidazo[l,2- a] [ 1,6]naphthyridin-4-yl)ureaV / i_64 (R)-l-(9-(2-chloro-5- fluorophenoxy) -1,8 -dimethyl - I y^GI4,5-dihydroimidazo[l,2- X -ONa] [ 1,6]naphthyridin-4-yl)urea Y^N -"4O^NHNH265 (R)-3-((l,3,4-thiadiazol-2- yl)amino)-7-chloro-8-((6- NLXSXC! y F cyclopropyl-3 -fluoropy ridin-2 - yl)oxy )- 1 -methyl -3,4- dihy droq uinolin-2( lH)-one M^oS_, NHVNMF-364282035Attorney Docket No.: 18407-20028.4066 (R)-7-chloro-8-((6-cyclopropyl- 3 -fluoropy ridin-2-yl)oxy)- 1 - NI JxCl methyI-3 -(pyridazin-3 -ylamino)- 3,4-dihydroquinolin-2(lH)-onek / RlY.L < NN67 / \ (S)-7-chioro-8-((6-cyclopropyl- T j 3 -fluoropyridin-2-yl)oxy)-l - N. Aci y F methyl -3 -(pyridazin-3 -ylamino)-,0 3,4-dihydroquinolin-2( lH)-onek yX N,UA0L < NN68 (R)-3-((l,3.4-thiadiazol-2- NL yl)amino)-7-chloro-8-((3-fluoro- Cl ^ F6-methylpyridin-2-yl)oxy)- 1 - methyl-3,4-dihydroquinolin- Y^N'"’2( lH)-onek(RlAs^y oS^NH< TN-N69 Fx^. (S)-3-((l,3,4-thiadiazol-2- yl)aniino)-8-((2-chloro-5- Y^cifluorophenyl)amino)- 1 -methyl- 3,4-dihydroquinoIin-2(lH)-one Y^N^y x)S^ / NHN-NMF-364282035Attorney Docket No.: 18407-20028.4070 (R)-3-((l,3.4-thiadiazol-2- yl)amino)-8-((2-chloro-5- fluorophenyl)aniino)- 1 -methyl - 3,4-dihydroquinolin-2(lH)-one2 ()?. \ W r - A\ro71 o o l-(8-((2-chloro-5- fluorophenyl)amino)-7 -fluoro- 1 - methyl -2 -oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea72 (S)-l-(9-(2-chloro-5- fluorophenoxy)-8 -fluoro- 1 - F \^^C|methyl-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)urea" AO^NHNH273 (R)~ 1 -(9-(2-chloro-5 -Ffluorophenoxy)-8 -fluoro- 1 - methyl-4,5-dihydroimidazo[l,2- / k / °a]quinolin-4-yl)ureaO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.4074 (S)- 1 -(8-chloro-9-isopropoxy- 1 - methyl -4, 5-dihydroimidazo[ 1,2- a] quinol in-4-yl)ureaO > —.6 O / - A A / / ” z A® (, Z > M®"“ - f75 / \ / Z \ ( o _ z: — (R)- 1 -(8-chloro-9-isopropoxy- 1 - / L --O methyl-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)ureaO^NHNH276 (S)-l-(8-chloro-9-ethoxy-l- ( O z \ -- - methyl-4,5-dihydroimidazo[l,2- / \\ / \ / _ Z£2—a]quinolin-4-yl)urea77 Cl (R)- 1 -(8-chioro-9-ethoxy- 1 - methyl-4,5-dihydroimidazo[1.2- a]quinolin-4-yl)ureaxMO^NHNH278 (S)- 1 -(8-chloro- 1 -methyl-9- Clr'CFsJ^Q (2,2,2-trifluoroethoxy)-4,5- dihydroimidazo [ 1,2-a] quinolin- 4-yi)urea0< Y'NHNH2MF-364282035Attorney Docket No.: 18407-20028.4079, CFa(R)- 1 -(8-chloro- 1 -methyl-9- Cl <3(2,2,24rifluoroethoxy)-4,5- dihydroimidazo [ 1, 2-a] quinolin- 4-yl)urea"n O^NHoNH22£(G KW33“ - 80 b ^2^----\ (S)-l-(8-chloro-9-ethoxy-6- fluoro- 1 -methyl-4,5 - dihydroimidazo [ 1,2-a. J quinolin- 4-yl)urea81 Cl (R)- 1 -(8-chloro-9-ethoxy-6- A -0 fluoro- 1 -methyl -4,5 - dihydroimidazo [ 1,2-a] quinolin- F Ju Yl. J4-yl)ureaCk t / NHNH282 (S)- 1 -( 1 -cyclopropoxy-9- methyl-5,6-dihydroimidazo[l,2- a] [ 1,7]naphthyridin-6-yl)ureaO^NHNH283 Y (R)- 1 -( 1 -cyclopropoxy-9- N^O methyl-5,6-dihydroimidazo[l,2- [ JZa] [ 1,7]naphthyridin-6-yl)ureaT 1''5, NHNH260MF-364282035Attorney Docket No.: 18407-20028.4084 (R)- 1 -(8-fluoro-9-isopropoxy- 1 - methyl -4, 5-dihydroimidazo[ 1,2- a] quinol in-4-yl)urea^'N ' “3*xOS O / ) i ( G Z -n T| / - - — — j -., / A / / Y x / )s ( Z<.i'. — / =85 / \ / \ V X _F / X) o G;z O —- / — (S)- 1 -(8-fluoro-9-isopropoxy- 1 - A^o \ Y O —methyl-4,5-dihydroimidazo[l,2- Qa]quinolin-4-yl)ureaO^NHNH286 (R)-3-((l,3,4-thiadiazol-2- yl)amino)-8-(2-chloro-5- fluorophenoxy)- 1,7-dimethyl- 3,4-dihydro- 1,6-naphthyridin- 2(lH)-one87 (S)-3-((l,3,4-thiadiazol-2- yl)amino)-8-(2-chloro-5- 1fluorophenoxy)- 1,7-dimethyl- A.3,4-dihydro- 1,6-naphthyridin- Y^N^ 2(lH)-one^AQSs, ^NH<\NY-NMF-364282035Attorney Docket No.: 18407-20028.40 88 (S)-l-(8-chloro-9- (difluoromethoxy)- 1 -methyl- 4,5-dihydroimidazo[l,2- a] quinol in-4-yl)ureaT MzO O r=\ - > • / \ 4 f y ’Z o) z\ W>— - — - - —! —, z=x.A / A / / A A “ I / ” T ' ) ( < z ) <3 m “H i 1 KS0 ■* ■ - —89 \z^fw (zO oz-——.. (R)-l-(8-chloro-9- J \ / \x"n o " H-- j° \y^ (difluoromethoxy)- 1 -methyl- Q 4,5-dihydroimidazo[l,2- a] quinoli n -4-yl)u rea90 C! 1 -(8-chloro-9-isopropoxy- 1 - methyl -4, 5 -dihydro- 1H- f T / naphtho[ 1,2-d] [ 1,2,3]triazol-4- I 1 ''Nyl)ureaD^NHNH291 (R)-3 -((5 -amino- 1,3,4"thiadiazol-2-yl)amino)-8-(2- chloro-5-fluorophenoxy)- 1 - ethyl-3,4-dihydroquinolin- 2(lH)-oneMF-364282035Attorney Docket No.: 18407-20028.4092 (R)-3 -((5 -amino- 1,3,4"thiadiazol-2-yl)amino)-8-(2- chloro-5-fluorophenoxy)- 1 - i sopropyl -3,4-dihydroquinolin- 2( lH)-oneS^-NHH2N— < JN-N93 (S)- 1 -(9-((2-chloro-5 - fluorophenyl)amino)- 1 -methyl - cr O y '4,5 -dihydroimidazo [1,2- a] quinol in-4-yl)ureaU~ JrNO^NHNH294 (R)-l-(9-((2-chloro-5- fluorophenyl)amino)- 1 -methyl - ci' y, NH 4,5 -dihydroimidazo [1,2- a] quinol in-4-yl)urea\OO^NHNH295 (S)- 1 -( 1 -(2-chloro-5-Ffluorophenoxy)-9-metliyl-5,6- X Y1 Cldihydroimidazo[l,2- ^N, ^0a] [ 1,7]naphthyridin-6-yl)ureaN 'N" J\O^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40 96 (R)-l-(l-(2-chloro-5- fluorophenoxy)-9-methyl-5,6- dihydroimidazo[l,2- a] [ 1,7]naphthyridin-6-yl)ureaj S yXAO^NHNH297 (S)- 1 -( 1 -((2-chloro-5 - fluorophenyl)aniino)-9-methyi- 5,6-dihydroimidazo[l,2- a] [ 1,7]naphthyridin-6-yl)urea)V ) / - I- - A K T- 98 (R)-l-(l-((2-chloro-5- fluorophenyl)aniino)-9-methyi- 5,6-dihydroimidazo[l,2- a] [ 1,7]naphthyridin-6-yl)urea99 (S)-l-(8-chloro-9- (difluoromethoxy)-6-fluoro- 1 - methyl-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)ureaMF-364282035Attorney Docket No.: 18407-20028.40100 (R)-l-(8-chloro-9- (difluoromethoxy)-6-fluoro- 1 - methyl -4, 5-dihydroimidazo[ 1.2- a] quinol in-4-yl)urea" H o o - > > -, >QQ—x r~A A Z Vt- — \ / g Z / \ LE / i / A N>' A — - re101 t X1 xA A j o ooozz-—-—\T / / | / / I “Hm \ \ r» (S)-l-(8-chloro-9-((Ll,l,3,3,3-w wZ o OX / X / Tj mco co hexafluoropropan-2-yl)oxy)- 1 - methyl-4,5-dihydroimidazo[l,2- a] quinoli n -4-yl)u rea102 (R)-l-(8-chloro-9-((l, 1,1,3, 3,3- hexafluoropropan-2-y l)oxy)- 1 - methyl -4, 5-dihydroimidazo[ 1,2- a] quinol in-4-yl)urea103 ci 'xy / (S)-l-(8-chloro-9- (isopropylamino)- 1 -methyl -4,5- dihydroimidazo [ 1,2-a] quinolin- 4-yl)ureaY^NO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40104 ci (R)-l-(8-chloro-9- (isopropylamino)- 1 -methyl -4, 5 - dihydroimidazo [ 1, 2-a] quinolin- 4-yl)ureaO^NHNH2105 F2HCO. (S)-l-(8-chloro-9-(5- o (difluoromethoxy)-2- Cl Y Ffluorophenoxy)- 1 -methyl -4,5- A- / Odihydroimidazo [ 1,2-a] quinolin- U / 4-yl)ureaO^ NHNH2106 F2HCO. (R)-l-(8-chloro-9-(5- (di fluoromethoxy) -2- cifl uorophenoxy ) - 1 -methyl -4,5 - dihydroimidazo [ 1,2-a] quinolin- CGf A 4-yl)ureaO^y^HNH2107 F2HCO^ > X- (S)- 1 -(8-chloro-9-(2-chloro-5- (di fluoromethoxy )phenoxy)- 1 - CI Y ’31methyl-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)ureai TXO^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40108 (R)-l-(8-chloro-9-(2-chloro-5- (difluoromethoxy)phenoxy)- 1 - Cl y^CImethyl -4, 5-dihydroimidazo[ 1.2- a] quinol in-4-yl)ureaTO^NHNH2109 CI Y (R) - 1 -( 8 -chloro-9-isopropoxy -1- methyl-4,5-dihydro- [ 1, 2,4]triazol o [4,3 -a] quinol in-4- 1 N yl)ureaM5^NO^NH z:\ INH2 / \ / l X °Z-110 / / A / \ — T: (S)- 1 -(8-chloro-9-isopropoxy- 1 - Q N= / \ °methyl-4,5-dihydro- [l,2,4]triazolo[4,3-a]quinolin-4- yl)urea111 F (S)-l-(8-chloro-9-(2,2- Cl difluoroethoxy)- 1 -methyl -4,5 - dihydroimidazo [ 1,2-a] quinolin- 4-yl)ureay^N\O^NHNH2MF-364282035Attorney Docket No.: 18407-20028.40112 F (R)-l-(8-chloro-9-(2,2- Cl difluoroethoxy)- 1 -methyl-4,5 - dihydroimidazo [ 1, 2-a] quinolin- 4-yl)ureaudNH2113 (R)-3-((5-amino-l,3,4- thi adi azol-2 -yl)amino) -8 -(2 - chloro-5-fluorophenoxy)-l,7- dimethy 1-3,4-dihydro- 1,6- naphthyridin-2( lH)-one114 ci (S)-l-(8-chloro-9- (i sopropylthio)- 1 -methyl-4,5 - dihydroimidazo [ 1,2-a] quinolin- l i > 4-yI)ureaO^NHNH2115 CI (R)-l-(8-chloro-9- (i sopropylthio)- 1 -methyl-4,5 - dihydroimidazo [ 1,2-a] q uinolin- 4-yl)ureaO^NHNH2

[0104] 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,68MF-364282035Attorney Docket No.: 18407-20028.40such 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 a compound depicted. For example,F F F / N-'N 'N-N Ci CI CI o N H n N n N n • L flJ fl U fl4 flo is O, O;ora 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 non-crystalline 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.

[0105] 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.

[0106] 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 ail salts and solvates of the compounds depicted here, as well as the non-salt 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.

[0107] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a 69MF-364282035Attorney Docket No.: 18407-20028.40compound 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.

[0108] Any variation or embodiment of m, n, p, q, A1, A2, A3, B, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, X1, X2, Y, Z, R3, R4, R5, R6, R7, R9, Ri0, Ra, Rw, Rx, R\ and ring A provided herein can be combined with every other variation or embodiment of m, n, p, q, A1, A2, A3, B, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, X1, X2, Y, Z, R3, R4, R5, R6, R7, R9, Ri0, Ra, Rw, Rx, R\ and ring A, as if each combination had been individually and specifically described.

[0109] 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.III. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

[0110] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0111] 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.

[0112] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0113] 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.70MF-364282035Attorney Docket No.: 18407-20028.40

[0114] 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) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.71MF-364282035Attorney Docket No.: 18407-20028.40

[0115] 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.

[0116] 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.

[0117] A compound detailed herein, or a pharmaceutically acceptable salt thereof, can be used in 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-wetting 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. Suitable formulations can be found, e.g., in Remington’s72MF-364282035Attorney Docket No.: 18407-20028.40Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.

[0118] A compound detailed herein, or a pharmaceutically acceptable salt thereof, may be 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.

[0119] 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 nig tablet.

[0120] 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.

[0121] 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 )73MF-364282035Attorney Docket No.: 18407-20028.40concurrent delivery, through the same route of delivery (e.g, tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery', or 3) delivery on different days, through the same route or different routes of delivery'.IV. METHODS OF USE

[0122] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of Formula (A), such as a compound of Formula (B’), (B), (I), (I-A), (I-Al), (C), (II), (II-A), (II-A1), (II-A1), (II-B), (II-B 1), (I-S I), (I-S2), (II-S 1), (II-S2), 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.

[0123] 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.

[0124] 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.74MF-364282035Attorney Docket No.: 18407-20028.40V. DOSING AND ADMINISTRATION

[0125] 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 as type 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.

[0126] 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.

[0127] 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.

[0128] 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 KITS

[0129] 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 in 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.75MF-364282035Attorney Docket No.: 18407-20028.40

[0130] 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 the treatment of Grave’s disease, Grave’s ophthalmology (GO) / thyroid eye disease (TED), a non-autoimmune thyroid disease, and / or thyroid cancer.

[0131] 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.

[0132] 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.

[0133] 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 instructi ons for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0134] 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.76MF-364282035Attorney Docket No.: 18407-20028.40VIII. GENERAL SYNTHETIC METHODS

[0135] 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.

[0136] 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).

[0137] 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, andE. L. Eliel and S. H. Wilen,” Stereochemistry of Organic Compounds’, Wiley-Interscience, 1994).

[0138] 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 known77MF-364282035Attorney Docket No.: 18407-20028.40structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures.

[0139] Compounds of Formula (A), such as compounds of Formula (B!), Formula (B), Formula (C), Formula (I), Formula (II), Formula (III), or Formula (IV), can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, and Scheme F, wherein m, n, p, A1, A2, A3, B1, B2, B3, B4, B5, W1, W2, W3, W4, W5, X1, X2, R5, R6, R7, R9, Raand ring A are as defined for Formula (A), or any applicable variation or subformulae thereof as detailed herein.Scheme AB2B4B5RAR^

[0140] As shown in Scheme A, wherein RAis H or a leaving group; and t is 0 or 1, compounds of formula A-a are coupled with compounds of formula A-b, in the presence of a base such as K2CO3 to give compounds of formula A-c.MF-364282035Attorney Docket No.: 18407-20028.40Scheme B

[0141] As shown in Scheme B, wherein RAis a leaving group; t is 0 or 1; and PG is a protecting group (such as Boc), compounds of formula A-c are cyclized with compounds of formula B-a, over one or more steps, to provide ketones of formula B-b. Ketones of formula B-b are converted to thiones of formula B-c by reacting with a thionating reagent (such as P2S5).Scheme C

[0142] As shown in Scheme C, wherein RAis a leaving group; t is 0 or 1; and PG is a protecting group (such as Boc), compounds of formula B-c are coupled with compounds of formula C-a, to give compounds of formula C-b. Compounds of formula C-b are cyclized over one or more steps, to provide compounds of formula C-c.79MF-364282035Attorney Docket No.: 18407-20028.40Scheme D^^2 - D-bD-a D-c

[0143] As shown in Scheme D, wherein RAis H or a leaving group; compounds of formula D-a are coupled with compounds of formula D-b, in the presence of a base such as DIEA to give compounds of formula D-c.Scheme EE-b

[0144] As shown in Scheme E, wherein RAis H or a leaving group; compounds of formula E-a are coupled with compounds of formula E-b, in the presence of a base such as DIEA to give compounds of formula E-c.80MF-364282035Attorney Docket No.: 18407-20028.40Scheme F

[0145] As shown in Scheme C, wherein RAis a leaving group; t is 0 or 1; and PG is a protecting group (such as Boc), compounds of formula F-a are coupled with compounds of formula F-b, to give compounds of formula F-c. Compounds of formula F-c are cyclized over one or more steps, to provide compounds of formula F-d.ENUMERATED EMBODIMENTS

