Methods of treating cardiometabolic diseases

Abstract

Provided herein are compounds of Formula (A), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: ring A, RA, I1, I2, I3, Q, and Z are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof, and methods of using a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof e.g., in the treatment of cardiometabolic and cardiovascular diseases.

Description

ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062METHODS OF TREATING CARDIOMETABOLIC DISEASES CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 753,846, filed February 4, 2025, U.S. Provisional Patent Application No. 63 / 754,459, filed February 5, 2025, and U.S. Provisional Patent Application No. 63 / 754,462, filed February 5, 2025, all of which are hereby incorporated by reference.BACKGROUND

[0002] Aldehyde dehydrogenases (Aldhs, ALDHs) belong to a superfamily of NAD(P+)-dependent enzymes that play a role in the metabolism of aldehydes by irreversibly catalyzing the oxidation of both endogenously and exogenously produced aldehydes to their respective carboxylic acids. ALDHs have a broad spectrum of biological activities, including biosynthesis of retinoic acid (RA), oxidation of lipid peroxides, and alcohol metabolism, among others. ALDH, such as ALDH isoform la3 (ALDHla3) is implicated in various diseases or disorders such as proliferative diseases or disorders, metabolic diseases or disorders, endothelial cell or smooth muscle cell diseases or disorders etc.

[0003] There is a need for compounds that selectively inhibit ALDH enzymes such ALDHla3, as well as compositions and methods for treating a disease or disorder that is treatable by administration of an inhibit ALDH inhibitor such as an ALDHla3 inhibitor, such as cardiometabolic and cardiovascular diseases.SUMMARY

[0004] The present disclosure is directed to, in part, compounds that inhibit one or more ALDH enzymes such as ALDHla3, as well as pharmaceutical compositions thereof and uses thereof in treating various diseases or disorders. In particular embodiments, the compounds of the present disclosure are selective inhibitors of ALDHla3. In one aspect, the use relates to methods of treating cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder, muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder.1331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0005] In embodiments, provided herein is a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of:(i) a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; or(ii) a pharmaceutical composition comprising a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof, and a pharmaceutically acceptable carrier:wherein:ring A is an optionally substituted heteroaryl, an optionally substituted heterocyclyl or an optionally substituted aryl;RAis -H or -Ci-ealkyl;IJis CR4orN;12is CR3or N;13is CR7or N;