[0146] The following enumerated embodiments are representative of some aspects of the invention.Embodiment 1, A compound of Formula (B) or (C):or a pharmaceutically acceptable salt thereof, wherein:B is optionally substituted Ce-ioaryl, optionally substituted Ci^alkyl, optionally substituted Cnehaloalkyl, optionally substituted Ca-scycloalkyl, optionally substituted Cs-shaolcycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl;MF-364282035Attorney Docket No.: 18407-20028.40zrepresents a single or double bond;X1is optionally substituted 5-6 membered heteroaryl;is optionally substituted 5-6 membered heteroaryl or -C(0)NHRa, wherein Rais H, optionally substituted Ci-6alkyl, or optionally substituted Ci-shaloalkyl;is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)~, wherein Rbis H or optionally substituted Cnealkyl;q is 0, 1, or 2;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci-ealkyl, optionally substituted Ci^alkoxy, optionally substituted Ci-ehaloalkyl, optionally substituted Ci-ehaloalkoxyl, optionally substituted -O-C3- ocycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, optionally substituted -NH(Ci-6alkyl), optionally substituted -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted -NH-C -6cycloalkyl, optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3- ecycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl;either W1and W2are both -C-, or one of W1and W2is -C- and the other of Wland W2is -N-;W3is -CRy-, -NH-, or -N-, wherein Ryis independently at each occurrence H,halogen, optionally substituted Cu-salkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted Cs-ehaol cycloalkyl or optionally substituted 4-8 membered heterocycloalkyl;82MF-364282035Attorney Docket No.: 18407-20028.40W4and W3are each independently -CH-, -NH-, or -N-;R3and R4are each independently H, deuterium, optionally substituted Ci-ealkyl, optionally substituted Ci-6haloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 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 4-8 membered heterocycloalkyl;R5and R° are each independently H, deuterium, optionally substituted Cnealkyl, optionally substituted Cnehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-scycloalkyl, or optionally substituted 4-8 membered heterocyclyl;R7is H, deuterium, optionally substituted Cuealkyl, or optionally substituted Ci- ehaloalkyl; andR9is optionally substituted Ci-6alkyl, optionally substituted Ci-dhaloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted Cs-ehalocycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl.Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:B is optionally substituted Ce-ioaryl, Cnsalkyl, Ci-dhaloalkyl, C3-6cycloalkyl, C3- ehaolcycloalkyl, 4-8 membered heterocycloalkyl, or 5-10 membered heteroaryl;X1is optionally substituted 5-6 membered heteroaryl;X2is 5-6 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or Ci-ehaloalkyl;83MF-364282035Attorney Docket No.: 18407-20028.40Y is -0-, -C(R3)(R4)-, -C(F)2-, -C(0)-, -S(0)q-, or -N(Rb)-, wherein Rbis H or Ci- 6alkyl;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, Cnealkyl, Cuealkoxy, Cn ehaloalkyl, optionally substituted Cnehaloalkoxyl, -O-C -ecycloalkyl, - S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, -NH(Ci-6alkyl), -N(Cn 6alkyl)(Ci-6alkyl -NH-C3-6cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl, C3-6cycloalkyl, or 4-8 membered heterocycloalkyl;W3is -CRy-, -NH-, or -N-, wherein Ryis independently at each occurrence H, Ci- 6alkyl, Ci-ehaloalkyl, C3-6Cycloalkyl, C3-6haolcycloalkyl or 4-8 membered heterocycloalkyl;R3and R4are each independently H, deuterium, optionally substituted Cnealkyl, Ci- ehaloalkyl, C3-6cycloalkyl, or 4-8 membered heterocycloalkyl, orR3and R4are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 4-8 membered heterocycloalkyl;R5and R6are each independently H, deuterium, Ci-salkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, or 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form C3- scycloalkyl, or 4-8 membered heterocyclyl;R7is H, deuterium, Cnealkyl, or Ci-ehaloalkyl; andR9is Cnoalkyl, Ci-ehaloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, or 4-8 membered heterocycloalkyl.Embodiment 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (B):84MF-364282035Attorney Docket No.: 18407-20028.40or a pharmaceutically acceptable salt thereof.Embodiment 4. The compound of any one of embodiment 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I) or (III):or a pharmaceutically acceptable salt thereof, whereinB1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl Ci-ealkoxy, Ci- ehaloalkyl, Ci-6haloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C'3-6cycloalkyl), - NH2, -NH(Ci-6alkyl), -N(Ci^alkyl)(Ci-6alkyl), Ce-ioaryl, 5-10 membered heteroaryl, Cs-scycloalkyl, Cs-shaolcycloalkyl, or 4-8 membered heterocycloalkyl; andR10is Ci-ealkyLEmbodiment 5. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein:MF-364282035Attorney Docket No.: 18407-20028.40X1is 5-6 membered heteroaryl optionally substituted with one or more -NH2, - NH(Ci-6alkyl), or N(Ci-6alkyl)2;Embodiment 6. The compound of any one of embodiments 1-5, or a pharmaceuticallyacceptable salt thereof, wherein X1isEmbodiment 7. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (C):or a pharmaceutically acceptable salt thereof.Embodiment 8. The compound of any one of embodiments 1, 2, and 7, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II) or (IV):(IV), or a pharmaceutically acceptable salt thereof, wherein86MF-364282035Attorney Docket No.: 18407-20028.40B1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl Cnealkoxy, Cn ohaloalkyl, Ci-ehaloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), - NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)(Ci-6alkyl), Ce-ioaryl, 5-10 membered heteroaryl, C3-6cycloalkyl, Cs-ehaolcycloalkyl, or 4-8 membered heterocycloalkyl; andR10is Ci-6alkylEmbodiment 9. The compound of any one of embodiments 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is optionally substituted 5-6 membered heteroaryl.Embodiment 10. The compound of any one of embodiments 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is -C(O)NHRaand Rais H or optionally substituted Cnealkyl.Embodiment 11. The compound of any one of embodiments 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is -C(O)NHRaand Rais H, methyl, or ethyl.Embodiment 12. The compound of any one of embodiments 1, 2, and 7-11, or a,,-W3W2" '\An.w4.wk- ' wzpharmaceutically acceptable salt thereof, wherein the moiety represented by5isEmbodiment 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein Y is -O-.Embodiment 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof wherein each of A1, A2, and A3is -CRW~.MF-364282035Attorney Docket No.: 18407-20028.40Embodiment 15. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or Ci^alkyl.Embodiment 16. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H or methyl.Embodiment 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H.Embodiment 18. The compound of any one of embodiments 1-16, or a pharmaceuticallyEmbodiment 19. The compound of any one of embodiments 1-18, or a pharmaceutically B1=B2I / Xacceptable salt thereof, wherein B is B5-B4,anc|each of B1, B2, BJ, B4, and B5is -CRX-.Embodiment 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein B is phenyl optionally substituted with one or more halogen.Embodiment 21. The compound of any one of embodiments 1-20, or a pharmaceuticallyacceptable salt thereof, whereinB isEmbodiment 22. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein B is Ri0, and R10is isopropyl.88MF-364282035Attorney Docket No.: 18407-20028.40Embodiment 23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein R5and Rbare each HEmbodiment 24. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein R7is H.Embodiment 25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R9is Ci-6alkyl.Embodiment 26. The compound of any of embodiments 1-25, or a pharmaceutically acceptbale salt thereof, wherein R9is methyl.Embodiment 27. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof wherein:B1„g2FX\Z / b3B is B5B4or Ci-ealkyl;X1is optionally substituted 5-6 membered heteroaryl;X2is -C(O)NHRa, wherein Rais H or optionally substituted Cnealkyl;Y is -O-;A1, A2, and A3are each independently -CRW-, wherein Rwis independently at each occurrence H, halogen, or optionally substituted Ci-salkyl;B1, B2, B3, B4and B5are each independently -CRX-, wherein Rxis independently at each occurrence H or halogen;W1and W2are each independently -C- or -N-;W3, W4, and W5are each independently -CH- or -N-;R5and R6are each H;89MF-364282035Attorney Docket No.: 18407-20028.40R7is H; andR9is optionally substituted Ci-ealkyl.Embodiment 28. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:90MF-364282035Attorney Docket No.: 18407-20028.40F FFMF-364282035Attorney Docket No.: 18407-20028.40andNH2Embodiment 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-S 1),(II-S 1), (III-S1), or (IV-S1):(II-S1),Embodiment 30. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-S2),(II-S2), (III-S2), or (IV-S2):92MF-364282035Attorney Docket No.: 18407-20028.40Embodiment 31. A pharmaceutical composition comprising the compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.Embodiment 32. 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 1-30, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 31.Embodiment 33. 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 1-30, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 31.MF-364282035Attorney Docket No.: 18407-20028.40Embodiment 34. The method of embodiment 33, 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.Embodiment 35. The method of embodiment 33 or 34, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease, Grave’s ophthalmology and thyroid eye disease.Embodiment 36. The method of any one of embodiments 33-35, wherein the disease, disorder, or condition is Grave’s disease.EXAMPLES

[0147] 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.

[0148] Abbreviations used in the Examples include the following: ACN: acetonitrile; CMBP: cyanomethylenetributylphosphorane; DCM. di chi orom ethan e; DIEA: diisopropylethylamine; DMF: dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol;1H NMR: proton nuclear magnetic resonance; HATU: hexafluorophosphate azabenzotriazole tetramethyl uronium; 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; TF A trifluoroacetic acid; and THF: tetrahydrofuran.IX. SYNTHETIC EXAMPLESExample 1: l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinoUn-4-yl)urea (Compound I)Step 1: Synthesis of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinoIin-3-yI)carbamate94MF-364282035Attorney Docket No.: 18407-20028.40

[0149] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (2.0 g, 4.73 mmol) in EtOH (40.0 mL) was added 2,2- dimethoxyethan-1 -amine (1.9 g, 17.60 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue 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 reduced pressure. The residue purified by flash column chromatography with petroleum ether / ethyl acetate (60 / 40, v / v) to afford tert-butyl (8-(2- chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)- 1,2,3, 4-tetrahydroquinolin-3-yl)carbamate (296.3 mg, 12%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 494.2.Step 2: Synthesis of tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamateTsOH, toluene

[0150] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (253,5 mg, 0.51 mmol) in toluene (30.0 mL) was added TsOH (17.8 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 1 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 (63 / 37, v / v) to afford tert-butyl (9-(2-chloro-5-95MF-364282035Attorney Docket No.: 18407-20028.40fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (183.9 mg, 83%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=430.1.Step 3: Synthesis of 9-(2-chIoro-5-fIuorophenoxy)-4,5-dihydroimidazo[l,2-a]quinoIin-4-amine

[0151] To a solution of tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (163.9 mg, 0.38 mmol) in 1,4-dioxane (2.0 mL) was added conc. HCl (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with saturated 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 vacuum to afford 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (153.9 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 330.1.Step 4: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yi)urea (Compound 1)Compound 1

[0152] To a mixture of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (139.6 mg, 0.42 mmol) and isocyanatotrimethylsilane (103.2 mg, 0.90 mmol) in THF (5.0 niL) was added TEA (181.4 mg, 1.80 mmol) at room temperature. The resulting mixture was 96MF-364282035Attorney Docket No.: 18407-20028.40stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions:(Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 52% B to 62% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 1) (29.2 mg, 18%) as a white solid. LCMS (ESI, m / z): [M+H]+=373.1. 'HNMR (400 MHz, DMSO-d6): 67.79 (d, J= 1.2 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.33 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 7.15 - 7.10 (m, 1H), 7.04 - 6.98 (m, 3H), 6.54 (d,.7 = 7.2 Hz, 1H), 5.68 (s, 2H), 5.02 - 4.99 (m, 1H), 3.31 - 3.27 (m, 1H), 2.99 - 2.92 (m, 1H).Example 2: Synthesis of 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo [4,3-a] quinolin-4-yl) urea (Compound 2)Step 1: Synthesis of l-bromo-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene

[0153] To a mixture of l-bromo-3-fluoro-2 -nitrobenzene (40.7 g, 185.00 mmol) and 2-chl oro-5 -fluorophenol (29.9 g, 204.02 mmol) in DMF (500.0 mL) were added K2CO3 (51.1 g, 369.74 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-bromo-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene (80.5 g, crude) as a pink solid.Step 2: Synthesis of 2-bromo-6-(2-chIoro-5-fluorophenoxy) aniline97MF-364282035Attorney Docket No.: 18407-20028.40

[0154] To a solution of l-bromo-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene (80.5 g, crude) in ethanol (1.0 L) and H2O (200.0 mL) were added Fe (103.9 g, 1860.50 mmol) and ammonium chloride (146.4 g, 2736.96 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate. The 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 dichloromethane / petroleum ether (90 / 10, v / v) to afford 2-bromo-6-(2-chloro-5-fluorophenoxy) aniline (55.8 g, 75%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 315.9.Step 3: Synthesis of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl) carbarn ate

[0155] To a solution of methyl 2-((tert-butoxy carbonyl) amino)-3-iodopropanoate (16.1 g, 48.91 mmol) in DMF (150.0 mL) was added Zinc (5.5 g, 84.12 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. Then a solution of 2-bromo-6-(2-chloro-5-fluorophenoxy) aniline (10.3 g, 32.53 mmol) in DMF (150.0 mL), Pd(OAc)2 (803.6 mg, 3.57 mmol) and XPhos (3.1 g, 6,50 mmol) were added to the mixture. The resulting mixture was stirred at 40 °C for additional 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered, the 98MF-364282035Attorney Docket No.: 18407-20028.40filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl) carbamate (7.8 g, 80% purity, 58%) as a green oil. LCMS (ESI, m / z): [M+H]+= 407.1.Step 4: Synthesis of tert-butyl (8-(2-chloro-5-fIuorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl) carbamate

[0156] To a solution of Na2CO3(4.7 g, 44.34 mmol) in THF (100.0 ml.,) was added phosphorus pentasulfide (9.8 g, 44.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. Then tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl) carbamate (7.8 g, 19.17 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 70 °C for additional 16 h. After the reaction was completed, the resulting mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were 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 petroleum ether / ethyl acetate (80 / 20, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl) carbamate (5.4 g, 66%) as a green oil. LCMS (ESI, m / z): [M+H]+= 423.1.Step 5: Synthesis of tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3-a] quinolin-4-yl) carbamate99MF-364282035Attorney Docket No.: 18407-20028.40

[0157] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-1,2,3,4-tetrahydroquinolin-3-yl) carbamate (1.5 g, 3.54 mmol) in cyclohexanol (20.0 mL) and acetic acid (1.5 mL) was added formohydrazide (565.9 mg, 9.42 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature. 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) to afford tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3-a] quinolin-4-yl) carbamate (622.2 mg, 40%) as a white solid. LCMS (ESI, m / z): [M+H]+= 431.1.Step 6: Synthesis of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3~a] quinolin-4-amineHCI, dioxane

[0158] A solution of tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3-a] quinolin-4-yl) carbamate (300.9 mg, 0.69 mmol) in HCl / l,4-di oxane (3.5 mL, 4.0 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with saturated NaHCO₃ (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 vacuum to afford 9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3-a] quinolin-4-amine (201.4 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 331.1.100MF-364282035Attorney Docket No.: 18407-20028.40Step 7: 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo [4,3-a] quinolin-4-yl) urea (Compound 2)FTMSNCO, TEA, THFCompound 2

[0159] To a solution of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo[4,3-a] quinolin-4-amine (158.6 mg, crude) in THF (3.5 mL) was added isocyanatotrimethylsilane (110.2 mg, 0.95 mmol) and EtsN (193.5 mg, 1.91 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 dichloromethane / methanol (13 / 87, v / v) and then purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 25% B to 40% B in 15 min; Wave Length: 254 / 220 nm) to afford 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydro- [1,2,4] triazolo [4,3-a] quinolin-4-yl) urea (Compound 2) (16.7 mg, 9%) as a white solid. LCMS (ESI, m / z): [M+H]+- 374.1.1H NMR (400 MHz, DMSO-d6): 59.03 (s, IH), 7.75 - 7.71 (m, IH), 7.34 - 7.18 (m, 4H), 6.96 - 6.93 (m, IH), 6.71 (d, J = 7.6 Hz, IH), 5.73 (s, 2H), 5.24 (d, J = 4.4 Hz,lH), 3.31 - 3.28 (m, IH), 3.09 - 3.06 (m, IH).Example 3: Synthesis of 3-((l,3,4-oxadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 3)Step 1: Synthesis of ethyl 5-((8-(2-chIoro-5-fluorophenoxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-oxadiazole-2-carboxyIate101MF-364282035Attorney Docket No.: 18407-20028.40

[0160] To a solution of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (181.4 mg, 0.56 mmol) in dioxane (5.0 mL) was added ethyl 5-bromo-l,3,4-oxadiazole-2-carboxylate (150.0 mg, 0.67 mmol), TMSONa (126.8 mg, 1.13 mmol) and Pd-PEPPSI-IHeptCl 3 -chloropyridine (110.1 mg, 0.11 mmol ) at room temperature under N2. The resulting mixture was stirred at 100 °C 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 sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2CI2 / MeOH (20 / 1) to afford ethyl 5-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-oxadiazole-2-carboxylate (100.0 mg, 38%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 461.1.Step 2: Synthesis of 5-((8-(2-chloro-5-fluorophenoxy)-l-methyI-2-oxo-l, 2,3,4- tetrahydroquiiiolm-3-yl)amino)-l,3,4-oxadiazole-2-carboxyIic acid

[0161] To a solution of ethyl 5-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-oxadiazole-2-carboxylate (80.0 mg, 0.17 mmol) in THF (2.0 mL) / H20 (1.0 mL) was added LiOH (12.0 mg, 0.50 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to pH 7 with HQ (1.0 mol / L in H2O). The resulting 102MF-364282035Attorney Docket No.: 18407-20028.40mixture was diluted with H2O and extracted with CH2CI2 The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-oxadiazole-2-carboxylic acid (100.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 433.1.Step 3: 3-((1,3,4-oxadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 3)FCompound 3

[0162] A solution of 5-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l, 3, 4-oxadiazole-2 -carboxylic acid (80.0 mg, crude) in HC1 (2.0 mL, 1.0 moL / L. in H2O) was stirred at room temperature for 30 min. After the reaction was completed, the pH value of the mixture was adjusted to 7 with saturated NaHCO₃ (aq.). The resulting mixture was diluted with H2O and extracted with CII2CI2. 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 mL / min; Gradient: 5% B to 5% B in 2 min, 33% B to 55% B in 10 min; Wave Length: 254 / 220 nm) to afford 3-((1,3,4-oxadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 3) (16.7 mg, 23%) as a white solid. LCMS (ESI, m / z): [M+H]+= 389.1.1H NMR (400 MHz, DMSO-6 / 6): 5 8.55 (s, IH), 8.02 (d,. / 7.2 Hz, IH), 7.69 - 7.65 (m, IH), 7.23 (d, J 7.2 Hz, 1H), 7.18 - 7.14 (m, IH), 7.10 - 7.05 (m, IH), 6.95 - 6.89 (m, 2H), 4.40 - 4.36 (m, IH), 3.30 (s, 3H), 3.24 - 3.09 (m, 2H).103MF-364282035Attorney Docket No.: 18407-20028.40Example 4: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin- 4-yl)-3-methylurea (Compound 4)Step 1: l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)-3-methylurea (Compound 4)FCompound 4

[0163] To a solution of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-amine (174.2 mg, crude) in DCM (5.0 niL) was added N-methyl-lH-imidazole-l-carboxamide (79.3 mg, 0.63 mmol) and EtaN (159.8 mg, 1.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: YMC-Actus Triart C18 ExRS, 20x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 41% B to 51% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)-3-methylurea (Compound 4) (84.9 mg, 41%) as a white solid. LCMS (ESI, m / z): [M+H]’ =387.1. *HNMR (400.0 MHz, DMSO-tTs): 57.79 (s, 1H), 7.73 - 7.69 (m, 1H), 7.31 (d,.7 = 7.6 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.15 - 7.10 (m, 1H), 7.03 - 6.98 (m, 3H), 6.48 (d, J = 7.2 Hz, 1H), 5.96 - 5.94 (m, 1H), 5.06 - 5.00 (m, 1H), 3.27 - 3.23 (m, 1H), 2.99 - 2.93 (m, 1H), 2.59 (s, 3H)Example 5: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a] quinolin- 4-yl)-3-ethylurea (Compound 5)Step 2: 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a] quinolin-4-yl)-3-ethylurea (Compound 5)104MF-364282035Attorney Docket No.: 18407-20028.40FEt3N, THFCompound 5

[0164] To a solution of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a] quinolin-4- amine (166.4 mg, crude) in THF (10.0 mL) were added isocyanatoethane(71.7 mg, 1.00 mmol) and EtsN (203.7 mg, 2.01 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 mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column30x 150 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, 35% B to 55% B in 10 min; Wave Length: 254 / 220 nm) to afford 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)-3-ethylurea (Compound 5) (39.0 mg, 19%) as a white solid. LCMS (ESI, m / z): [M+H]’ = 401.2. 'HNMR (400 MHz, DMSO-dk): 67.79 (d, J= 1.6 Hz, IH), 7.71 - 7.68 (m, 1H), 7.31 - 7.25 (m, 2H), 7.15 - 7.10 (m, 1H), 7.03 - 6.98 (m, 3H), 6.40 (d, J= 7.2 Hz, IH), 6.05 (d, J= 7.2 Hz, IH). 5.06 - 5.01 (m, IH), 3.28 - 3.26 (m, IH), 3.07 - 3.03 (m, 2H), 2.96 - 2.92 (m, IH), 1.03 - 0.99 (m, 3H).Example 6: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 6)Step 1: Synthesis of 3-fIuoro-4-methyl-2-nitroanilineHC≡C-OHIXphos, Xphos Pd G3K2CO3, dioxane, H2O

[0165] To a mixture of 4-bromo-3-fluoro-2 -nitroaniline (20.0 g, 85.10 mmol) and methylboronic acid (25.5 g, 426.0 mmol) in 1,4-dioxane (200.0 mL) / H2O (40.0 mL) were added K2CO3 (35.3 g, 255.27 mmol), XPhos (8.1 g, 17.01 mmol) and XPhos Pd G3 (7.2 g, 8.51 mmol)105MF-364282035Attorney Docket No.: 18407-20028.40at room temperature under N2. The resulting mixture was stirred at 100 °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 ethyl acetate / petroleum ether (20 / 80, v / v) to afford 3-fluoro-4-methyl-2-nitroaniline (13.7 g, 95%) as an orange solid. LCMS (ESI, m / z): [M+H]+= 171.0.Step 2: Synthesis of l-bromo-3-fluoro-4-methyl-2-nitrobenzeneCuBr, t-BuONO, ACN1 T -NH2Br

[0166] To a solution of 3-fluoro-4-methyl-2-nitroaniline (13.7 g, 80.52 mmol) in MeCN (200.0 mL) was added CuBr (5.8 g, 40.26 mmol) and t-BuONO (12.5 g, 120.83 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 to afford 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (14.4 g, crude) as a brown oil.Step 3: Synthesis of 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene

[0167] To a mixture of l-bromo-3-fluoro-4-methyl-2-nitrobenzene (14.4 g, 61.53 mmol) and 2-chloro-5-fluorophenol (9.0 g, 61.53 mmol) in DMF (200.0 mL) were added K2CO3 (17.0 g, 123.01 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. After the 106MF-364282035Attorney Docket No.: 18407-20028.40reaction 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 CH2Q2 / petroleum ether (10 / 90, v / v) to afford 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (8.0 g, 36%) as an orange solid.Step 4: Synthesis of 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-methylanilineFe, NH4CIMeOH, H2O

[0168] To a solution of l-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (8.0 g, 22.19 mmol) in MeOH (100.0 mL) / H20 (20.0 mL) was added Fe (6.2 g, 110.94 mmol) and NH4CI (5.9 g, 110.94 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (60 / 40, v / v) to afford 6-bromo-2-(2-chloro-5-fluorophenoxy)-3 -methylaniline (6.2 g, 85%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 330.0.Step 5: Synthesis of tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate107MF-364282035Attorney Docket No.: 18407-20028.40

[0169] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.0 g, 12.15 mmol) in DMF (40.0 mL) was added Zinc (1.9 g, 29.06 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 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-methylaniline (4.0 g, 12.10 mmol) in DMF (10.0 mL), XPhos (576.8 mg, 1.21 mmol) and Pd(OAc)2 (64.4 nig, 0.61 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature 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 (80 / 20, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.0 g, 39%) as an orange oil. LCMS (ESI, m / z): [M+H]+::::421.1.Step 6: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-thioxo-1, 2,3,4- tetrahydroquinolin-3-yl)carbamateP2S5, Na2CO3, THF

[0170] To a solution of Na2CO3 (579.2 mg, 5.47 mmol) in THF (10.0 mL) was added P2S5(1.2 g, 5.47 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.0 g, 2.38 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 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 vacuum. The residue was purified by flash column chromatography with 108MF-364282035Attorney Docket No.: 18407-20028.40CHzCh / petroleum ether (50 / 50, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (700.0 nig, 67%) as a white solid. LCMS (ESI, m / z): [M+H]+= 437.1.Step 7: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-methyl-1,2,3,4-tetrahydroquinolin-3-yl)carbamate

[0171] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-methyl-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (400.0 mg, 0.92 mmol) in EtOH (5.0 mL) was added 2,2- dim ethoxy ethan-1 -amine (288.7 mg, 2.75 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 0.5 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 ethyl acetate / petroleum ether (68 / 32, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-methyl-1, 2,3, 4-tetrahydroquinolin-3-yl)carbamate (350.2 mg, 75%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 508.2.Step 8: Synthesis of Tert-butyl (9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamate109MF-364282035Attorney Docket No.: 18407-20028.40

[0172] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-methyl-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (300.0 mg, 0.59 mmol) in toluene (6.0 mL) was added TsOH (20.3 mg, 0.12 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 CHzCh / petroleum ether (50 / 50, v / v) to afford tert-butyl (9-(2-chloro-5- fluorophenoxy)-8-methyl-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamate (250.0 mg, 95%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 444.1.Step 9: Synthesis of 9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[1,2-a] quinolin-4-amineTFA DCM

[0173] To a solution of tert-butyl (9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (200.0 mg, 0.45 mmol) in DCM (4.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. / After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO₃ (aq.). The resulting mixture was extracted with ethyl acetate. The combined organicMF-364282035Attorney Docket No.: 18407-20028.40layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (160.2 mg, crude) as a colorless oil. LCMS (ESI, m / z):[M+H]+= 344.1.Step 2: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)iirea (Compound 6)TMSNCO, MeOHO^NHNH2Compound 6

[0174] To a solution of 9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (110.0 mg, 0.32 mmol) in methanol (5.0 mL) was added TMSNCO (36.9 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature 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 CH₂Cl₂ / MeOH (80 / 20, 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 (B%): 5% B to 5% B in 2 min, 33% B to 53% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(9-(2-chloro-5-fluorophenoxy)-8-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 6) (77.9 mg, 63%) as a white solid. LCMS (ESI, m / z): [M+H]+= 387.1. 'HNMR (400 MHz, DMSO- d6) 57.67 - 7.65 (m, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.26 (d, J= 7.6 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.55 (d, J = 7.2 Hz, 1H), 6.43 (s, 1H), 5.70 (s, 2H), 5.05 - 5.00 (m, 1H), 3.27 - 3.23 (m, 1H), 2.96 - 2.67 (m, 1H), 2.08 (s, 3H)MF-364282035Attorney Docket No.: 18407-20028.40Example 7: Synthesis of 3-((l, 3, 4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 7)Step 1: Synthesis of ethyl 5-((8-(2-chIoro-5-fluorophenoxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolm-3-yl)amino)-l,3,4-thiadiazole-2-carboxyIateDIEA, DMF

[0175] To a mixture of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (500,0 mg, 1.55 mmol) and ethyl 5-chloro-l,3,4-thiadiazole-2-carboxylate (390.3 mg, 2.02 mmol) in DMF (5.0 mL) was added DIEA (674.9 mg, 5.22 mmol) at room temperature under N2. The resulting mixture was stirred at 90°C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and then extracted with EtOAc. 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 / CH₃OH (12 / 1, v / v) to afford ethyl 5-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo- 1,2,3, 4-tetrahy droquinolin-3-yl)amino)-l,3,4-thiadiazole-2-carboxylate (351.0 mg, 47%) as a yellow solid. LCMS (ESI, m / z): [M+H]⁺ =477.2.Step 2: Synthesis of 3-((l,3,4-thiadiazol-2-yI)amino)-8-(2-chIoro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinoIin-2(lH)-one (Compound 7)Compound 7MF-364282035Attorney Docket No.: 18407-20028.40

[0176] To a solution of ethyl 5-{[8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-3,4-dihydroquinolin-3-yl]amino}-l,3,4-thiadiazole-2-carboxylate (300.0 mg, 0.63 mmol) in THF (5.0 mL) and H2O (1.0 mL) was added LiOH (45.1 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the pH value of the mixture was adjusted to 2.0 with HC1 (1.0 mol / L). The mixture was extracted with EtOAc. 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 Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 19 x 250 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeOH; Flow rate: 20 mL / min; Gradient (B%): 80% B to 90% B in 15min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(l,3,4-thiadiazol-2-ylamino)-3,4-dihydroquinolin-2-one (Compound 7) (37.6 mg, 14%) as a white solid. LCMS (ESI, m / z): [M+H]+=405.1. 'HNMR (400 MHz, DMSO-d₆): 5 8.68 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.25 (d, J --7.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.10 - 7.05 (m, 1H), 6.96 - 6.89 (m, 2H), 4.62 - 4.58 (m, 1H), 3.43 - 3.38 (m, 1H), 3.32 (s, 3H), 3.05 - 2.95 (m, 1H).Example 8: Synthesis of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(lH)-one (Compound 8)Step 1: 8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-(pyrimidin-2-yIamino)-3,4-dihydroquino!in-2(lH)~one (Compound 8)NaHCO3, THF, H2O

[0177] To a solution of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (100.0 mg, 0.31 mmol) in THF (2.0 niL) / H2O (0.5 mL) was added 2-chloropyrimidine (40.0 mg, 0.35 mmol) and NaHCOs (130.0 mg, 1.55 mmol) at room113MF-364282035Attorney Docket No.: 18407-20028.40temperature. The resulting mixture was stirred at 100 °C 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 Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD Cl 8 Column 30 x 150 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, 45% B to 65% B in 10 min; wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l -methyl -3-(pyrimidin-2-ylamino)-3, 4-dihydroquinolin- 2(lH)-one (Compound 8) (9.5 mg, 8%) as a white solid. LCMS (ESI, m / z): [M+H]+= 399.1. *H NMR (400 MHz, DMSO-d6): 68.31 (d, J = 4.4 Hz, 2H), 7.69 - 7.65 (m, 1H), 7.23 - 7.06 (m, 4H), 6.93 - 6.90 (m, 2H), 6.67 - 6.65 (m, 1H), 4.70 - 4.63 (m, 1H), 3.30 (s, 3H), 3.14 - 3.11 (m, 2H).Example 9: Synthesis of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 9)Step 1: 8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinoIin-2-one (Compound 9)CAS: 1612891-29-8,t-BuONa, dioxane

[0178] To a solution of 3-amino-8-(2-chloro-5-fluorophenoxy)-l -methyl-3,4-dihydroquinolin-2-one (213.0 mg, 0.66 mmol) in dioxane (5.0 mL) was added 3-chloropyridazine (127.8 mg, 1.12 mmol), t-BuONa (127.6 mg, 1.33 mmol) and (SP-4-l)-[l,3-BIs[2,6-bis(l -ethylpropyl )phenyl]-4,5-di chi oro-1, 3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (55.8 mg, 0.07 mmol) at room temperature under N2. The resulting114MF-364282035Attorney Docket No.: 18407-20028.40mixture was stirred at 100 °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 Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (30 / 70, 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, 36% B to 56% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5- fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 9) (40.2 mg, 15%) as an off-white solid. LCMS (ESI, m / z): [M+Hf = 399.1. *HNMR (400 MHz, CD3OD): 38.47 - 8.45 (m, 1H), 7.58 - 7.54 (m, 1H), 7.39 - 7.35 (m, 1H), 7.24 - 7.18 (m, 2H), 7.12 - 7.09 (m, 1H), 6.96 - 6.90 (m, 2H), 6.69 - 6.65 (m, 1H), 4.86 - 4.80 (m, 1H), 3.45 (s, 3H), 3.44 - 3.40 (m, 1H), 3.07 - 3.00 (m, 1H).Example 10: Synthesis of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-3-ylamino)-3,4- dihydroquinolin-2-one (Compound 10)Step 1: 8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-(pyridin-3-yIamino)-3,4-dihydroquinoIin- 2-one (Compound 10)Compound 10

[0179] To a solution of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (96.8 mg, 0.30 mmol) in dioxane (8.0 mL) was added 3 -bromopyridine (51.3 mg, 0.33 mmol), Pd-PEPPSI-IHeptCl 3 -chloropyridine (CAS: 1814936-54-3) (29.9 mg, 0.03 mmol) and sodium trimethylsilanolate (69.2 mg, 0.62 mmol) at room temperature under N2.115MF-364282035Attorney Docket No.: 18407-20028.40The resulting mixture was stirred at 100 °C for 6 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature. The mixture 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 (73 / 27, 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 (B%): 5% B to 5% B in 2 min, 42% B to 62% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 10) (14.2 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H]+= 398.1.fH NMR (400 MHz, DMSO-de): 58.09 (d, J= 1.2 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.68 - 7.64 (m, 1H), 7.28 (d, J= 7.2 Hz, 1H), 7.20 - 7.16 (m, 1H), 7.09 - 7.02 (m, 3H), 6,98 (d, J --- 8.0 Hz, 1H), 6.89 - 6.85 (m, 1H), 6.09 (d, J = 7.2 Hz, 1H), 4.39 - 4.33 (m, 1H).3.27 (s, 3H), 3.23 - 3.18 (m, 1H), 3.01 - 2.94 (m, 1H).MF-364282035Attorney Docket No.: 18407-20028.40Example 11: Synthesis of (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 11) and (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 12)Step 1: Synthesis of (3R)-8-(2-chloro-5-fIuorophenoxy)-l-methyI-3-(pyridazin-3-ylamino)- 3,4-dihydroquinoIin-2-one (Compound II) and (3S)-8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-yIamino)-3,4-dihydroquinoIin-2-one (Compound 12)Chiral-HPLCCompound 9 Compound 11 Compound 12

[0180] The racemic product of 8-(2-chloro-5-fluorophenoxy)-l -methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (37.6 mg, 0.09 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2MNH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 30% B to 30% B in 20min; Wave Length: 220 / 254 nm; RTl(min): 8.54;RT2(min): 14.87) to afford (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (assumed, 14.0 mg, 37%) as a white solid and (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (assumed, 14.0 mg, 37%) as a white solid.(3R)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3-(pyridazin-3-ylamino)-3,4-dihydroquinolin-2-one (Compound 11): RTl(min): 8.54; LCMS (ESI, m / z): [M+H]+= 399.1.lHNMR (400 MHz, DMSO-de): 58.49 - 8.47 (m, IH), 7.70 - 7.66 (m, IH), 7.32 - 7.24 (m, 2H), 7.20 - 7.15 (m, 2H), 7.10 - 7.05 (m, 2H), 6.96 - 6.90 (m, 2H), 4.88 - 4.82 (m, IH), 3.36 - 3.31 (m, 4H), 3.01 - 2.94 (m, IH).117MF-364282035Attorney Docket No.: 18407-20028.40

[0181] (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridazm-3-ylamino)-3,4- dihydroquinoIin-2-one (Compound 12): RT2(min): 14.87; LCMS (ESI, m / z): [M+H]+= 399.1. fll NMR (400 MHz, DMSO-d6): 58.49 - 8.47 (m, 1H), 7.69 - 7.66 (m, III), 7.31 - 7.24 (m, 2H), 7.19 - 7.14 (m, 2H), 7.10 - 7.05 (m, 2H), 6.96 - 6.90 (m, 2H), 4.88 - 4.82 (m, 1H), 3.36 - 3.31 (m, 4H), 3.01 - 2.94 (m, 1H).Example 12: Synthesis of 3-((5-amino-l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3)4-dihydroquinolin-2(lH)-one (Compound 13)Step 1: Synthesis of 3-((5-amino-l,3,4-thiadiazol-2-yI)amino)-8-(2-chIoro-5-fluorophenoxy)- l-methyI-3,4-dihydroquinolin-2(lH)-one (Compound 13)NaHCO3, EtOHCompound 13

[0182] To a mixture of 3-amino-8-(2-chloro-5-fluorophenoxy)-l -methyl-3,4- dihydroquinolin-2(lH)-one (300 mg, 0.93 mmol) and 5-chloro-1,3,4-thiadiazol-2-amine (336.7 mg, 1.87 mmol) in EtOH (3.0 mL) was added NaHCO₃ (235.7 mg, 2.80 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed. The resulting mixture was diluted with water and extracted with EtOAc. 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 30 x 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 33% B to 53% B in 10 min; Wave Length: 254 / 220 nm) to afford 3 -((5-ami no- 1,3,4-thiadiazol-2-yl)amino)-8-(2-chl oro- 5 -fluorophenoxy)- 1 -methyl -3,4- dihydroquinolin-2(lH)-one (Compound 13) (48.8 mg, 12%) as a white solid. LCMS (ESI, m / z):[M+H]+= 420.1.1H NMR (400 MHz, DMSO-de): 57.69 - 7.65 (m, 1H), 7.24 - 7.21 (m, 2H),118MF-364282035Attorney Docket No.: 18407-20028.407.18 - 7.14 (m, 1H), 7.10 - 7.05 (m, 1H), 6.95 - 6.86 (m, 2H), 6.30 (s, 2H), 4.45 - 4.39 (m, 1H), 3.38 - 3.34 (m, 1H), 3.26 (s, 3H), 2.94 - 2.86 (m, 1H).Example 13: Synthesis of (R)-3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 14) and (S)-3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 15)Step 1: (R)-3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fIuorophenoxy)-l-methyI-3,4-dihydroquino!in-2(lH)-one (Compound 14) and (S)-3-((l,3.4-thiadiazoI-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(l H)-one (Compound 15)Chiral-HPLCCompound 7 Compound 14 Compound 15

[0183] The product of 3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (37.0 mg, 0.091 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRALPAK IG-3; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH), Mobile Phase B: MeOH: DCM=1:1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 40% B to 40% B in 12.5 min; Wave Length: 220 / 254 nm; RTl(min): 6.998; RT2 (min): 10.996) to afford (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(l,3,4-thiadiazol-2-ylamino)-3,4-dihydroquinolin-2-one (assumed, 5.2 mg, 19%) as a white solid and (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(l,3,4-thiadiazol-2-ylamino)-3,4-dihydroquinolin-2-one (assumed, 8.1 mg, 30%) as a white solid.

[0184] (R)-3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3,4-dihydroquinolin-2(lH)-one (Compound 14): RTl(min): 6.998; LCMS (ESI, m / z): [M+H]+= 405.0. 'HNMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.21 (d, J= 6.4 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.19 - 7.15 (tn, 1H), 7.10 - 7.05 (m, 1H), 6.95 - 6.89 (m, 2H), 4.63 - 4.57 (m, 1H), 3.39 - 3.36 (m, 1H), 3.31 (s, 3H), 3.03 - 2.98 (m, 1H).MF-364282035Attorney Docket No.: 18407-20028.40

[0185] (S)-3-((l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3,4-dihydroquinoIin-2(lH)~one (Compound 15): RT2 (min): 10.996; LCMS (ESI, m / z): [M+H] = 405.0. ^INMR (400 MHz, DMSO-d6): δ 8.68 (s, 1 H), 8.21 (d, J -- 6.4 Hz, 1 H), 7.69 - 7.65 (m, 1H), 7.25 (d, J= 7.6 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.09 - 7.04 (m, 1H), 6.95 - 6.89 (m, 2H), 4.63 - 4.56 (m, 1H), 3.41 - 3.37 (m, 1H), 3.31 (s, 3H), 3.03 - 2.98 (m, 1H).Example 14: Synthesis of l-(7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 16)Step 1: l-bromo-5-chloro-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene

[0186] To a mixture of l-bromo-5-chloro-3-fluoro-2-nitrobenzene (9.4 g, 36.94 mmol) and 2-chloro-5-fluorophenol (5.4 g, 36.85 mmol) in DMF (100.0 mL) was added K2CO3 (10.2 g, 73.81 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with water 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 (91 / 9, v / v) to afford l-bromo-5-chloro-3-(2-chloro-5-fluorophenoxy)-2 -nitrobenzene (13.8 g, 98%, 70% purity) as a black solid.Step 2: 2-bromo-4-chloro-6-(2-chloro-5-fluorophenoxy)aniIineFe, NH4CI EtOH, H2O

[0187] To a solution of 1 -bromo-5-chl oro-3 -(2-chloro-5-fluorophenoxy)-2-nitrobenzene (13.8 g, 36.22 mmol ) in EtOH (150.0 mL) and H2O (150.0 mL) was added Fe (16.1 g, 288.30120MF-364282035Attorney Docket No.: 18407-20028.40mmol) and ammonium chloride (23.2 g, 433.73 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water at room temperature. 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 2-bromo-4-chloro-6-(2-chloro-5-fluorophenoxy)aniline (12.6 g, crude) as a black oil. LCMS (ESI, m / z): [M+H]+=350.1.Step 3: tert-butyl (6-chIoro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate3) CS2CO3

[0188] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (17.5 g, 53.17 mmol) in DMF (100.0 mL) was added Zinc (6.0 g, 91.77 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h under N2. Then a solution of 2-bromo-4-chloro-6-(2-chloro-5-fluorophenoxy)aniline (12.5 g, crude) in DMF (100.0 mL), Pd(OAc)2 (0.8 g, 3.56 mmol) and XPhos (3.4 g, 7.13 mmol) were added to the mixture at room temperature. The resulting mixture was stirred at 40 °C for additional 16 h under N2. Then CS2CO3 (34.8 g, 106.81 mmol) was added to the mixture at 80 °C. The resulting mixture was stirred at 80 °C for additional 2 h under N2. After the reaction was completed, the resulting mixture 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 reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (84 / 16, v / v) to afford tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (11.8 g, 75%) as a brown solid. LCMS (ESI, m / z): [M+H]+=441.1.121MF-364282035Attorney Docket No.: 18407-20028.40Step 4: tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate

[0189] To a solution of Na2CO3(6.6 g, 62.27 mmol) in THF (150.0 mL) was added phosphorus pentasulfide (12.3 g, 55.34 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. Then tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (11.3 g, 25.61 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 70 °C for additional 16 h. After the reaction was completed, the resulting mixture 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 reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (82 / 18, v / v) to afford tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.6 g, 47%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=457.1.Step 5: 1 tert-butyl (6-chloro-8-(2-chloro-5-fIuorophenoxy)-2-((2,2-diinethoxyethyI)iinino)- l,2,3,4-tetrahydroquino!in-3-yI)carbamate

[0190] To a solution of tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate (5.5 g, 12.03 mmol) in EtOH (100.0 mL) was added 2,2- dimethoxyethan-1 -amine (3.9 g, 37.09 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum 122MF-364282035Attorney Docket No.: 18407-20028.40ether / ethyl acetate (76 / 24, v / v) to afford tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.4 g, 84%) as a white solid. LCMS (ESI, m / z): [M+H]+= 528.1.Step 6: tert-butyl (7-chIoro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)carbamate

[0191] To a solution of tert-butyl (6-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.0 g, 9.46 mmol) in toluene (20.0 mL) was added p-toluenesulfonic acid monohydrate (520.1 mg, 2.73 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 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 (78 / 22, v / v) to afford tert-butyl (7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroiniidazo[l,2-a]quinolin-4-yl)carbamate (3.2 g, 72%) as a white solid. LCMS (ESI, m / z): [M+H]+= 464.1.Step 7: 7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinoIin-4-amine

[0192] A solution of tert-butyl (7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (3.1 g, 6.68 mmol) in HCl / dioxane (30.0 mL, 4.0 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with saturated NaHCO₃ (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium123MF-364282035Attorney Docket No.: 18407-20028.40sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (2.8 g, crude) as a yellow solid. LCMS (ESI, m / z): [MH H j ===364.1.Step 8: l-(7-chIoro-9-(2-chIoro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 16)Compound 16

[0193] To a solution of 7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (388.5 mg, crude) in methanol (10.0 mL) was added isocyanatotrimethylsilane (491.5 mg, 4.27 mmol) and Et3N (427.4 mg, 4.22 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture 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 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 mL / min; Gradient: 5% B to 5% B in 2 min, 42% B to 62% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(7-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 16) (67.5 mg, 15%) as a white solid. LCMS (ESI, m / z): [M+H];=407.0. ’H NMR (400 MHz, DMSO- &): 5 7.77 (d, J= 1.2 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.19 - 7.15 (m, 2H), 7.07 - 7.04 (m, 2H), 6.56 (d,. / = 7.2 Hz, 1H), 5.68 (s, 2H), 5.06 - 5.00 (m, 1H), 3.32 - 3.28 (m, 1H), 3.01 - 2.95 (m, 1H).Example 15: Synthesis of 3-((1H-1,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 17)Step 1: 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazoIe124MF-364282035Attorney Docket No.: 18407-20028.40NaH, THF, SEMCISEM~N ]N'Br

[0194] To a solution of 4-bromo-2H- 1,2, 3 -triazole (3.7 g, 25.00 mmol) in THF (60.0 mL) was added NaH (1.2 g, 60% purity) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. To the above mixture was added [2-(chloromethoxy)ethyl]trimethylsilane (8.5 g, 50.98 mmol). The resulting mixture was stirred at room temperature for additional 1 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was diluted with H2O 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 (5 / 1, v / v) to afford 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole (3.8 g, 54%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=278.0.Step 2: 8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-((2-((2-(trimethylsilyI)ethoxy)methyI)-2H-l,2,3-triazol-4-yI)amino)-3,4-dihydroquinoIin-2(lH)-one

[0195] To a mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole (1.3 g, 4.67 mmol) and 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (500.0 mg, 1.55 mmol) in 1,4-dioxane (15.0 mL) were added TMSONa (349.7 mg, 3.11 mmol) and Pd-PEPPSI-IHeptCl 3 -chloropyridine (151.8 mg, 0.15 mmol) at room temperature under N2. The resulting mixture was stirred with microwave radiation at 130 °C for 9 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and then extracted 125MF-364282035Attorney Docket No.: 18407-20028.40with 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 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (110.0 mg, 13%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 518.2.Step 3: 3-((lH-l,2,3-triazol-5-yI)amino)-8-(2-chIoro-5-fluorophenoxy)-l-metliyl-3,4-dihydroquino!in-2(lH)-one (Compound 17)TFA, DCM NH3. H2O, AONCompound 17

[0196] To a solution of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((2-((2- (trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (80.0 mg, 0.15 mmol) in CH2Q2 (1.0 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was dissolved in MeCN (1.0 mL) and NH3 H2O (0.5 mL). The resulting mixture was stirred at room temperature for additional 1 h. After the reaction was completed, the resulting mixture was diluted with H2O 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 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 (B%): 38% B to 48% B in 10 min; Wave Length: 254 / 220 nm) to afford 3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 17) (4.3 mg, 7%) as a white solid. LCMS (ESI, m / z): [M+H]+= 388.1. ^INMR (400 MHz, DMSO-fifc): δ 7.64 - 7.60 (m, 1H), 7.22 - 7.12 (m, 3H), 7.05 - 7.00 (m, 1H), 6.91 (d, J126MF-364282035Attorney Docket No.: 18407-20028.40= 8.4 Hz, IH), 6.78 - 6.74 (m, IH), 4.14 - 4.09 (m, 1H), 3.25 (s, 3H), 3.23 - 3.20 (m, IH), 2.98 - 2.90 (m, IH).Example 16: Synthesis of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyrimidin-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 18)Step 1: 8-(2-chIoro-5-fluorophenoxy)-l-methyl-3-(pyrimidin-4-ylamino)-3,4-dihydroquinoIin-2-one (Compound 18)DIEA, 1-PrOH, 150 °C, MWCompound 18

[0197] To a mixture of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (97.6 mg, 0.30 mmol) and 4-chloro-pyrimidine hydrochloride (64.9 mg, 0.43 mmol) in i-PrOH (5.0 mL) was added DIEA (145.4 mg, 1.13 mmol) at room temperature. The mixture was stirred with microwave at 150 °C for 1.5 h. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. The mixture was extracted with DCM. 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 CH3OH / CH2Q2 (11 / 89, 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 (B%): 5% B to 5% B in 2 min, 38% B to 58% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyrimidin-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 18) (7.9 mg, 7%) as a white solid. LCMS (ESI, m / z):[M+H]+= 399.2. ’HNMR (400 MHz, DMSO-< / 6): 58.42 (s, IH), 8.10(d, 6.0 Hz, IH), 7.75 - 7.66 (m, 2H), 7.23 (d, J= 7.2 Hz, IH), 7.18 - 7.14 (m, IH), 7.11 - 7.06 (m, IH), 6.95 - 6.90 (m,127MF-364282035Attorney Docket No.: 18407-20028.402H), 6.73 (d, J = 6.0 Hz, 1H), 4.82 - 4.77 (m, 1H), 3.31 (s, 3H), 3.22 - 3.18 (m, 1H), 3.04 - 2.97 (m, 1H).Example 17: Synthesis of (R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lI{)-one (Compound 19) and (S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (Compound 20)Step 1: 5-bromo-N-(2,4-dimethoxybenzyl)-N-methyl-l,3,4-thiadiazol-2-amine

[0198] A mixture of dibromo-l,3,4-thiadiazole (5.0 g, 20.54 mmol), [(2,4-dimethoxyphenyl)methyl](methyl)amine (3.7 g, 20.54 mmol) and DIEA (5.3 g, 41.08 mmol) in dioxane (50.0 mL) was stirred at 110 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 5-bromo-N-(2,4-dimethoxybenzyl)-N-methyl-l,3,4-thiadiazol-2-amine (5.0 g, 78%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 344.0.Step 2: 8-(2-chIoro-5-fluorophenoxy)-3-((5-((2,4-dimethoxybenzyl)(methyl)amino)-l,3?4-thiadiazol-2-yI)amino)-l-methyI-3,4-dihydroquinolin-2(lH)-one128MF-364282035Attorney Docket No.: 18407-20028.40F

[0199] A mixture of 5-bromo-N-(2,4-dimethoxybenzyl)-N-methyl-l,3,4-thiadiazol-2-amine (1.2 g, 3.74 mmol), (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (600.2 mg, 1.87 mmol), { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloropalladium (182.2 mg, 0.19 mmol) and sodium trimethylsilanolate (417.7 mg, 3.72 mmol) in dioxane (6.0 mL) was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 8-(2-chloro-5-fluorophenoxy)-3-((5-((2,4-diniethoxybenzyl)(methyl)amino)-l,3,4-thiadiazol-2-yl)amino)-l-methyl-3,4-dihydroquinolin-2(lH)-one (600.0 mg, 58%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 584.1.Step 3: 8-(2-Chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one129MF-364282035Attorney Docket No.: 18407-20028.40

[0200] A solution of 8-(2-chloro-5-fluorophenoxy)-3-((5-((2,4-diniethoxybenzyl)(methyl)aniino)-l,3,4-thiadiazol-2-yl)amino)-l-methyl-3,4-dihydroquinolin- 2(lH)-one (580.2 mg, 1.05 mmol) in TFA (6.0 mL) was stirred at 70 °C for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with saturated NaHCO₃ (aq.). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 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 (B%): 5% B to 5% B in 2 min, 38% B to 58% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-Chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (104.2 mg, 22%) as a white solid. LCMS (ESI, m / z): [M+H]+= 434.2.Step 4: (R)-8-(2-chloro-5-fIuorophenoxy)-l-methyI-3-((5-(methyIaniino)-l,3,4-thiadiazoI-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (Compound 19) and (S)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinoIin-2(lH)-one (Compound 20)Chiral-HPLC

[0201] The racemic product of 8-(2-Chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (104.2 mg, 0.24 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3·MeOH)-HPLC, Mobile Phase B: ETOH: DCM=1: 1— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 40% B to 40% in 14min; Wave Length: 220 / 254 nm; RTl(min): 9,1; RT2(min): 11.87) to afford (R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)- 130MF-364282035Attorney Docket No.: 18407-20028.403,4-dihydroquinolin-2(lH)-one (Compound 19) (assumed, 15.8 mg, 15%) as a white solid and (S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5-(methylamino)-l,3,4-thiadiazol-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (Compound 20) (assumed, 28.9 mg, 28%) as a white solid.Example 18: Synthesis of 8-chloro- 9-(2-chloro-5-fluorophenoxy)-4, 5-dihydroimidazo[l, 2-a quinolin-4-amine (Compound 21)Step 1: l-bromo-4-chloro-3-fluoro-2-nitrobenzeneC!CuBr2, t-BuONO, ACNNH2

[0202] To a solution of 4-chloro-3-fluoro-2-nitroaniline (3.0 g, 15.74 mmol) in ACN (30.0 mL) was added CuBr2 (5.3 g, 23.73 mmol) and t-BuONO (2.4 g, 23.27 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 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 (96 / 4, v / v) to afford l-bromo-4-chloro-3-fluoro-2-nitrobenzene (2.5 g, 62%) as a white solid.Step 2: l-bromo-4-chloro-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzeneBr Br

[0203] To a solution of 1 -bromo-4-chloro-3-fluoro-2-nitrobenzene (4.5 g, 17.69 mmol) in DMF (40.0 mL) was added 2-chloro-5-fluorophenol (2.6 g, 17.74 mmol) and K2CO3 (4.9 g, 35.46 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted 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 by131MF-364282035Attorney Docket No.: 18407-20028.40flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford 1-bromo-4-chloro-3-(2-chloro-5-fluorophenoxy)-2 -nitrobenzene (4.0 g, 53%) as a brown yellow solid.Step 3: 6-bromo-3-chloro-2-(2-chloro-5-fliiorophenoxy)aniIineFe, NH4CIMeOH, H2OBr

[0204] To a solution of l-bromo-4-chl oro-3 -(2-chloro-5-fluorophenoxy)-2-nitrobenzene (4.0 g, 10,50 mmol) in MeOH (50.0 mL) / H₂O (10.0 mL) was added Fe (2.9 g, 51.93 mmol) and NH4Cl (2.8 g, 52.35 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (93 / 7, v / v) to afford 6-bromo-3-chloro-2-(2-chloro-5-fluorophenoxy)aniline (2.3 g, 62%) as a white solid. I -CMS (ESI, m / z): [M+H]+= 349.9.Step 4: methyl 3-(2-amino-4-chIoro-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoateBr

[0205] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.8 g, 8.51 mmol) in DMF (30.0 mL) was added Zn (1.0 g, 15.27 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 6-bromo-3-chloro-2-(2-chloro-5-fluorophenoxy [aniline (2.3 g, 6.55 mmol), XPhos (312.4132MF-364282035Attorney Docket No.: 18407-20028.40mg, 0.66 mmol) and Pd(0Ac)2 (73.6 mg, 0.33 mmol) at room temperature under N2. The resulting mixture was stirred at 40 °C for additional 2 h under N2. After the reaction was completed, the resulting mixture was diluted 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 filtrate was purified by flash column chromatography with petroleum ether / ethyl acetate (85 / 15, v / v) to afford methyl 3-(2-amino-4-chloro-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.6 g, 52%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 473.1.Step 5: tert-butyl (7-chIoro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate

[0206] To a solution of methyl 3-(2-amino-4-chloro-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.6 g, 3.38 mmol) in ACN (20.0 mL) was added K2CO3 (1.4 g, 10.13 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 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 (90 / 10, v / v) to afford tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (1.1 g, 74%) as a white solid. LCMS (ESI, m / z): [M+H]+= 441.1.Step 6: tert-butyl (7-chIoro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate133MF-364282035Attorney Docket No.: 18407-20028.40

[0207] To a solution of Na2COs (527.1 mg, 4.97 mmol) in THF (20.0 mL) was added P2S5(1.1 g, 4.95 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (950.0 mg, 2.15 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 2 h. After the reaction was completed, the mixture was diluted with H2O 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 (93 / 7, v / v) to afford tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (800.0 mg, 77%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 457.0.Step 7: tert-butyl (7-chIoro-8-(2-chloro-5-fIuorophenoxy)-2-((2,2-dimethoxyethyI)imino)-l,2,3,4-tetrahydroquinoIin-3-yl)carbamateNHBoc

[0208] To a solution of tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (800.0 mg, 1.75 mmol) in EtOH (10.0 mL) was added 2,2- dimethoxyethanamine (559.1 mg, 5.32 mmol) at room temperature under N2. The resulting 134MF-364282035Attorney Docket No.: 18407-20028.40mixture was stirred at 80 °C for 30 min 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 (90 / 10, v / v) to afford tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.0 g, 93%) as a white solid. LCMS (ESI, m / z): [M+H]+= 528.1.Step 8: tert-butyl (8-chIoro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamateTsOH, tolueneNHBoc

[0209] To a solution of tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (500.0 mg, 0.95 mmol) in toluene (5.0 mL) was added TsOH (36.1 nig, 0.19 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 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 (90 / 10, v / v) to afford tert-butyl (8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (360.0 mg, 82%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 464.1.Step 9: 8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinoIin-4-aniine135MF-364282035Attorney Docket No.: 18407-20028.40HCI in dioxaneNHBoc

[0210] A solution of tert-butyl (8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (320.0 mg, 0.69 mmol) in HCl / l,4-di oxane (3.0 mL, 4.0 mol / L) was stirred at room temperature for 30 minutes. After the reaction was completed, the pH of the mixture was adjusted to 7 with NaHCO₃ (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 8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (220.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 364.0.Step 10: l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 21)TMSNCO, MeOHCompound 21

[0211] To a solution of 8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (180.0 mg, crude) in methanol (3.0 mL) was added isocyanatotrimethylsilane (74.0 mg, 0.64 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 reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD 136MF-364282035Attorney Docket No.: 18407-20028.40C18 Column 30x150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 61 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 31% B to 51% B in 10 min; Wave Length: 254 / 221 nm) to afford l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 21) (55.6 mg, 28%) as a white solid. LCMS (ESI, m / z): [M+H]+= 407.1. 'HNMR (400 MHz, DMSO-< / 6): 87.71 - 7.49 (m, 4H), 7.02 - 6.99 (m, 2H), 6.65 - 6.57 (m, 2H), 5.67 (s, 2H), 5.10 - 5.07 (m, 1H), 3.29 - 3.25 (m, 1H), 3.04 - 2.92 (m, 1H).Example 19: Synthesis of l-(8-fluoro-9-isopropoxy-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 22)Step 1: tert-butyl N-(7-fluoro-8-isopropoxy-2-suIfanylidene-3,4-dihydro-lH-quinolin-3-yl)carbamateNa2CO3, THFNHBoc NHBoc

[0212] To a solution of Na2COs (1.7 g, 16.04 mmol) in THF (40.0 mL) was added P2S5(3.6 g, 16.20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added tert-butyl N-(7-fluoro-8-isopropoxy-2-oxo-3,4-dihydro-lH-quinolin-3-yl)carbamate (2.4 g, 7.09 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 16 h. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was diluted with H2O and then extracted with ethyl acetate. The combined organic layers were 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 (87 / 13, v / v) to afford tert-butyl N-(7-fluoro-8-isopropoxy-2-sulfanylidene-3,4-dihydro-l H-quinolin-3-yl)carbamate (1.9 g, 76%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 355.1.Step 2: tert-butyl (2-((2,2-dimethoxyethyI)imino)-7-fluoro-8-isopropoxy-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate137MF-364282035Attorney Docket No.: 18407-20028.40EtOHNHBoc

[0213] To a solution of tert-butyl N-(7-fluoro-8-isopropoxy-2-sulfanylidene-3,4-dihydro-lH-quinolin-3-yl)carbamate (1.8 g, 5.12 mmol) in EtOH (40.0 mL) was added 2,2- dimethoxyethanamine (1.6 g, 15.41 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 30 minutes under N2. After the reaction was completed, the mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (69 / 31, v / v) to afford tert-butyl (2-((2,2-dimethoxyethyl)imino)-7-fluoro-8-isopropoxy-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.8 g, 83%) as a light yellow oil. LCMS (ESI, m / z): [M+H]+= 426.2.Step 3: 8-fluoro-9-isopropoxy-4,5-dihydroimidazo[l,2-a]quinolin-4-amine

[0214] To a solution of tert-butyl (2-((2,2-dimethoxyethyl)imino)-7-fluoro-8-isopropoxy-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (300.0 mg, 0.71 mmol) in methanol (10.0 mL) was added cone. HC1 (8.0 mL) at 0 °C. The resulting mixture was stirred at 60 °C for 1 h. After the reaction was completed, the mixture cooled to room temperature. The pH value of the mixture was adjusted to 7 with saturated NaHCOs (aq. ) at 0 °C. The resulting mixture was diluted with H2O and then extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-fluoro-9-isopropoxy-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (210.0 mg, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 262.1.138MF-364282035Attorney Docket No.: 18407-20028.40Step 4: l-(8-fluoro-9-isopropoxy-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 22)TMSNCO, MeOHNH2Compound 22

[0215] To a solution of 8-fluoro-9-isopropoxy-4H,5H-imidazo[l,2-a]quinolin-4-amine (190.0 mg, 0.73 mmol) in methanol (5.0 mL) was added isocyanatotrimethylsilane (100.5 mg, 0.87 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 DCM / MeOH (97 / 3, v / v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 20% B to 40% B in 10 min; Wave Length: 254 / 220 nm) to afford l-(8-fluoro-9-isopropoxy-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 22) (72.8 mg, 33%) as a white solid. LCMS (ESI, m / z): [M+H]+= 305.1. ‘HNMR (400 MHz, DMSO- e): 87.98 (s, 1H), 7.20 - 7.12 (m, 2H), 7.07 (s, 1H), 6.45 (d, J= 6.8 Hz, 1H), 5.69 (s, 2H), 4.94 - 4.89 (m, 1H), 4.43 - 4.37 (m, 1H), 3.20 - 3.15 (m, 1H), 2.85 - 2.78 (m, 1H), 1.45 - 1.28 (m, 6H).Example 20: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-l-tnethyl-4,5-dihydroitnidazo[l,2-a]quinolin-4-yl) rea (Compound 23)Step 1: tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyI)imino)-l, 2,3,4-tetrahydroquinolm-3-yl)carbamate139MF-364282035Attorney Docket No.: 18407-20028.40NHBoc

[0216] To a solution of tert-butyl N-[8-(2-chloro-5-fluorophenoxy)-2-sulfanylidene-3,4-dihydro-lH-quinolin-3-yl]carbamate (1.0 g, 2.37 mmol) in EtOH (10.0 mL) was added 2,2-dimethoxypropan-1 -amine (0.9 g, 6.71 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 1 h under N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyl)imino)-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (1.1 g, 87%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 508.2.Step 2: tert-butyl N-[9-(2-chIoro-5-fluorophenoxy)-l-methyI-4H,5H-imidazo[l,2-a] quinolin-4-yI] carbamate

[0217] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (500.0 mg, 0.98 mmol) in toluene (5.0 mL) was added p-toluenesulfonic acid (33.9 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 1 h. After the reaction was completed, the140MF-364282035Attorney Docket No.: 18407-20028.40mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (79 / 21, v / v) to afford tert-butyl N-[9-(2-chloro-5-fluorophenoxy)- 1 -methyl-4H,5H-imidazo[l,2-a]quinolin-4-yl]carbamate (220.0 mg, 50%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 444.1.Step 3: 9-(2-chIoro-5-fluorophenoxy)-l-methyl-4H,5H-imidazo[l,2-a]quinolin-4-amine

[0218] A solution of tert-butyl N-[9-(2-chloro-5-fluorophenoxy)-l-methyl-4H,5H-imidazo[l,2-a]quinolin-4-yl]carbamate (210.0 mg, 0.47 mmol) in HCl / l,4-di oxane (4.0 mL, 4.0 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with saturated NaHCO₃ (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-(2-chloro-5-fluorophenoxy)-l-methyl-4H,5H-imidazo[l,2-a]quinolin-4-amine (160.0 mg, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 344.1.Step 4: l-(9-(2-chloro-5-fluorophenoxy)-l-methyI-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea141MF-364282035Attorney Docket No.: 18407-20028.40TMSNCO, MeOHCompound 23

[0219] To a solution of 9-(2-chloro-5-fluorophenoxy)-l-meth}d-4H,5H-imidazo[l,2-a]quinolin-4-amine (150.0 mg, 0.44 mmol) in methanol (2.0 mL) was added isocyanatotrimethylsilane (60.3 mg, 0.52 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was filtered. The solid was washed with MeOH, DCM and then collected to afford l-(9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 23) (44.2 mg, 26%) as a white solid. LCMS (ESI, m / z): [M+H]+= 387.1.NMR (400 MHz, DMSO-tfc): 6 7.68 - 7.64 (m, 1H), 7.33 - 7.28 (m, 2H), 7.12 - 7.07 (m, 1H), 6.97 - 6.94 (m, 2H), 6.75 (s, 1H), 6.47 (d, J 6.8 Hz, 1H), 5.77 (s, 2H), 4.83 - 4.77 (m, 1H), 3.21 - 3.16 (m, 1H), 2.76 - 2.68 (m, 1H), 2.35 (s, 3H).Example 21: Synthesis of(S)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one and (R)-3-((lII-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l- ethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 24 and Compound 25)Step 1: Synthesis of Methyl 2-(2-chIoro-5-fluorophenoxy)-4-iodonicotinateK2CO3, AONMF-364282035Attorney Docket No.: 18407-20028.40

[0220] To a stirred solution of methyl 2-fluoro-4-iodonicotinate (8.0 g, 28.46 mmol) in ACN (100.0 mL) were added 2-chloro-5-fluorophenol (5.0 g, 34.16 mmol) and K2CO3 (11.80 g, 85.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (75 / 15, v / v) to afford methyl 2-(2-chloro-5-fluorophenoxy)-4-iodonicotinate (7.2 g, 62%) as a colorless oil. LCMS (ESI, m / z): [M+H]’ = 407.9.Step 2: Synthesis of 2-(2-ChIoro-5-fluorophenoxy)-4-iodonicotinic acid

[0221] To a stirred solution of methyl 2-(2-chloro-5-fluorophenoxy)-4-iodonicotinate (7.2 g, 17.66 mmol) in THF / H2O (90.0 mL / 30.0 mL) was added LiOH (1.3 g, 53.02 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 36 h. After the reaction was completed, the pH value of the mixture was adjusted to 4 with HC1 aqueous (5.0 mol / L). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (10 / 1, v / v) to afford 2-(2-chloro-5-fluorophenoxy)-4-iodonicotinic acid (5.1 g, 73%) as a white solid. LCMS (ESI, m / z): [M+H]+= 393.9.Step 3: Synthesis of Tert-butyl (2-(2-chloro-5-fIuorophenoxy)-4-iodopyridin-3-yl)carbamate143MF-364282035Attorney Docket No.: 18407-20028.40DPPA, TEA t-BuOH

[0222] To a stirred solution of 2-(2-chloro-5-fluorophenoxy)-4-iodonicotinic acid (5.1 g, 12.95 mmol) in t-BuOH (50.0 mL) were added DPPA (7.1 g, 25.91 mmol) and TEA (3.9 g, 38.87 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and then diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate 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-(2-chloro-5-fluorophenoxy)-4-iodopyridin-3-yl)carbamate (4.5 g, 74%) as a white solid. LCMS (ESI, m / z):[M+H]+= 465.0.Step 4: Synthesis of 2-(2-Chloro-5-fluorophenoxy)-4-iodopyridin-3-amineTFA, DCM

[0223] To a stirred solution of tert-butyl (2-(2-chloro-5-fluorophenoxy)-4-iodopyridin-3-yl)carbamate (1.5 g, 3.22 mmol) in DCM (14.0 mL) were added TFA (7.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with saturated NaHCO₃ aqueous. The mixture was extracted with CH2Cl2 The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by 144MF-364282035Attorney Docket No.: 18407-20028.40flash column chromatography with petroleum ether / ethyl acetate (10 / 1, v / v) to afford 2-(2-chloro-5-fluorophenoxy)-4-iodopyridin-3-amine (1.0 g, 84%) as a white solid. LCMS (ESI, m / z):[M+H]+- 364.9.Step 5: Synthesis of Tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yI)carbamate1) Zn, DMF2) Pd(OAc)2, XPhos, DMF

[0224] To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.3 g, 3.82 mmol) in DMF (5.0 mL) were added Zn (0.5 g, 6.88 mmol) at room temperature under N?. The resulting mixture was stirred at room temperature for 4 h under N2. To the above mixture was added a mixture of 2-(2-chloro-5-fluorophenoxy)-4-iodopyridin-3-amine (1.0 g, 2.74 mmol), Pd(OAc)2 (0.1 g, 0.27 mmol) and XPhos (0.3 g, 0.54 mmol) in DMF (5.0 mL) at room temperature under N2. The resulting mixture was stirred at 40 °C for 16 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (60 / 40, v / v) to afford tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl [carbamate (800.0 mg, 71%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 408.1.Step 6: Synthesis of Tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3?4-tetrahydro- 1,7-na ph thyridin-3-yl)ca rbama te145MF-364282035Attorney Docket No.: 18407-20028.40NHBoc

[0225] To a stirred mixture of tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-2-oxo-l, 2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (607.4 mg, 1.48 mmol) and K2CO3 (411.6 mg, 2.97 mmol) in DMF (8.0 mL) were added CH3I (317.0 mg, 2.23 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 water and then extracted with EtOAc. The combined organic layers were 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 (62 / 38, v / v) to afford tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)- 1 -methyl-2-oxo- 1,2,3,4-tetrahydro- 1,7-naphthyridin-3-yl)carbamate (587.3 mg, 93%) as a white solid. LCMS (ESI, m / z): [M+H]+= 422.1.Step 7: Synthesis of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(l H)-oneTFA, DCM

[0226] To a stirred solution of tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (523.4 mg, 1.24 mmol) in DCM (10.0 mL) were added TFA (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with saturated NaHCOs 146MF-364282035Attorney Docket No.: 18407-20028.40aqueous. The mixture was extracted with CH2Cl2 The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CEbCh / MeOH (10 / 1, v / v) to afford (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (394.6 nig, 98%) as a light yellow solid. LCMS (ESI, m / z): [M+H] = 322.1.Step 8: Synthesis of 8-(2-ChIoro-5-fluorophenoxy)-l-niethyl-3-((2-(tetrahydro-2H-pyran-2-yl)-2H-l,2,3-triazoI-4-yI)amino)-3,4-dihydro-l,7-naphthyridin-2(lH)-one

[0227] To a stirred mixture of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (376.5 mg, 1.17 mmol) and 4-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H- 1,2,3 -triazole (543,1 mg, 2.34 mmol) in toluene (40.0 mL) were added GPhos (62.8 mg, 0.11 mmol), GPhos Pd G6 TES (110.5 mg, 0.11 mmol) and CS2CO3 (1143.8 mg, 3.51 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (55 / 45, v / v) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((2-(tetrahydro-2H-pyran-2-yl)-2H-l,2,3-triazol-4-yl)amino)-3,4-dihydro-l,7-naphthyridin-2(lH)-one (305.4 mg, 55%) as a light yellow solid. LCMS (ESI, m / z): [M+H]’ = 473.1.Step 9: Synthesis of 3-((lH-l,2,3-triazol-5-yI)amino)-8-(2-chIoro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one147MF-364282035Attorney Docket No.: 18407-20028.40F HCI in dioxane, MeOH

[0228] To a stirred solution of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((2-(tetrahydro-2H- pyran-2-yl)-2H-l,2,3 -tri azol -4-yl)amino)-3,4-dihy dro- 1,7-naphthyridin-2( 1 H)-one (278.5 mg, 0.58 mmol) in MeOH (8.0 mL) were added HCl / dioxane (0.5 mL, 4 mol / L) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 32% B to52 % B in lOmin; Wave Length: 254 / 220 nm) to afford 3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7- naphthyridin-2(lH)-one (143.3 nig, 62%) as a yellow solid. LCMS (ESI, m / z): [M+H] = 389.1.Step 10: Synthesis of (S)-3-((lH-l,2,3-triazol-5-yI)amino)-8-(2-chloro-5-fluorophenoxy)-l- methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one and (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8- (2-chIoro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 24 and Compound 25)FChlral-HPLCCompound 24 Compound 25

[0229] The racemic of product of3-((lH-l,2,3-triazo1-5-yl)amino)-8-(2-chloro-5- fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (143.3 mg, 0.36 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex— HPLC, Mobile Phase B: EtOH: DCM=1:148MF-364282035Attorney Docket No.: 18407-20028.401— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 20% B to 20% in 21min% B; Wave Length: 220 / 254 nm; RTl(min): 14.48; RT2(min): 17.37) to afford (S)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l -methyl -3, 4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 24) (20.7 mg, 7%) as a white solid and (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 25) (23.2 mg, 8%) as a white solid.

[0230] (S)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3,4-dihydro-l,7-naphthyridin-2(lH)-one: RTl(min): 14.48; LCMS (ESI, m / z): [M+H]+= 389.1.41 NMR (400 MHz, DMSO-d6): 5 13.66 (s, 1H), 7.84 (d, J === 4.8 Hz, 1 H), 7.68 - 7.63 (m, 111).7.40 - 7.37 (m, 1H), 7.22 - 7.16 (m, 3H), 5.99 - 5.93 (m, 1H), 4.23 - 4.16 (m, 1H), 3.46 (s, 3H), 3.31 - 3.26 (m, 1H), 3.06 - 2.99 (m, 1H).

[0231] (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3,4-dihydro-l,7-naphthyridin-2(lH)-one: RT2(min): 17.37; LCMS (ESI, m / z): [M+H]+=== 389.1. 'HNMR (400 MHz, DMSO-^): 6 13.65 (s, 1H), 7.84 (d, J= 4.8 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.40 - 7.37 (m, 1H), 7.21 - 7.16 (m, 3H), 5.99 - 5.94 (m, 1H), 4.21 - 4.18 (m, 1H), 3.47 (s, 3H), 3.31 - 3.27 (m, 1H), 3.06 - 2.99 (m, IH).Example 22: Synthesis of (R)-3-((lH-l, 2, 3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro-l, 7-naphthyridin-2(lH)-one and (S)-3-((lH-l,2,3-triazol-5-yl)anuno)-8-(2-chloro-5-fluorophenoxy)-l,6-diinethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 26 and Compound 27)Step 1: Synthesis of propyl 2-fluoro-4-iodo-6-methylnicotinate

[0232] To a solution of 2-fluoro-4-iodo-6-methylpyridine (5.0 g, 21.10 mmol) in THF (100,0 mL) was dropwise added LDA (13.0 mL, 2.0 niol / L in THF) at -78 °C under N2. The mixture 149MF-364282035Attorney Docket No.: 18407-20028.40was stirred at -78 °C for 1 h under N2. To the above mixture was added propyl carbonochloridate (5.2 g, 42.19 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 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 vacuum. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (10 / 90, v / v) to afford propyl 2-fluoro-4-iodo-6-methylnicotinate (2.6 g, 38%) as a light yellow oil. LCMS (ESI, m / z): [M+H]+= 324.0.Step 2: Synthesis of propyl 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylnicotinate

[0233] To a solution of propyl 2-fluoro-4-iodo-6-methylnicotinate (2.5 g, 7.74 mmol) in DMF (50.0 mL) was added 2-chloro-5-fluorophenol (1,3 g, 8.87 mmol) and K2CO3 (3.1 g, 22,43 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. 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. The residue was purified by flash column chromatography with DCM / petroleum ether (55 / 45, v / v) to afford propyl 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylnicotinate (900.0 mg, 26%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 450.0.Step 3: Synthesis of 2-(2-chIoro-5-fluorophenoxy)-4-iodo-6-ni ethylnicotinic acid150MF-364282035Attorney Docket No.: 18407-20028.40

[0234] To a solution of propyl 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylnicotinate (520.0 mg, 1.16 mmol) in THF (8.0 mL) / MeOH (4.0 mL) / H2O (2.0 mL) was added LiOH (89.0 mg, 3.72 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the resulting mixture was cooled to 0 °C. The pH value of the mixture was adjusted to 7.0 with HCl (1 mol / L). 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 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylnicotinic acid (320.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H] ' = 408.0.Step 4: Synthesis of tert-butyl (2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylpyridin-3-yl)carbamateDPPA, TEA, t-BuOH

[0235] To a solution of 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylnicotinic acid (650.0 mg, 1.60 mmol) in t-BuOH (10.0 mL) was added TEA (485.6 mg, 4.80 mmol) and DPPA (886.1 mg, 3.22 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and then quenched with water. 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. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (92 / 8, v / v) to afford tert-butyl (2-(2-chloro-5- 151MF-364282035Attorney Docket No.: 18407-20028.40fluorophenoxy)-4-iodo-6-methylpyridin-3-yl)carbamate (460.0 mg, 60%) as a colorless solid. LCMS (ESI, m / z): [M+H]+= 479.1.Step 5: Synthesis of 2-(2-chIoro-5-fIuorophenoxy)-4-iodo-6-methylpyridin-3-amine

[0236] To a solution of tert-butyl (2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylpyridin-3-yl)carbamate (390.0 mg, 0.82 mmol) in DCM (6.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with NaHCO3(aq.) at 0 °C. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylpyri din-3 -amine (290,0 mg, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 379.0.Step 6: Synthesis of tert-butyl (R)-(8-(2-chIoro-5-fluorophenoxy)-6-methyl-2-oxo-l, 2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamateNHBoc

[0237] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (308.6 mg, 0,94 mmol) in DME (6.0 mL) was added Zinc (77.2 mg, 1.18 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 2-(2-chloro-5-fluorophenoxy)-4-iodo-6-methylpyridin-3-amine (270.0 mg, crude), Pd(OAc)2 (15.2 mg, 0.07 mmol) and XPhos (65.6 mg, 0.14 mmol) at room152MF-364282035Attorney Docket No.: 18407-20028.40temperature. The resulting mixture was stirred at 40 °C for 16 h under N2. After the reaction was completed, the resulting mixture was cooled to the room temperature and diluted with water. 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. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-6-methyl-2-oxo-l, 2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (200.0 mg, 66%) as a light yellow' solid. LCMS (ESI, m / z): [M+H]+= 422.1.Step 7: Synthesis of tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)carbamate

[0238] To a solution of tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-6-methyl-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (190.0 mg, 0.45 mmol) in DMF (5.0 mL) was added Mel (81.8 mg, 0.58 mmol) and K2CO3 (91.5 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was diluted with water 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 to afford tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)- 1.6-dimethyl-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (180.0 mg, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 436.1.Step 8: Synthesis of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro- 1.7-naphthyridin-2(lH)-one153MF-364282035Attorney Docket No.: 18407-20028.40

[0239] A solution of tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridin-3-yl)carbamate (170.0 mg, crude) in HC1 (3.0 mL, 4 mol / L in dioxane) was stirred at room temperature for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with NaHCO₃ (aq.) at 0 °C. The mixture was extracted with DCM 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 DCM / CH3OH (96 / 4, v / v) to afford (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (95.0 mg, 73%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 336.1.Step 9: Synthesis of (3R)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3-((2-(tetrahydro-2H-pyran-2-yl)-2H-l,2 -triazol-4-yI)amino)-3,4-dihydro-l,7-naphthyridin-2(lH)-one

[0240] To a mixture of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro-1,7-naphthyridin-2(lH)-one (85.0 mg, 0,25 mmol) and 4-bromo-2-(oxan-2-yl)-l,2,3-triazole (88.2 mg, 0.38 mmol) in dioxane (8.0 mL) was added t-BuBrettPhos (22.6 mg, 0.05 mmol), t-BuBrettPhos Pd G3 (19.5 mg, 0.02 mmol) and CS2CO3 (201.4 mg, 0.62 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 3 h under N2. After the reaction was completed, the mixture was cooled to room temperature and diluted with water. The154MF-364282035Attorney Docket No.: 18407-20028.40mixture was extracted with ethyl acetate. The combined organic layers were 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 / CH3OH (96 / 4, v / v) to afford (3R)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3-((2-(tetrahydro-2H-pyran-2-yl)-2H-l,2,3-triazol-4-yl)amino)-3,4-dihydro-l,7-naphthyridin-2(lH)-one (96.0 mg, 78%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 487.2.Step 10: Synthesis of (R)-3-((lH-l,2 -triazol-5-yI)amino)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyi-3,4“dihydro-l,7-naphthyridin-2(lH)-oneHCI in dioxane, DCM

[0241] To a solution of (3R)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3-((2-(tetrahydro-2H-pyran-2-yl)-2H-l,2,3-triazol-4-yl)amino)-3,4-dihydro-l,7-naphthyridin-2(lH)-one (96.0 mg, 0.20 mmol) in DCM (4.0 mL) was added HCI (0.2 mL, 4.0 mol / L in 1,4-dioxane) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with H2O / CH3OH (73 / 27, v / v) to afford (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (38.2 mg, 48%, e.e. - 28.3%) as a white solid. LCMS (ESI, m / z): [M+H]+= 403.1.Step 11: Synthesis of (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fIuorophenoxy)-l,6-dimethyI-3,4-dihydro-l,7-naphthyridin-2(lH)-one and (S)-3-((lH-l,2,3“triazoI-5-yI)amino)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (Compound 26 and Compound 27)155MF-364282035Attorney Docket No.: 18407-20028.40Compound 26 Compound 27

[0242] The product of (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)- l,6-dimethyl-3,4-dihydro-l,7-naphthyridin-2(lH)-one (38.2 mg, 0.10 mmol, e.e. = 28.3%) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5pm Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex (0.2% FA)-HPLC, Mobile Phase B: MeOH: EtOH=l:1— HPLC; Flow rate: 20 mL / min; Gradient (B%): 40% B to 40% B in 10.5 min; Wave Length:220 / 254 nm; RTl(min): 7.74; RT2(min): 9.44) to afford (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8- (2-chloro-5-fluorophenoxy)- 1,6-dimethyl-3,4-dihydro- 1,7-naphthyridin-2( lH)-one (Compound 26) (17.8 mg, 37%) as a white solid and (3S)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyl-3-(3H- l,2,3-triazol-4-ylamino)-3,4-dihydro-l,7-naphthyridin-2-one (Compound 27) (10.1 mg, 37%) as a white solid.

[0243] (R)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l,6-dimethyI- 3,4-dihydro-l,7-naphthyridin-2(lH)-one: RTl(min): 7.74; LCMS (ESI, m / z): [M+H]+=403.1. 'HNMR (400 MHz, DMSO-d6): 5 13.70 (s, 1H), 7.67 - 7.63 (m, 1H), 7.35 - 7.07 (m, 4H), 5.92 (s, 1H), 4.19 - 4.13 (m, 1 H), 3.42 (s, 3H), 3.28 - 3.23 (m, 1H), 3.00 - 2.93 (m, 1H), 2.24 (s, 3H).

[0244] (S)-3-((lH-l,2,3-triazol-5-yl)amino)-8-(2-chloro-5-fIuorophenoxy)-l,6-dimethyI- 3,4-dihydro-l,7-naphthyridin-2(lH)-one: RT2(min): 9.44; LCMS (ESI, m / z): [MAH]’ =403.1. NMR (400 MHz, DMSO- e): 5 13.69 (s, 1H), 7.67 - 7.63 (m, 1H), 7.34 - 7.31 (m, 1H), 7.20 - 7.07 (m, 3H), 5.92 (s, 1H), 4.19 - 4.13 (m, 1H), 3.42 (s, 3H), 3.28 - 3.23 (m, 1H), 3.00 - 2.93 (m, 1H), 2.24 (s, 3H).Example 23: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2- a]quinolin-4-yl)urea (Compound 28)Step 1: Synthesis of l-bromo-3-(2-chIoro-5-fluorophenoxy)-4-fluoro-2-nitrobenzene156MF-364282035Attorney Docket No.: 18407-20028.40FBr

[0245] To a mixture of l-bromo-3,4-difluoro-2-nitrobenzene (4.0 g, 16.81 mmol) and 2-chloro-5-fluorophenol (2.5 g, 16.81 mmol) in DMF (40.0 mL) were added K2CO3 (4.7 g, 33.62 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with H2O 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 ethyl acetate / petroleum ether (75 / 25, v / v) to afford l-bromo-3-(2-chloro-5-fluorophenoxy)-4-fluoro-2-nitrobenzene (3.2 g, 52%) as a yellow' solid.Step 2: Synthesis of 6-bromo-2-(2-chIoro-5-fluorophenoxy)-3-fluoroaniIineFe, NH4CI MeOH, H2OBr

[0246] To a solution of l-bromo-3-(2-chloro-5-fluorophenoxy)-4-fluoro-2-nitrobenzene (3.2 g, 8.78 mmol) in methanol (80.0 mL) / H20 (16.0 mL) was added Fe (2.5 g, 43.89 mmol) and NH4CI (2.4 g, 43.89 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography157MF-364282035Attorney Docket No.: 18407-20028.40with ethyl acetate / petroleum ether (61 / 39, v / v) to afford 6-bromo-2-(2-chloro-5-fluorophenoxy)-3 -fluoroaniline (2.9 g, 99%) as a white solid. LCMS (ESI, m / z): [M+H]+= 333.9.Step 3: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate

[0247] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.9 g, 8.67 mmol) in DMF (40.0 mL) was added Zinc (1.4 g, 20.81 mmol) at room temperature under Nz, The mixture was stirred at room temperature for 2 h under N2. To the above mixture was added a solution of 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-fluoroaniline (2.9 g, 8.67 mmol) in DMF (10.0 mL), XPhos (413.3 mg, 0.87 mmol) and Pd(OAc)2(46.1 mg, 0.43 mmol) at room temperature under N2. 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 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 (80 / 20, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-7- fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.5 g, 68%) as a white solid. LCMS (ESI, m / z): [M+H]+= 425.1.Step 4: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate158MF-364282035Attorney Docket No.: 18407-20028.40

[0248] To a solution of Na2CO3(1.4 g, 13.0 mmol) in THF (20.0 mL) was added P2S5(2.9 g, 13.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.4 g, 5.65 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 16 h. After the reaction was completed, the reaction mixture was diluted with H2O 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 CH2Cl2 / petroleum ether (50 / 50, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.9 g, 76%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 441.1.Step 5: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-fluoro-l,2,3,4-tetrahydroquinolin-3-yI)carba

[0249] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.8 g, 4.08 mmol) in EtOH (15.0 mL) was added 2,2- 159MF-364282035Attorney Docket No.: 18407-20028.40dimethoxy ethanamine (1.3 g, 12.25 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 0.5 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 ethyl acetate / petroleum ether (50 / 50, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-fluoro-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.4 g, 67%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 512.2.Step 6: Synthesis of Tert-butyl (9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)carbamate

[0250] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-7-fluoro-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.3 g, 2.54 mmol) in toluene (15.0 mL) was added TsOH (874.5 mg, 5.08 mmol) at room temperature. The resulting mixture was stirred at 110 °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 ethyl acetate / petroleum ether (30 / 70, v / v) to afford tert-butyl (9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (1.0 g, 88%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 448.1.Step 7: Synthesis of 9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-amine160MF-364282035Attorney Docket No.: 18407-20028.40HCI in dioxaneNHBoc

[0251] A solution of tert-butyl (9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamate (200.0 mg, 0.45 mmol) in HCl / 1,4-dioxane (3.0 mL, 4.0 mol / L) was stirred at room temperature for 0.5 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO₃ (aq.). The resulting mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (180.2 mg, crude) as a yellow oil. LCMS (ESI, m / z): \l • H | - 348.1.Step 8: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 28)TMSNCOMeOHCompound 28

[0252] To a solution of 9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (150.0 mg, crude) in methanol (5.0 niL) was added TMSNCO (49.7 mg, 0.43 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 reduced161MF-364282035Attorney Docket No.: 18407-20028.40pressure. The residue was purified by flash column chromatography with CH^Ch / MeOH (80 / 20, v / v) and then purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient (B%): 40% B to 50% B in 15min; Wave Length: 254 / 220 nm) to afford l-(9-(2-chloro-5-fluorophenoxy)-8-fluoro-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (119.3 mg, 71%) (Compound 28) as a white solid. LCMS (ESI, m / z): [M+H]+= 391.0. ’HNMR (400 MHz, DMSO- < / 6): 57.71 - 7.67 (m, 1H), 7.63 (d, J 1.2 Hz, IH), 7.60 - 7.46 (m, IH), 7.35 - 7.31 (m, IH), 7.07 - 7.02 (m, 2H), 6.83 -6.80 (m, IH), 6.59 (d, J= 7.2 Hz, IH), 5.66 (s, 2H), 5.10 - 5.04 (m, IH), 3.31 - 3.26 (m, IH), 2.97 - 2.91 (m, IH).Example 24: Synthesis of N-(9-(2-chloro-5-fluorophenoxy)-4, 5-dihydroimidazo[l,2-a]quinolin-4-yl)-l,3)4-thiadiazol-2-amine (Compound 29)Step 1: Synthesis of 1-bromo-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzeneBr

[0253] To a mixture of l-bromo-3-fluoro-2 -nitrobenzene (10.0 g, 45.46 mmol) and 2-chloro- 5 -fluorophenol (6.7 g, 45.72 mmol) in DMF (200.0 mL) was added K2CO3 (18.9 g, 136.75 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the resulting mixture was poured into water and then filtered. The solids were washed with water and then collected to afford l-bromo-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene (10.0 g, crude) as a white solid.Step 2: Synthesis of 2-bromo-6-(2-chloro-5-fluorophenoxy)aniline162MF-364282035Attorney Docket No.: 18407-20028.40Fe, NH4CIMeOH, H2O

[0254] To a solution of 2-(3-bromo-2-nitrophenoxy)-l-chloro-4-fluorobenzene (10.0 g, crude) in methanol (200.0 mL) / H20 (40.0 niL) was added Fe (8.1 g, 145.04 mmol) and NH4CI (7.7 g, 143.95 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petr oleum ether (85 / 15, v / v) to afford 2-bromo-6-(2-chloro-5-fluorophenoxyjaniline (8.5 g, 93%) as a colorless oil. LCMS (ESI, m / z): [M+H]’ = 315.9.Step 3: Synthesis of Methyl 3-(2-amino-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0255] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (10.8 g, 32.81 mmol) in DMF (200.0 mL) was added Zinc (4.0 g, 61.18 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 2-bromo-6-(2-chloro-5-fluorophenoxy)aniline (8.0 g, 25.27 mmol), XPhos (1.2 g, 2.52 mmol) and Pd(OAc)2 (283.7 mg, 1.26 mmol) at room temperature under N2. 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 163MF-364282035Attorney Docket No.: 18407-20028.40extracted 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 (40 / 60, v / v) to afford methyl 3-(2-amino-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (10.0 g, 90%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 439.1.Step 4: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate

[0256] To a solution of methyl 3-(2-amino-3-(2-chloro-5-fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (9.5 g, 21.65 mmol) in ACN (200.0 mL) was added K2CO3 (8.9 g, 64.40 mmol) at room temperature. The resulting mixture was stirred at 100 °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 ethyl acetate / petroleum ether (85 / 15, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (6.0 g, 68%) as a light orange oil. LCMS (ESI, m / z): [M+H]+= 407.1.Step 5: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate164MF-364282035Attorney Docket No.: 18407-20028.40P2S5, Na2CO3, THFNHBoc NHBoc

[0257] To a solution of Na2CO3(3.0 g, 28.31 mmol) in THF (100.0 mL) was added P2S5(6.5 g, 29.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.0 g, 12.29 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 2 h. After the reaction was completed, the reaction mixture was diluted with H2O 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 ethyl acetate / petroleum ether (10 / 90, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (4.0 g, 77%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 423.1.Step 6: Synthesis of Tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate

[0258] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (4.0 g, 9.46 mmol) in EtOH (100.0 mL) was added 2,2- 165MF-364282035Attorney Docket No.: 18407-20028.40dimethoxy ethan-1 -amine (3.0 g, 28.53 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 0.5 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 ethyl acetate / petroleum ether (20 / 80, v / v) to afford tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (3.0 g, 64%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 494.2.Step 7: Synthesis of Tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamateClTsOH, tolueneNHBoc

[0259] To a solution of tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxyethyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (3.0 g, 6.07 mmol) in toluene (20.0 mL) was added TsOH (231.0 mg, 1.21 mmol) at room temperature. The resulting mixture was stirred at 110 °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 ethyl acetate / petroleum ether (15 / 85, v / v) to afford tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (1.0 g, 38%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 430.1.Step 8: Synthesis of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-amine166MF-364282035Attorney Docket No.: 18407-20028.40

[0260] A solution of tert-butyl N-[9-(2-chloro-5-fluorophenoxy)-4H,5H-imidazo[l,2-a]quinolin-4-yl]carbamate (500.0 mg, 1.16 mmol) in HCl / 1,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 0.5 h. After the reaction was completed, the pH of the mixture was adjusted to 7 with NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 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 CH2C12 / MeOH (92 / 8, v / v) to afford 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (470.0 mg, crude) as a brown oil. LCMS (ESI, m / z):[M+H]+= 330.1.Step 9: Synthesis of Ethyl 5-((9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)amino)-1,3,4-thiadiazole-2-carboxylate

[0261] To a solution of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (470.0 mg, crude) in DMF (5.0 mL) was added ethyl 5-chloro-l,3,4-thiadiazole-2-carboxylate (411.8 mg, 2.14 mmol) and DIEA (736.9 mg, 5.70 mmol) at room temperature. The 167MF-364282035Attorney Docket No.: 18407-20028.40resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O 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 ethyl acetate / petroleum ether (70 / 30, v / v) to afford ethyl 5-((9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)amino)-1,3,4-thiadiazole-2-carboxylate (550.0 mg, 79%) as a brown yellow soild. LCMS (ESI, m / z): [M+H]+= 486.1.Step 10: Synthesis of N-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)-1,3,4-thiadiazol-2-amine (Compound 29)1) LiOH, H2O, THF 2) HCl (1 mol / L)Compound 29

[0262] To a solution of ethyl 5-{[9-(2-chloro-5-fluorophenoxy)-4H,5H-imidazo[l,2-a]quinolin-4-yl]amino}-l,3,4-thiadiazole-2-carboxylate (200.0 mg, 0.41 mmol) in THF (1.5 mL) / H2O (0.5 mL) was added LiOH (30.0 mg, 1.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 7 with HCI (aq.) (1 mol / L). The resulting 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 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 25% B to 60% B in 10 min;168MF-364282035Attorney Docket No.: 18407-20028.40wave Length: 254 / 220 nm) to afford N-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l, 2-a]quinolin-4-yl)-l,3,4-thiadiazol-2-amine (Compound 29) (8.9 mg, 5%) as a white solid. LCMS (ESI, m / z): [M+H]+= 414.1. fl-INMR (400 MHz, DMSO-d6): 88.70 (s, 1H), 8.42 (d, J 2.0 Hz, 1H), 7.85 - 7.60 (m, 2H), 7.35 - 7.01 (m, 6H), 5.36 - 5.30 (m, 1H), 3.46 - 3.41 (m, 1H), 3.28 - 3.25 (m, 1H).Example 25: Synthesis of 9-(2-chloro-5-fluorophenoxy)-N-(pyridazin-3-yl)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (Compound 30)Compound 30

[0263] To a solution of 9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (100.0 mg, 0.30 mmol) in dioxane (3.0 mL) was added 3-bromopyridazine (72.3 mg, 0.46 mmol), t-BuONa (58.6 mg, 0.61 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (51.0 mg, 0.06 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 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 CH2Cl2 / MeOH (10 / 1, 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 mL / min; Gradient (B%): 25% B to 60% B in 12 min; Wave Length: 254 nm / 220 nm) to afford 9-(2-chloro-5-fluorophenoxy)-N-(pyridazin-3-yl)-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (Compound 30) (15.8 mg, 13%) as a white solid.LCMS (ESI, m / z): [M+H]+= 408.0.1H NMR (400 MHz, DMSO-d6): δ8.51 (d, J= 4.8 Hz, 1H), 7.85 (s, 1H), 7.74 - 7.70 (m, 1H), 7.34 - 7.23 (m, 4H), 7.16 - 7.11 (m, 1H), 7.07 - 6.95 (m, 4H), 5.61 - 5.56 (m, 1H), 3.45 - 3.40 (m, 1H), 3.24 - 3.18 (m, 1H).169MF-364282035Attorney Docket No.: 18407-20028.40Example 26: Synthesis of (3R)-3-[(5-amino-1,3,4-thiadiazol-2-yl)amino]-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one and (3S)-3-[(5-amino-l,3,4-thiadiazol- 2-yl)amino]-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (Compound 31 and Compound 32)Step 1: Synthesis of 2-chIoro-4,5-difluorophenol

[0264] To a solution of 3,4-difluorophenol (5 g, 38.43 mmol) in DMF (70.0 mL) was added NCS (5.2 g, 38.94 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 h. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. 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. The residue was purified by flash column chromatography with petroleum ether / CH2Cl2 (23 / 77, v / v) to afford 2-chloro-4,5-difluorophenol (3.8 g, 60%) as a light yellow oil.Step 2: Synthesis of 1-(3-bromo-2-nitrophenoxy)-2-chloro-4,5-difluorobenzene

[0265] To a solution of 2-chloro-4,5-difluorophenol (3.8 g, 23.10 mmol) in DMF (100.0 mL) was added l-bromo-3-fluoro-2-nitrobenzene (5.1 g, 23.18 mmol) and K2CO3 (9.4 g, 68.02 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 8 h. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. 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 170MF-364282035Attorney Docket No.: 18407-20028.40vacuum. The residue was purified by flash column chromatography with petroleum ether / CfhCh (15 / 85, v / v) to afford l-(3-bromo-2-nitrophenoxy)-2-chloro-4,5-difluorobenzene (3.9 g, 46%) as a white solid. LCMS (ESI, m / z): [M+Hf:::363.9.Step 3: Synthesis of 2-bromo-6-(2-chloro-4,5-difluorophenoxy)aniline

[0266] To a solution of l-(3-bromo-2-nitrophenoxy)-2-chloro-4,5-difluorobenzene (3.7 g, 10.15 mmol) in EtOH (60.0 mL) and H2O (15.0 mL) was added Fe (1.7 g, 30.44 mmol) and ammonium chloride (1.7 g, 31.78 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM / petroleum ether (40 / 60, v / v) to afford 2-bromo-6-(2-chloro-4,5-difluorophenoxy)aniline (3.1 g, 91%) as a colorless oil. LCMS (ESI, m / z): [M+H]' = 333.9.Step 4: Synthesis of 2-bromo-6-(2-chIoro-4,5-difIuorophenoxy)-N-methylanilineCH3I, CH3Li, THF

[0267] To a solution of 2-bromo-6-(2-chloro-4,5-difluorophenoxy)aniline (2.9 g, 8,67 mmol) in THF (80.0 mL) was dropwise added methyllithium (7.8 mL, 1.6 mol / L in diethyl ether) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. To the above mixture was dropwise added Mel (1,6 g, 11.27 mmol) at -78 °C. 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 vacuum. The residue was purified by flash column chromatography with 171MF-364282035Attorney Docket No.: 18407-20028.40petroleum ether / CHbCh (65 / 35, v / v) and then purified by reverse phase flash column chromatography with ACN / H? O (78 / 22, v / v) to afford 2-bromo-6-(2-chloro-4,5-difluorophenoxy)-N-methylani1ine (3.0 g, 99%) as a colorless oil. LCMS (ESI, m / z): [M+H]+:::438.0.Step 5: Synthesis of tert-butyl N-[(3R)-8-(2-chloro-4,5-difluorophenoxy)-l-inethyl-2-oxo- 3,4-dihydroquinoIin-3-yI]carbamate1)Zn, DMF, rt 2) Pd(OAc)2, XPhos, DMF

[0268] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (4.1 g, 12,46 mmol) in DMF (50.0 mL) was added Zn (1.1 g, 16.82 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 h under N2. To the mixture was added 2-bromo-6-(2-chloro-4,5-difluorophenoxy)-N-methylaniline (2.9 g, 8.32 mmol), XPhos (749.2 mg, 1.57 mmol) and Pd(OAc)2 (193.4 mg, 0.86 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with water. 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. The residue was purified by flash column chromatography with ethyl acetate / petroleum (33 / 67, v / v) to afford tert-butyl N-[(3R)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-2-oxo-3,4-dihydroquinolin-3-yl]carbamate (1.2 g, 32%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+::::439.1.Step 6: Synthesis of (3R)-3-amino-8-(2-chloro-4,5-difluorophenoxy)-l-niethyl-3,4-dihydroquinoIin-2-one172MF-364282035Attorney Docket No.: 18407-20028.40

[0269] A solution of tert-butyl N-[(3 R)-8-(2-chl oro-4, 5-difluorophenoxy)-l-methyl-2-oxo-3,4-dihydroquinolin-3-yl]carbamate (298.6 nig, 0.68 mmol) in HC1 / 1,4 -di oxane (5.0 mL, 4.0 molZL) was stirred at room temperature for 3 h. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with NaHCO₃ (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 (3R)-3-amino-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (274.6 nig, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 339.1.Step 7: Synthesis of 3-[(5-amino-1,3,4-thiadiazol-2-yI)amino]-8-(2-chloro-4,5-difIiiorophenoxy)-l-methyl-3,4-dihydroquinoIin-2-one; formic acid

[0270] To a mixture of (3R)-3-amino-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (225.8 mg, 0.67 mmol) and 5-bromo-l,3,4-thiadiazol-2-amine (118.6 mg, crude) in EtOH (5.0 mL) was added NaHCO₃ (112.5 mg, 1.34 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column:Xselect CSH OBD Column 30* 150mm, 5 pm; Mobile Phase A: Water (0,1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 22% B to 42% B in 173MF-364282035Attorney Docket No.: 18407-20028.40lOmin; Wave Length: 254 / 220 nm) to afford 3-[(5-amino-l,3,4-thiadiazol-2-yl)amino]-8-(2- chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one; formic acid (101.6 mg, 32%, e.e.:::53.5%) as a white solid. LCMS (ESI, m / z): [M+H]+:::438.1.Step 8: Synthesis of (3R)-3-[(5-amino-ly3,4-thiadiazol-2-yl)amino]-8-(2-chIoro-4,5- difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one and (3S)-3-[(5-amino-l,3,4- thiadiazoI-2-yI)amino]-8-(2-chloro-4,5-difluorophenoxy)-l-methyI-3,4-dihydroquinolin-2- one (Compound 31 and Compound 32)Chlral-HPLCCompound 31

[0271] The product of3-[(5-amino-l,3,4-thiadiazol-2-yl)amino]-8-(2-chloro-4,5- difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one; formic acid (100.0 mg, 0.21 mmol, e.e.::::53.5%) was separated by Prep-Chiral-HPLC with the following conditions (Column:CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH)- HPLC, Mobile Phase B: ETOH: DCM=1: 1— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 40% B to 40% in 17min; Wave Length: 220 / 254 nm; RTl(min): 13.38; RT2(min):15.75) to afford (3R)-3-[(5-amino-l,3,4-thiadiazol-2-yl)amino]-8-(2-chloro-4,5- difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (Compound 31) (43.6 mg, 28%) as a white solid and (3S)-3-[(5-amino-l,3,4-thiadiazol-2-yl)amino]-8-(2-chloro-4,5- difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (Compound 32) (15.4 mg, 33%) as a white solid.

[0272] (3R)-3-[(5-amino-1,4-thiadiazol-2-yI)amino]-8-(2-chIoro-4,5-difIuorophenoxy)- l-methyl-3,4-dihydroquinolin-2-one: RTl(min): 13.38; LCMS (ESI, m / z): [M+H]+= 438.1.]H NMR (400 MHz, DMSO- s): 57.96 - 7.91 (m, 1H), 7.32 - 7.27 (m, 1H), 7.21 - 7.18 (m, 2H),7.15 - 7.11 (m, 1H), 6.85 (d,. / = 8.0 Hz, 1H), 6.26 (s, 2H), 4.46 - 4.40 (m, 1H), 3.36 - 3.31 (m, 4H), 2.93 - 2.86 (m, 1H).174MF-364282035Attorney Docket No.: 18407-20028.40

[0273] (3S)-3-[(5-amino-1 54-thiadiazol-2-yl)amino]-8-(2-chloro-4,5-difluorophenoxy)- l-methyI-3,4-dihydroquinolin-2-one: RTl(min): 15.75; LCMS (ESI, m / z): [M+H] =438.1.!H NMR (400 MHz, DMSO-: 57.96 - 7.91 (m, 1H), 7.32 - 7.27 (m, 1H), 7.21 - 7.18 (m, 2H)7.15 - 7.11 (m, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.26 (s, 2H), 4.46 - 4.40 (m, 1H), 3.36 - 3.31 (m, 4H), 2.93 - 2.86 (m, 1H).Example 27: Synthesis of (Rj-S-^S-anuno-l ^-thiadiazol^-ytyanuno^S- -chloro-S- fluorophenoxy^l-methyl-S^-dihydroquinolin^lE -one and (S)-3-((5-amino-l,3,4- thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinoHn-2(lH)-one (Compound 33 and Compound 34)Chiral-HPLCCompound 33 Compound 34(assumed) (assumed)

[0274] The racemic of3-[(5-amino-l,3,4-thiadiazol-2-yl)amino]-8-(2-chloro-5- fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (48.8 mg, 0.11 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRALPAK IG, 2 x 25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3·MeOH)-HPLC, Mobile Phase B: ETOH: DCM=1: 1-HPLC;Flow rate: 20 mL / min; Gradient (B%): isocratic 30; Wave Length: 220 / 254 nm; RTl(min):12,79; RT2(min): 19.17) to afford (R)-3-((5-amino-l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5- fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 33) (assumed, 14.9 mg, 31%) as a white solid and (S)-3-((5-amino-l,3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5- fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (Compound 34) (assumed, 13.9 mg, 29%) as a white solid.

[0275] (R)-3-((5-amino-l,3,4-thiadiazol-2-yI)amino)-8-(2-chloro-5-fluorophenoxy)-l- methyl-3,4-dihydroquinoIin-2(lH)-one: RTl(min): 12.79; LCMS (ES, m / z): [M+H]’ = 420.0.'H NMR (400.0 MHz, DMSO-d6): 87.68 - 7.65 (m, 1H), 7.24 - 7.21 (m, 2H), 7.18 - 7.14 (m, 1H), 7.09 - 7.04 (m, 1H), 6.94 - 6.92 (m, 1H), 6.88 - 6.85 (m, 1H), 6.29 (s, 2H), 4.44 - 4.38 (m, 1H), 3.24 (s, 3H), 2.94 - 2.86 (m, 1H).175MF-364282035Attorney Docket No.: 18407-20028.40

[0276] (S)-3-((5-amino-l 3,4-thiadiazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinoIin-2(lH)-one: RT2(min): 19.17; LCMS111: (ES, m / z): [M+H] = 420.1. NMR (400.0 MHz, DMSO-^): 57.69 - 7.65 (m, 1H), 7.24 - 7.21 (m, 2H), 7.18 - 7.16 (m, 1H), 7.09 - 7.04 (m, 1H), 6.95 - 6.92 (m, 1H), 6.89 - 6.86 (m, 1H), 6.30 (s, 2H), 4.44 - 4.40 (m, 1H), 3.30 - 3.26 (m, 1H), 3.24 (s, 3H), 2.93 - 2.86 (m, 1H).Example 28: Synthesis of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)-3,4-dihydroquinolin-2-one and 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)quinolin-2-one (Compound 35 and Compound 36)C!1612891-29-8 Cs2CO3, dioxaneCompound 36

[0277] To a solution of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (500.1 mg, 1.56 mmol) in dioxane (10.0 mL) was added 2 -bromopyridine (739.1 mg, 4.68 mmol), Cs2CO3(1.5 g, 4.68 mmol) and (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridinejpalladium (130.9 mg, 0.16 mmol) at room temperature under N2.. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O 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 (80 / 20, v / v) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)-3,4-dihydroquinolin-2-one (crude) and with petroleum ether / ethyl acetate (84 / 16, v / v) to afford 8-(2-chloro-5-fluorophenoxy)-l-niethyl-3-(pyridin-2-ylamino)quinolin-2-one (crude).176MF-364282035Attorney Docket No.: 18407-20028.40

[0278] The crude product of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)-3,4-dihydroquinolin-2-one was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30x150 mm; Mobile Phase A: Water(10 mmol / L NH4IICO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 52% B to 73% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)-3,4-dihydroquinolin-2-one (Compound 35) (107.9 mg, 17%) as a white solid.

[0279] The crude product of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)quinolin-2-one 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 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 63% B to 83% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(pyridin-2-ylamino)quinolin-2-one (Compound 36) (14.8 mg, 2%) as a white solid.

[0280] 8-(2-chIoro-5-fluorophenoxy)-l-methyI-3-(pyridin-2-yIamino)-3,4-dihydroquinoIin-2-one: LCMS (ESI, m / z): [M+H]+= 398.1. ^NMR (400 MHz, DMSO- &): 8 7.96 (d, J= 3.6 Hz, IH), 7.69 - 7.65 (m, 1H), 7.44 - 7.39 (m, IH), 7.23 - 7.18 (m, IH), 7.16 - 7.10 (m, IH), 7.09 - 7.05 (m, IH), 6.94 - 6.88 (m, 2H), 6.76 - 6.70 (m, 2H), 6.56 - 6.52 (m, IH), 4.74 - 4.68 (m, IH), 3.31 (s, 3H), 3.25 - 3.20 (m, IH), 2.97 - 2.90 (m, IH).

[0281] 8-(2-chIoro-5-fluorophenoxy)-l-methyI-3-(pyridin-2-yIamino)quinoIin-2-one: LCMS (ESI, m / z): [M+H]+= 396.1.!H NMR (400 MHz, DMSO-tfc): 68.95 (s, IH), 8.89 (s, IH), 8.34 - 8.32 (m, IH), 7.71 - 7.64 (m, 2H), 7.55 - 7.52 (m, IH), 7.39 (d, J = 8.4 Hz, IH), 7.27 - 7.23 (m, IH), 7.10 - 7.05 (m, IH), 7.00 - 6.97 (m, IH), 6.92 - 6.88 (m, IH), 6.83 - 6.79 (m, IH), 3.91 (s, 3H).Example 29: Synthesis of 8-(2-Chloro-5-fluorophenoxy)-l-methyl-3-((5,6,7,8-tetrahydro- [1,2,4]tria.olo[4,3-apyrimidin~3-yl)amino)~3,4-dihydroquinolin-2(lH)-one (Compound 37) Step 1: Synthesis of [l,2,4]TriazoIo[4,3-a]pyrimidine177MF-364282035Attorney Docket No.: 18407-20028.40NH2

[0282] A solution of 2-hydrazineylpyrimidine (6.4 g, 58.30 mmol) in trimethoxymethane (70.0 mL) was stirred at 105 °C for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CTLCh / MeOH (5 / 1, v / v) to afford [l,2,4]triazolo[4,3-a]pyrimidine (5.1 g, 72%) as a yellow solid. LCMS (ESI, m / z): [M+Hf = 121.0.Step 2: Synthesis of 5,6,7,8-Tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidinePd / C, H2MeOH

[0283] To a stirred solution of [l,2,4]Triazolo[4,3-a]pyrimidine (5.0 g, 41.62 mmol) in methanol (80.0 mL) were added Pd / C (2.2 g, dy') at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under H2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CHfeCh / MeOH (10 / 1, v / v) to afford 5, 6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidine (4.5 g, 87%) as a white solid. LCMS (ESI, m / z): [M+H]+ =::125.1.Step 3: Synthesis of Tert-butyl 6,7-dihydro-[l,2,4]triazoIo[4,3-a]pyrimidine-8(5H)-carboxylate(BOC)2O dioxane

[0284] To a stirred solution of 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidine (3.9 g, 31.97 mmol) in dioxane (100.0 mL) were added (BochO (10.4 g, 47.96 mmol) at room178MF-364282035Attorney Docket No.: 18407-20028.40temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with ClfcCk / MeOH (10 / 1, v / v) to afford tert-butyl 6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate (4.2 g, 58%) as a white solid. LCMS (ESI, m / z): [M+H]+= 225.1.Step 4: Synthesis of Tert-butyl 3-bromo-6,7-dihydro-[l,2,4]triazoIo[4,3-a]pyrimidine- 8(5H)-carboxylateNBS, DCM

[0285] To a stirred solution of tert-butyl 6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate (4.2 g, 18.72 mmol) in DCM (50.0 mL) were added NBS (4.0 g, 22.47 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 CH? Ch / MeOH (92 / 8, v / v) to afford tert-butyl 3-bromo-6,7-dihydro-[I,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate (1.0 g, 17%) as a white solid. LCMS (ESI, m / z): [M+H]+= 303.0.Step 5: Synthesis of Tert-butyl 3-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,354- tetrahydroquinolin-3-yl)amino)-6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate1612891-29-8, Cs2CO3, dioxane179MF-364282035Attorney Docket No.: 18407-20028.40

[0286] To a stirred mixture of 3-amino-8-(2-chloro-5-fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (456.3 mg, 1.42 mmol) and tert-butyl 3-bromo-6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate (431.2 mg, 1,42 mmol) in dioxane (30.0 m ) were added CS2CO3 (1390.5 mg, 4.268mmol) and (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichl oro-1, 3-dihy dro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (239.0 mg, 0.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (95 / 5, v / v) to afford tert-butyl 3-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine- 8(5H)-carboxylate (Compound 36) (212.6 mg, 27%) as a dark yellow solid. LCMS (ESI, m / z):[M+H]+= 543.2.Step 6: Synthesis of 8-(2-ChIoro-5-fluorophenoxy)-l-methyl-3-((5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidin-3-yl)amino)-3,4-dihydroquinolin-2(lH)-one (Compound 37)Compound 37

[0287] To a stirred solution of tert-butyl 3-((8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)aniino)-6,7-dihydro-[l,2,4]triazolo[4,3-a]pyrimidine-8(5H)-carboxylate (198.7 mg, 0.36 mmol) in DCM (4.0 mb) were added TFA (2.0 mb) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with saturated NaHCOs solution. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 180MF-364282035Attorney Docket No.: 18407-20028.40residue 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 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 26% B to 46% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidin-3-yl)amino)-3,4-dihydroquinolin-2(lH)-one (Compound 37) (24.5 mg, 15%) as a white solid. LCMS (ESI, m / z): [M+H]+= 443.1. ’HNMR (400 MHz, CD3OD): 67.55 - 7.53 (m, 1H), 7.23 - 7.16 (m, 2H), 6.95 - 6.89 (m, 2H), 6.67 - 6.64 (m, 1H), 4.41 - 4.36 (m, 1H), 3.91 - 3.75 (m, 2H), 3.44 (s, 3H), 3.39 - 3.34 (m, 1H), 3.30 - 3.26 (m, 2H), 3.09 - 3.01 (m, 111). 2.12 - 2.05 (m, 2H).Example 30: Synthesis of 8-[(6-isopropylpyridin-2-yl) oxy fl -methyl-3-(l, 3, 4-thiadiazol-2-ylamino)-3, 4-dihydroquinolin-2-one ( Compound 38)Step 1: Synthesis of 6-isopropylpyridin-2-ol

[0288] To a solution of 2-chloro-6-isopropylpyridine (8.9 g, 57.19 mmol) in dioxane (100.0 mL) and H2O (20.0 mL) was added KOH (9.8 g, 174.67 mmol), Pd2(dba)s (5.2 g, 5.68 mmol) and t-BuXPhos (4.4 g, 10.36 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature. The mixture was extracted with ethyl acetate. The combined organic layers were 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 CH2C12 / eOH (91 / 9, v / v) to afford 6-isopropylpyridin-2-ol (4.1 g, 52%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 138.1.Step 2: Synthesis of 2-(3-bromo~2-nitrophenoxy)-6-isopropylpyridine181MF-364282035Attorney Docket No.: 18407-20028.40Br

[0289] To a solution of 6-isopropylpyridin-2-ol (4.0 g, 29.16 mmol) in DMF (100.0 mL) was added l-bromo-3-fluoro-2-nitrobenzene (6.4 g, 29.09 mmol) and CS2CO3 (19.0 g, 58.32 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with H2O. The mixture was extracted with ethyl acetate. The combined organic layers were 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 petroleum ether / ethyl acetate (75 / 25, v / v) to afford 2-(3-bromo-2-nitrophenoxy)-6-isopropylpyridine (8.0 g, 81%) as a light yellow oil. LCMS (ESI, m / z): [M+H]+= 337.0.Step 3: Synthesis of 2-bromo-6-[(6-isopropyIpyridin-2-yl)oxy] aniline

[0290] To a solution of 2-(3-bromo-2-nitrophenoxy)-6-isopropylpyridine (8.0 g, 23.73 mmol ) in EtOH (60.0 mL), AcOH (20.0 mL) and H2O (10.0 mL) was added Fe (6.6 g, 118.18 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with NaHCO₃ (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and 182MF-364282035Attorney Docket No.: 18407-20028.40filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (81 / 19, v / v) to afford 2-bromo-6-[(6-isopropylpyridin-2-yl)oxy]aniline (6.1 g, 84%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 307.0.Step 4: Synthesis of tert-butyl (8-((6-isopropyIpyridin-2-yI)oxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate

[0291] To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (9.7 g, 29.47 mmol) in DMF (100.0 mL) was added Zn (6.5 g, 99.42 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 2-bromo-6-[(6-isopropylpyri din-2 -yl)oxy]aniline (6.1 g, 19.86 mmol), XPhos (1.7 g, 3.57 mmol) and XPhos Pd G3 (1.7 g, 2.01 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was diluted with water and then extracted with ethyl acetate. The combined organic layers were 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 petroleum ether / ethyl acetate (76 / 24, v / v) to afford tert-butyl (8-((6-isopropylpyridin-2-yl)oxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.3 g, 67%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 398.2.Step 5: Synthesis of tert-butyl (8-((6-isopropylpyridin-2-yI)oxy)-l-niethyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate183MF-364282035Attorney Docket No.: 18407-20028.40CH3I, K2CO3DMFNHBoc NHBoc

[0292] To a solution of tert-butyl (8-((6-isopropylpyridin-2-yl)oxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.0 g, 2.52 mmol) in DMF (15.0 mL) was added Mel (642.8 mg, 4.53 mmol) and K2CO3 (695.4 mg, 5.03 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 water and then extracted with ethyl acetate. The combined organic layers were 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 petroleum ether / ethyl acetate (81 / 19, v / v) to afford tert-butyl (8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (950.0 mg, 92%) as a light yellow solid. LCMS (ESI, m / z): [M+Hf = 412.2.Step 6: Synthesis of 3-amino-8-((6-isopropylpyridm-2-yl)oxy)-l-methyl-3,4-dihydroquinoIin- flJ / y-one

[0293] A solution of tert-butyl (8-((6-isopropylpyridin-2-yl)oxy )-l -methyl -2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (895.0 mg, 2.18 mmol) in HC1 / dioxane (5.0 mL, 4 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the 184MF-364282035Attorney Docket No.: 18407-20028.40mixture was adjusted to 7 with NaHCOs (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 3-amino-8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-3,4-dihydroquinolin-2(127)-one (796.0 mg, crude) as a light yellow oil. LCMS (ESI, m / z): [M+H]+= 312.2.Step 7: Synthesis of ethyl 5-((8-((6-isopropylpyridin-2-yl)oxy)-l-methyI-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-thiadiazole-2-carboxylate

[0294] To a solution of 3-amino-8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-3,4-dihydroquinolin-2(l / / )-one (756.0 mg, crude) in DMF (5.0 mL) was added ethyl 5-chloro-l,3,4-thiadiazole-2-carboxylate (561.2 mg, 2.91 mmol) and DIEA (1.3 g, 10.06 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with H2O. The mixture was extracted with ethyl acetate. The combined organic layers were 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 petroleum ether / ethyl acetate (65 / 35, v / v) to afford ethyl 5-((8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-thiadiazole-2-carboxylate (550.0 mg, 48%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 468.2.Step 8: Synthesis of 3-((l,3,4-thiadiazol-2-yI)amino)-8-((6-isopropyIpy idin-2-yl)oxy)-l-methyl-3,4-dihydroquino!in-2(l / / )-one (Compound 38)185MF-364282035Attorney Docket No.: 18407-20028.401) LiOH. H2O, THF, H2O2) HCI (1 mol / L)Compound 38

[0295] To a solution of ethyl 5-((8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)amino)-l,3,4-thiadiazole-2-carboxylate (150.0 mg, 0.32 mmol) in THF (4.0 mL) was added LiOH. H2O (67.3 mg, 1.60 mmol) in H2O (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, HC1 (1.0 mL, 1 mol / L) was added to the mixture at room temperature. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD Cl 8, 30x150 mm, 5 pm; 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, 37% B to 57% B in 10 min; Wave Length: 254 / 220 nm) to afford 3-((l,3,4-thiadiazol-2-yl)amino)-8-((6-isopropylpyridin-2-yl)oxy)-l-methyl-3,4-dihydroquinolin-2(177)-one (Compound 38) (80.8 mg, 64%) as a white solid. LCMS (ESI, m / z): [M+H]+= 396.2.NMR (400 MHz, DMSO-d6): 38.68 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.25 - 7.15 (m, 2H), 7.09 (d, J= 8.0 Hz, 1H), 7.00 (d, J - 7.6 Hz, 1H), 6.85 (d,. / 8.0 Hz, 1H), 4.50 - 4.43 (m, 1H), 3.42 - 3.37 (m, 1H), 3.17 (s, 3H), 3.00 - 2.92 (m, 1H), 2.87 - 2.76 (m, 1H), 1.08 - 1.05 (m, 6H).186MF-364282035Attorney Docket No.: 18407-20028.40Example 31: Synthesis of (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(3H-l,2,3-triazol-4- ylamino)-3,4-dihydroquinolin-2-one and (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(3H- l,2,3-triazol-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 39 and Compound 40)FCompound 40

[0296] The racemic product of 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(3H-l,2,3-triazol- 4-ylamino)-3,4-dihydroquinolin-2-one (80.0 mg, 0.21 mmol) was separated by Prep-Chiral- HPLC with the following conditions: (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: Hex— HPLC, Mobile Phase B: ETOH: DCM=1: 1— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 30% B to 30% in 16min% B; Wave Length: 220 / 254 nm; RTl(min): 7.22;RT2(min): 12.01) to afford (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(3H-l,2,3-triazol-4- ylamino)-3,4-dihydroquinolin-2-one (Compound 39) (16.9 mg, 21%) as a white solid and (3S)- 8-(2-chloro-5-fluorophenoxy)-l-methyl-3-(3H-l,2,3-triazol-4-ylamino)-3,4-dihydroquinolin-2- one (Compound 40) (17.1 mg, 21%) as a white solid.

[0297] (3R)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3-(3H-l,2,3-triazoI-4-ylamino)-3,4- dihydroquinoIin-2-one: RTl(min): 7.22; LCMS (ESI, m / z): [M+H]+= 388.1.1H NMR (400 MHz, DMSO-d6): δ 13.64 (s, 1H), 7.69 - 7.64 (m, 1H), 7.25 - 7.04 (m, 4H), 6.95 - 6.85 (m, 2H), 5.87 (s, 1H), 4.19 - 4.12 (m, 1 H), 3.32 - 3.28 (m, 4H), 2.97 - 2.90 (m, 1 H).

[0298] (3S)-8-(2-chloro-5-fluorophenoxy)-l-methyI-3-(3H-l,2,3-triazol-4-yIamino)-3,4- dihydroquinoIin-2-oiie: RT2(min): 12.01; LCMS (ESI, m / z): [M+H]+= 388.1.rH NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 7.69 - 7.65 (m, 1H), 7.25 - 7.04 (m, 4H), 6.99 - 6.85 (m, 2H), 5.88 (s, 1H), 4.18 - 4.13 (m, 1H), 3.32 - 3.29 (m, 4H), 2.96 - 2.89 (m, 1H).Example 32: Synthesis of (3R)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-(lI{-l,2,3-triazol- 4-ylamino)-3,4-dihydroquinolin-2-one and (3S)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3- (1 II-l,2,3-triazol-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 41 and Compound 42) Step 1: Synthesis of 4-bromo-l-(oxan-2-yl)-l,2,3-triazole187MF-364282035Attorney Docket No.: 18407-20028.40H THF>NN,TsOH, DCMNBr

[0299] To a solution of 4-bromo-lH-l,2,3-triazole (2.0 g, 13.52 mmol) and 3,4-dihydro-2H-pyran (2.3 g, 27.03 mmol) in DCM (25.0 mL) was added 4-methylbenzene-l -sulfonic acid hydrate (1.3 g, 6.76 mmol) at room temperature. The resulting mixture was stirred at room temperature for 6 h. After the reaction was completed, the resulting mixture diluted with DCM. The mixture was washed with NaHCO₃ (aq ), brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography petroleum ether / ethyl acetate (15 / 85, v / v) to afford 4-bromo-l-(oxan-2-yl)~ 1,2,3-triazole (2.8 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 232.0.Step 2: Synthesis of 8-(2-chIoro-4,5-difIuorophenoxy)-l-methyI-3-((l-(tetrahydro-2H-pyran-2-yI)-lH-l,2,3-triazol-4-yI)amino)-3,4-dihydroqiiinolin-2(ZH)-oneTHPyNN, NBr

[0300] To a mixture of 4-bromo-l-(oxan-2-yl)- 1,2, 3 -triazole (515.2 mg, crude) and 3-amino- 8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3,4-dihydroquinolin-2-one (496.0 mg, 1.46 mmol) in toluene (20.0 mL) was added GPhos Pd G6 TES (108.1 mg, 0.11 mmol), CS2CO3 (1.1 g, 3.38 mmol) and GPhos (62.0 mg, 0.12 mmol) at room temperature under N?. The resulting mixture was stirred at 100 °C for 3 h under N2. After the reaction was completed, the resulting mixture was cooled to room and diluted with water. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and fdtered. The filtrate was concentrated under vacuum. The residue was purified by flash column 188MF-364282035Attorney Docket No.: 18407-20028.40chromatography with CH3OH / CH2CI2 (5 / 95, v / v) to afford 8-(2-chloro-4,5-difluorophenoxy)-l- methyl-3-((l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,3-triazol-4-yl)amino)-3,4-dihydroquinolin- 2(7 T)-one (606.2 mg, 85%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 490.1.Step 3: Synthesis of 8-(2-chloro-4,5-difluorophenoxy)-l -methyl-3-(3H-l,2,3-triazol-4- ylamino)-3,4-dihydroquinolin-2-oneF

[0301] To a solution of 8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-((l-(tetrahydro-2H- pyran-2-yl)-lH-l,2,3-triazol-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (385.8 mg, 0.79 mmol) in MeOH (12.0 mL) was added HCl / l,4-di oxane (0.7 mL, 4.0 mol / L) at 0 °C. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the pH value of the mixture was adjusted to 7.0 with NaHCO₃ (aq). at 0 °C. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 8-(2-chloro- 4,5-difluorophenoxy)-l-methyl-3-(3H-l,2,3-triazol-4-ylamino)-3,4-dihydroquinolin-2-one(221.3 mg, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H] = 406.1.Step 4: Synthesis of (3R)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-(lH-l,2,3-triazol-4- ylamino)-3,4-dihydroquinolin-2-one and (3S)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3- (lH-l,2,3-triazol-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 41 and Compound 42)FChiral-HPLCCompound 41 Compound 42 (assumed) (assumed)189MF-364282035Attorney Docket No.: 18407-20028.40

[0302] The racemic product of 8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-(3H-l,2,3- triazol-4-ylamino)-3,4-dihydroquinolin-2-one (220.0 nig, 0.54 mmol) was separated by Chiral- Prep-HPLC with the following conditions (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: Hex— HPLC, Mobile Phase B: ETOH: DCM=1: 1— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 30% B to 30% B in 12 min; Wave Length: 220 / 254 nm; RTl(min): 7.89; RT2(min): 10.18) to afford (3R)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-(lH-l,2,3- triazol-4-ylamino)-3,4-dihydroquinolin-2-one (Compound 41) (assumed, 45.9 mg, 21%) as a white solid and (3S)-8-(2-chloro-4,5-difluorophenoxy)-l-methyl-3-(lH-l,2,3-triazol-4-ylamino)- 3.4-dihydroquinolin-2-one (Compound 42) (assumed, 33.8 mg, 15%) as a white solid.

[0303] (3R)-8-(2-chloro-4,5-difIuorophenoxy)-l-methyI-3-(lH-l,2,3-triazol-4-ylainino)- 3.4-dihydroquinoIin-2-one: RTl(min): 7.89; LCMS (ESI, m / z): [M+H]+= 406.2. ’HNMR (400 MHz, DMSO-d6): δ 13.64 (s, 1H), 7.97 - 7.92 (m, 1H), 7.32 - 7.27 (m, 1H), 7.21 - 7.11 (m, 3H), 6.86 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 4.20 - 4.14 (m, 1H), 3.31 - 3.27 (m, 1H), 2.96 - 2.89 (m, 1H).

[0304] (3S)-8-(2-chloro-4,5-difluorophenoxy)-l-methyI-3-(lH-l,2,3-triazol-4-yIamino)- 3.4-dihydroquinolin-2-one: RTl(min): 10.18; LCMS (ESI, m / z): [M+H]+= 406.2.!HNMR (400 MHz, DMSO-d6): δ 13.66 (s, 1H), 7.97 - 7.92 (m, 1H), 7.32 - 7.27 (m, 1H), 7.21 - 7.11 (m, 3H), 6.86 (d,. / 7.6 Hz, III), 5.87 (s, III), 4.20 - 4.14 (m, 1H), 3.31 - 3.27 (m, 1H), 2.96 - 2.89 (m, 1H).Example 33: Synthesis of Synthesis of (S)-l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl- 4.5-dihydroimidazo[l,2-a]quinolin-4-yl)urea and (R)-l -(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroiniidazo[l,2-a]quinolin-4-yl)urea (Compound 43 and Compound 44)Step 1: Synthesis of Tert-butyl (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l, 2,3,4- tetrahydroquinolin-3-yl)carbamate190MF-364282035Attorney Docket No.: 18407-20028.401)Zn, DMF2) Pd(OAc)2, XPhosBr

[0305] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (6.1 g, 18.53 mmol) in DMF (100.0 mL) was added Zn (2.1 g, 32.12 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 6-bromo-3-chloro-2-(2-chloro-5-fluorophenoxy)aniline (5.0 g, 14.25 mmol), XPhos (679.1 mg, 1.42 mmol) and Pd(OAc)2 (159.9 mg, 0.71 mmol) at room temperature under N2. The resulting mixture was stirred at 40 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H? O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 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) to afford tert-butyl (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (5.0 g, 80%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 441.1.Step 2: Synthesis of Tert-butyl (7-chIoro-8-(2-chloro-5-fliiorophenoxy)-2-thioxo-l,2,3?4-tetrahydroquinolin-3-yl)carbamate

[0306] To a solution of Na2COs (1.7 g, 16.04 mmol) in THF (100.0 niL) was added P2S5(3.5 g, 15.75 mmol) at room temperature. The resulting mixture was stirred at room temperature for 191MF-364282035Attorney Docket No.: 18407-20028.4030 min. To the above mixture was added tert-butyl N-[(3R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-3,4-dihydro-lH-quinolin-3-yl]carbamate (3.0 g, 6.80 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 2 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 (80 / 20, v / v) to afford tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (2.0 g, 64%) as a light yellow solid. LCMS (ESI, m / z): [M+H] = 457.0.Step 3: Synthesis of Tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyl)iniino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate

[0307] To a solution of tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (1.9 g, 4.15 mmol) in EtOH (30.0 mL) was added 2,2-dim ethoxypropan- 1 -amine (1.5 g, 12.59 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 30 min 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 (30 / 70, v / v) to afford tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.2 g, 53%) as a white solid. LCMS (ESI, m / z): [M+H]4= 542.2.Step 4: Synthesis of Tert-butyl (8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinoIin-4-yl)carbamate192MF-364282035Attorney Docket No.: 18407-20028.40

[0308] To a solution of tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-((2,2-dimethoxypropyl)imino)-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.1 g, 2.03 mmol) in toluene (10.0 mL) was added TsOH. H O (77.2 mg, 0.41 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 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 (60 / 40, v / v) to afford tert-butyl (8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (620.0 mg, 64%) as a pink solid. LCMS (ESI, m / z): [M+H]+::::478.1.Step 5: Synthesis of 8-chIoro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amineHCI in dioxaneNHBoc

[0309] A solution of tert-butyl (8-chloro-9-(2-chloro-5-fluorophenoxy)-l -methyl -4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (600.0 mg, 1.25 mmol) in HCl / 1,4-dioxane (5.0 mL, 4.0 mol / L) was stirred at room temperature for 30 min. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCOs (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous 193MF-364282035Attorney Docket No.: 18407-20028.40sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (610.0 mg, crude) as a red solid. LCMS (ESI, m / z): [M+H]+:::378.0.Step 6: Synthesis of l-(8-chloro-9-(2-chIoro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinoIin-4-yl)urea

[0310] To a solution of 8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (600.0 mg, crude) in methanol (10.0 niL) was added isocyanatotrimethylsilane (219.3 mg, 1.90 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 20% B to 40% B in lOmin; Wave Length: 254 / 220 nm) to afford l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (300.0 mg, 45%) as a white solid. LCMS (ESI, m / z): [M+H]+= 421.1.Step 7: Synthesis of (S)-l-(8-chIoro-9-(2-chloro-5-fluorophenoxy)-l-methyI-4,5-dihydroimidazo[l,2-a]quino!in-4-yI)urea and (R)-l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyI-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)urea (Compound 43 and Compound 44)194MF-364282035Attorney Docket No.: 18407-20028.40Chiral-HPLCCompound 43 Compound 44

[0311] The product of l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (100.0 mg, 0.24 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3·MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1- HPLC; Flow rate: 20 mL / min; Gradient (B%): 30% B to 30% B in 13.5 min% B; wave Length: 220 / 254 nm; RTl(min). 6.98; RT2(min): 10.34) to afford (S)-l-(8-chloro-9-(2-chloro-5- fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 43) (30.3 mg, 32%) as a white solid and (R)-l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 44) (27.6 mg, 28%) as a white solid.

[0312] (S)-l-(8-chloro-9-(2-chloro-5-fluorophenoxy)-l-methyI-4,5-dihydroimidazo[l,2-a] quinolin-4-yI)urea: RT 1 (min): 6.98; LCMS (ESI, m / z): [M+H]+= 421.0. 'HNMR (400 MHz, DMSO- de): 57.63 - 7.59 (m, 2H), 7.54 (d, J= 8.0 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.71 (d, J = 0.8 Hz, 1H), 6.48 (s, 1H), 6.35 - 6.32 (m, 1H), 5.78 (s, 2H), 4.98 - 4.93 (m, 1H), 3.25 - 3.21 (m, 1H), 2.77 - 2.70 (m, 1H), 2.39 (s, 3H).

[0313] (R)-l-(8-chloro-9-(2-chIoro-5-fluorophenoxy)-l-methyI-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)urea: RT2(min): 10.34; LCMS (ESI, m / z): [M+H]+= 421.0. ‘HNMR (400 MHz, DMSO- de): 87.63 - 7.53 (m, 3H), 6.96 - 6.92 (m, 1H), 6.72 (s, 1H), 6.48 (d,.7= 5.2 Hz, 1H), 6.35 - 6.32 (m, 1H), 5.78 (s, 2H), 4.98 - 4.93 (m, 1H), 3.26 - 3.21 (m, 1H), 2.77 - 2.68 (m, 1H), 2.39 (s, 3H).195MF-364282035Attorney Docket No.: 18407-20028.40Example 34: Synthesis of l-(8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl) rea (Compound 45)Step 1: Synthesis of l-bromo-4-chloro-3-isopropoxy-2-nitrobenzeneBr

[0314] To a solution of propan-2-ol (708.6 mg, 11.79 mmol) in THF (50.0 mL) was added NaH (1.4 g, 60%) at 0 °C under N2. The resulting mixture was stirred at room temperature for 0.5 h under N2. To the above mixture was added l-bromo-4-chloro-3-fluoro-2-nitrobenzene (3.0 g, 11.79 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. After the 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 Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford l-bromo-4-chloro-3-isopropoxy-2-nitrobenzene (3.6 g, crude) as a brown oil.Step 2: Synthesis of 6-bromo-3-chloro-2-isopropoxyanilineFe, NH4CIMeOH, H2OBr Br

[0315] To a solution of l-bromo-4-chl oro-3 -isopropoxy -2 -nitrobenzene (3.6 g, crude) in MeOH (100.0 mL) / H2O (20.0 mL) was added Fe (3.4 g, 60.88 mmol) and NH4C1 (3.3 g, 61.69 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (90 / 10, v / v) to afford 6-bromo-3-chloro-2-isopropoxyaniline (1.5 g, 46%) as a brown oil. LCMS (ESI, m / z): [M+H]+= 264.0.196MF-364282035Attorney Docket No.: 18407-20028.40Step 3: Synthesis of Tert-butyl (7-chIoro-8-isopropoxy-2-oxo-l,2,3,4-tetrahydroqiiinoIin-3-yl)carbamate1) Zn, DMF2) Pd(OAc)2>XPhosBr

[0316] To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.3 g, 6.99 mmol) in DMF (20.0 mL) was added Zn (833.8 mg, 12.75 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. To the above mixture was added 6-bromo-3-chloro-2-isopropoxyaniline (1.4 g, 5.29 mmol), XPhos (252.3 mg, 0.53 mmol) and Pd(OAc)2 (59.4 mg, 0.27 mmol) at room temperature under N?. The resulting mixture was stirred at 40 °C for additional 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure. The filtrate was was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford tert-butyl (7-chloro-8-isopropoxy-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.2 g, 64%) as a yellow7solid. l. CViS (ESI, m / z): [M+H]+= 355.1.Step 4: Synthesis of Tert-butyl (7-chIoro-8-isopropoxy-2-thioxo-l,2y3,4-tetrahydroquinolin-3-yl)carbamateP2S5, NaCO3, THFNHBoc

[0317] To a solution of Na2COs (820.8 mg, 7.74 mmo) in THF (20.0 mL) was added P2S5(1.7 g, 7.78 mmol) at room temperature. The resulting mixture was stirred at room temperature 197MF-364282035Attorney Docket No.: 18407-20028.40for I h. To the above mixture was added tert-butyl (7-chloro-8-isopropoxy-2-oxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (1.2 g, 3.38 mmol) at room temperature. The resulting mixture was stirred at 70 °C for additional 2 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 (80 / 20, v / v) to afford tert-butyl (7-chloro-8-isopropoxy-2-thioxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (1.0 g, 80%) as a yellow solid. LCMS (ESI, m / z): [M+H]4= 371.1.Step 5: Synthesis of Tert-butyl (7-chloro-2-((2,2-dimethoxypropyl)imino)-8-isopropoxy-l,2,3,4-tetrahydroquinolin-3-yl)carbamateNHBoc

[0318] To a solution of tert-butyl (7-chloro-8-isopropoxy-2-thioxo-l, 2,3,4-tetrahydroquinolin-3-yl)carbamate (1.0 g, 2.70 mmol) in EtOH (10.0 mL) was added 2,2-dimethoxypropan-1 -amine (1.0 g, 8.39 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N?. 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 (70 / 30, v / v) to afford tert-butyl (7-chloro-2-((2,2-dimethoxypropyl)imino)-8-isopropoxy-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (700.0 mg, 57%) as a white solid. LCMS (ESI, m / z): [M+H]4= 456.2.Step 6: Synthesis of Tert-butyl (8-chIoro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate198MF-364282035Attorney Docket No.: 18407-20028.40

[0319] To a solution of tert-butyl (7-chloro-2-((2,2-dimethoxypropyl)imino)-8-isopropoxy-l,2,3,4-tetrahydroquinolin-3-yl)carbamate (600.0 mg, 1.32 mmol) in toluene (10.0 mL) was added TsOHl O (50.1 mg, 0.26 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 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 (80 / 20, v / v) to afford tert-butyl (8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (400.0 mg, 78%) as a yellow solid. LCMS (ESI, m / z): | M • I::::392.2.Step 7: Synthesis of 8-chIoro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amineHCI in dioxaneNHBoc

[0320] A solution of tert-butyl (8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (300.0 mg, 0.77 mmol) in HC1 / 1,4-di oxane (5,0 mL, 4.0 mol / L) was stirred at room temperature for 30 min. After the reaction was completed, the pH ovalue f the mixture was adjusted to 7 with NaHCO₃ (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 8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (300.0 mg, crude) as a brown oil. LCMS (ESI, m / z): [M+H]+= 292.1.199MF-364282035Attorney Docket No.: 18407-20028.40Step 8: Synthesis of l-(8-chIoro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]qumolin- 4-yI)urea (Compound 45)Compound 45

[0321] To a solution of 8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-amine (300.0 mg, crude) in methanol (5.0 mL) was added TMSNCO (129.6 mg, 0,99 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep C18 OBD Column, 19x250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient (B%): 44% B to 54% B in 10 min; wave Length: 254 / 220 nm) to afford l-(8-chloro-9-isopropoxy-l-methyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl )urea (Compound 45) (122.7 mg, 36%) as a white solid. LCMS (ESI, m / z): [M+H]+= 335.1. ’HNMR (400 MHz, DMSO-de): 57.45 - 7.43 (m, 1H), 7.26 (d, J ------ 8.4 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 6.57 - 6.45 (m, 1H), 5.82 (s, 2H), 4.67 (s, 1H), 4.09 - 4.00 (m, 1H), 3.13 - 3.10 (m, 1H), 2.68 - 2.55 (m, 1H), 2.29 (s, 3H), 1.22 - 1.16 (m, 3 H ) 0.93 - 0.87 (m, 3H).Example 35: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4,5-dihydroimidazo[l,2-a quinolin-4-yl)urea (Compound 46)Step 1: Synthesis of tert-butyl N-[2-amino-8-(2-chIoro-5-fluorophenoxy)-3,4-dihydroquinoIin-3-yI]carbamateMF-364282035Attorney Docket No.: 18407-20028.40ClNH3, MeOHNHBoc NHBoc

[0322] A solution of tert-butyl N-[8-(2-chloro-5-fluorophenoxy)-2-sulfanylidene-3,4-dihydro-lH-quinolin-3-yl]carbamate (1.0 g, 2.37 mmol) inNHs / 'MeOH (10.0 mL, 7 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford tert-butyl N-[2-amino-8-(2-chloro-5-fluorophenoxy)-3,4-dihydroquinolin-3-yl]carbamate (1.1 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 406.1.Step 2: Synthesis of tert-butyl N-[8-(2-chloro-5-fluorophenoxy)-2-[(2-cydopropyl-2-oxoethyI)amino]-3,4-dihydroquinoIin-3-yI]carbamate and tert-butyl (9-(2-chIoro-5-fluorophenoxy)-2-cydopropyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamateNHBoc

[0323] To a mixture of tert-butyl N-[2-amino-8-(2-chloro-5-fluorophenoxy)-3,4-dihydroquinolin-3-yl]carbamate (370.0 mg, 0.91 mmol) and 2-bromo-l -cyclopropylethanone (445.8 mg, 2.74 mmol) in i-PrOH (5.0 mL) was added DIEA (235.6 mg, 1.82 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (30 / 70, v / v) to afford tert-butyl N-[8-(2-chloro-5-fluorophenoxy)-2-[(2-cyclopropyl-2-201MF-364282035Attorney Docket No.: 18407-20028.40oxoethyl)amino]-3,4-dihydroquinolin-3-yl]carbamate (240.0 mg, 54%) as a yellow solid and and tert-butyl (9-(2-chloro-5-fluorophenoxy)-2-cyclopropyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)carbamate (70.0 mg, 16%) as a yellow solid.

[0324] tert-butyl N-[8-(2-chIoro-5-fluorophenoxy)-2-[(2-cyclopropyl-2-oxocthyl)amino]-3,4-dihydroquinolin-3-yI]carbamate: LCMS (ESI, m / z): [M+H]+= 488.2.fH NMR (400 MHz, DMSO-dk): 67.53 - 7.50 (m, 1H), 7.30 (d, J= 8.8 Hz, 1H), 7.04 - 6.98 (m, 3H), 6.92 - 6.88 (m, 1H), 6.86 - 6.81 (m, 1H), 6.36 - 6.32 (m, 1H), 4.27 - 4.19 (m, 1H), 3.88 - 3.86 (m, 2H), 2.83 (d, J = 9.2 Hz, 2H), 1. 92 - 1.86 (m, 1H), 1.42 (s, 9H), 0.83 - 0.79 (m, 2H), 0.75 - 0.71 (m, 2H).

[0325] tert-butyl (9-(2-chIoro-5-fluorophenoxy)-2-cycIopropyI-4,5-dihydroimidazo[l,2-a]quinolin-4-yI)carbamate: LCMS (ESI, m / z): [M+H]4= 470.2.!H NMR (400 MHz, DMSO- d6) 57.71 - 7.68 (m, 1H), 7.54 (s, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.23 - 7.19 (m, 1H), 7.11 - 7.06 (m, 1H), 7.02 - 6.99 (m, 1H), 6.96 - 6.93 (m, 1H), 4.90 (s, 1H), 3.21 - 3.16 (m, 1H), 3.05 - 3.00 (m, 111). 1.83 - 1.76(m, 111) 1.42 (s, 9H), 0.79 - 0.74 (m, 2H), 0.63 - 0.59 (m, 2H).Step 3: Synthesis of tert-butyl N-[9-(2-chloro-5-fIuorophenoxy)-l-cydopropyI-4H,5H-imidazo [1,2-a] quinolin-4-yl] carbamateLawesson's Reagentdioxane, rt

[0326] To a solution of tert-butyl N-[8-(2-chloro-5-fluorophenoxy)-2-[(2-cyclopropyl-2-oxoethyl)amino]-3,4-dihydroquinolin-3-yl]carbamate (180.0 nig, 0.37 mmol) in dioxane (2.0 mL) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide (73.1 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and then extracted with ethyl acetate. The combined organic layers were washed with brine,202MF-364282035Attorney Docket No.: 18407-20028.40dried 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 (75 / 25, v / v) to afford tert-butyl N-[9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4H,5H-imidazo[l,2-a]quinolin-4-yl]carbamate (75.0 mg, 43%) as a yellow oil. LCMS (ESI, m / z):[M+H]4= 470.2.Step 4: Synthesis of 9-(2-chIoro-5-fluorophenoxy)-l-cycIopropyl-4H,5H-iniidazo[l,2-a]quinolin-4-amineHCI, dioxane

[0327] A solution of tert-butyl N-[9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4H,5H-imidazo[l,2-a]quinolin-4-yl]carbamate (70.0 mg, 0.15 mmol) in HCl / l,4-di oxane (4.0 mol / L, 1.0 mL) was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with saturated NaHCO₃ (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4H,5H-imidazo[l,2-a]quinolin-4-amine (60.0 mg, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]4= 370.1.Step 5: Synthesis of l-(9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4,5-dihydroimidazo[l,2-a]quinolin-4-yl)urea (Compound 46)203MF-364282035Attorney Docket No.: 18407-20028.40TMSNCO, MeOHCompound 46

[0328] To a solution of9-(2-chloro-5-fluorophenoxy)-l-cyclopropyl-4H,5H-imidazo[l,2-a] quinol in-4-am in e (55.0 mg, 0.15 mmol) in methanol (2.0 mL) was added isocyanatotrimethylsilane (20.5 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After t...

Claims

Attorney Docket No.: 18407-20028.40CLAIMSWhat is claimed is:Claim 1. A compound of Formula (B’) or (C):or a pharmaceutically acceptable salt thereof, wherein:B is optionally substituted Ce-ioaryl, optionally substituted Ci-ealkyl, optionally substituted Cj-ehaloalkyl, optionally substituted Ca-scycloalkyl, optionally substituted Cs-ehaolcycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl;— represents a single or double bond;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-6alkyl, or optionally substituted Cj-shaloalkyl;X is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Cnealkyl, or optionally substituted Ci^haloalkyl;Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or optionally substituted Ci-galkyl;q is 0, 1, or 2;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, optionally substituted Ci^alkyl, optionally substituted Ci-salkoxy, optionally substituted Ci-ehaloalkyl,398MF-364282035Attorney Docket No.: 18407-20028.40optionally substituted Ci^haloalkoxyl, optionally substituted -O-C3- 6cycloalkyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, optionally substituted -NH(Ci-6alkyl), optionally substituted -N(Ci-6alkyl)(Cj -ealkyl), optionally substituted -NH-C3-6cycloalkyl, optionally substituted Ce-ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3- ecycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl;either W1and W2are both -C-, or one of W1and W2is -C- and the other of W1and W2is -N-;WJis -CRy-, -NRy-, or -N-, wherein Ryis independently at each occurrence H,halogen, optionally substituted Ci-salkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C -6cycloalkyl, optionally substituted Cs- haolcycloalkyl or optionally substituted 4-8 membered heterocycloal yl;W4and W5are each independently -CH-, -NH-, or -N-;R3and R4are each independently H, deuterium, optionally substituted Cj-ealkyl, optionally substituted Ci-ehaloalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4-8 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 4-8 membered heterocycloalkyl;R5and R6when present, are each independently H, deuterium, optionally substituted Ci- 6alkyl, optionally substituted Ci- ialoalkyl, optionally substituted Cs-scycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form an optionally substituted Ch-scycloalkyl, or optionally substituted 4-8 membered heterocyclyl;R7when present, is H, deuterium, optionally substituted Ci-ealkyl, or optionally substituted Cuehaloalkyl; and399MF-364282035Attorney Docket No.: 18407-20028.40R9is optionally substituted Ci-ealkyl, optionally substituted Cj-ehaloalkyl, optionally substituted Cs-ecycloalkyl, optionally substituted Cs-ehalocycloalkyl, or optionally substituted 4-8 membered heterocycloalkyl.Claim 2, The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:B is optionally substituted Ce-ioaryl, Ci-ealkyl, Ci-ehaloalkyl, C^cycloalkyl, C3- 6haol cycloalkyl, 4-8 membered heterocycloalkyl, or 5-10 membered heteroaryl;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or Ci-ehaloalkyl;X2is 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H, optionally substituted Ci-ealkyl, or Ci-ehaloalkyl;Y is -O-, -C(R3)(R4)-, -C(F)2-, -C(O)-, -S(O)q-, or -N(Rb)-, wherein Rbis H or Ci- 6alkyl;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-salkyl, Cnealkoxy, Ci- ehaloalkyl, optionally substituted Ci-ehaloalkoxyl, -O-C3-6cycloalkyl, - S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), -NH2, -NH(Ci-6alkyl), -N(Ci- 6alkyl)(Ci-6alkyl -NH-Cs-ecycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl, C3-6cycloalkyl, or 4-8 membered heterocycloalkyl;W3is -CRy-, -NRy~, or -N-, wherein Ryis independently at each occurrence H, Ci- ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, Cs-ehaolcycloalkyl or 4-8 membered heterocycloalkyl;RJand R4are each independently H, deuterium, optionally substituted Ci-6alkyl, Ci- ehaloalkyl, Cs-ecycloalkyl, or 4-8 membered heterocycloalkyl, orRJand R4are taken together with the carbon atom to which they are attached to form an C3-8 cycloalkyl, or 4-8 membered heterocycloalkyl;400MF-364282035Attorney Docket No.: 18407-20028.40R5and R6when present, are each independently H, deuterium, Ci-ealkyl, Ci-ehaloalkyl, C3- 6cycloalkyl, or 4-8 membered heterocycloalkyl, orR5and R6are taken together with the carbon atom to which they are attached to form C3- scycloalkyl, or 4-8 membered heterocyclyl;R7when present, is H, deuterium, Ci^alkyl, or Ci-ehaloalkyl; andR9is Ci-6 lkyl, Ci-ehaloalkyl, C3-6cycloalkyl, C3-ehalocycloalkyl, or 4-8 membered heterocycloalkyl.Claim 3, The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (B):or a pharmaceutically acceptable salt thereof.Claim 4. The compound of any one of claim 1 -3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I) or (III):or a pharmaceutically acceptable salt thereof, wherein401MF-364282035Attorney Docket No.: 18407-20028.40B1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl, Ci-ealkoxy, Ci- ohaloalkyl, Ci-ehaloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), - NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)(Ci-6alkyl), Ce-ioaryl, 5-10 membered heteroaryl, C3-6cycloalkyl, Cs-ehaolcycloalkyl, or 4-8 membered heterocycloalkyl; andR10is Ci-6alkyl, Cj-shaloalkyl, or Ca-scycloalkyl.Claim 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X1is 5-9 membered heteroaryl or -C(O)NH2, wherein the 5-9 membered heteroaryl is optionally substituted with one or more -NH2, -NH(Ci-6alkyl), or N(Ci-6alkyl)2;Claim 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable saltthereof, wherein X1isClaim 7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (C):or a pharmaceutically acceptable salt thereof.402MF-364282035Attorney Docket No.: 18407-20028.40Claim 8. The compound of any one of claims 1, 2, and 7, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II) or (IV):or a pharmaceutically acceptable salt thereof, whereinB1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, -CN, -OH, -NO2, halogen, Ci-ealkyl, Ci^alkoxy, Cn ehaloalkyl, Cj-6haloalkoxyl, -S(O)q(Ci-6alkyl), -S(O)q(C3-6cycloalkyl), - NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)(Ci^,alkyl), Cg-ioaryl, 5-10 membered heteroaryl, C3-6cycloalkyl, Cs-^haolcycloalkyl, or 4-8 membered heterocy cl oal ky I; andR10is Ci-6alkyl, Cj-shaloalkyl, or Cs-ecycloalkyl.Claim 9, The compound of any one of claims 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is optionally substituted 5-6 membered heteroaryl.Claim 10. The compound of any one of claims 1, 2, 7, and 8, or a pharmaceuticallyacceptable salt thereof, wherien X2isClaim 11. The compound of any one of claims 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is -C(O)NHRaand Rais H or optionally substituted Cnealkyl.Claim 12. The compound of any one of claims 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein X2is -C(O)NHRaand Rais H, methyl, or ethyl.403MF-364282035Attorney Docket No.: 18407-20028.40Claim 13. The compound of any one of claims 1, 2, and 7-12, or a pharmaceuticallyacceptable salt thereof, wherein the moiety represented byClaim 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Y is -O-, -NH-, or -S-.Claim 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each of A1, A2, and A3is -CRW-.Claim 16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein one of A1, A2, and A3is -N-, and the remainder are -CRW-.Claim 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, halo, or Ci-calkyl.Claim 18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H, Cl, F, or methyl.Claim 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein Rwis independently at each occurrence H.404MF-364282035Attorney Docket No.: 18407-20028.40Claim 20. The compound of any one of claims 1-18, or a pharmaceutically acceptable saltClaim 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt B1=B2I - ( / \xB3’ V / / thereof, wherein B isB5-B4,and at least four of B1, B2, B3, B4, and B5are -CRX-.Claim 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein B is phenyl or pyridyl optionally substituted with one or more halogen, Cn 6alkyl, Ci-ehaloalkoxyl, or C3-6cycloalkyl.Claim 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable saltClaim 24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt405MF-364282035Attorney Docket No.: 18407-20028.40Claim 25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H.Claim 26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R7is H.Claim 27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R9is Ci-salkyl.Claim 28. The compound of any of claims 1-27, or a pharmaceutically acceptbale salt thereof, wherein R9is methyl, ethyl, or isopropyl.Claim 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:B1=B2(\ / XBis B5-B4, Ci-6alkyl, Cnehaloalkyl, or C3-6cycloalkyl;X1is optionally substituted 5-9 membered heteroaryl or -C(O)NHRa, wherein Rais H;X2is 5-6 membered heteroaryl or -C(O)NHRa, wherein Rais H or optionally substituted Cnealkyl;Y is -O-, -NH-, or -S-;A1, A2, and A3are each independently -CRW- or -N-, wherein Rwis independently at each occurrence H, halogen, or optionally substituted Cj-salkyl;B1, B2, B3, B4and B5are each independently -CRX- or -N-, wherein Rxis independently at each occurrence H, halogen, Ci-salkyl, Cj-ehaloalkoxyl, or Ch-ecycloalkyl;W1and W2are each independently -C- or -N-;W3is -CRy-, -NR5'-, or -N-, wherein Ryis independently at each occurrence H, Ci- ealkyl, or C3-6cycloalkyl;406MF-364282035Attorney Docket No.: 18407-20028.40W4and W3are each independently -CH- or -N-;R5and R6when present, are each H;when present, is H; andis optionally substituted Ci-6alkyl.Claim 30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting ofMF-364282035Attorney Docket No.: 18407-20028.40FFF408MF-364282035Attorney Docket No.: 18407-20028.40FMF-364282035Attorney Docket No.: 18407-20028.40410MF-364282035Attorney Docket No.: 18407-20028.40F411MF-364282035Attorney Docket No.: 18407-20028.40MF-364282035Attorney Docket No.: 18407-20028.40MF-364282035Attorney Docket No.: 18407-20028.40414MF-364282035Attorney Docket No.: 18407-20028.40NH2S^ / NHH2N-< TN-N415MF-364282035Attorney Docket No.: 18407-20028.40NH2MF-364282035Attorney Docket No.: 18407-20028.40and NH2Claim 31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I-S 1),(II-S 1), (III-S1), or (IV-S1):Claim 32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (1-S2),(II-S2), (III-S2), or (IV-S2):417MF-364282035Attorney Docket No.: 18407-20028.40Claim 33. A pharmaceutical composition comprising the compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.Claim 34. 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 1-32, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 31.Claim 35. 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 1-32, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 33.MF-364282035Attorney Docket No.: 18407-20028.40Claim 36. The method of claim 35, 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.Claim 37. The method of claim 35 or 36, wherein the disease, disorder, or condition is selected from the group consisting of Grave’s disease, Grave’s ophthalmology and thyroid eye disease.Claim 38. The method of any one of claims 35-37, wherein the disease, disorder, or condition is Grave’s disease.MF-364282035

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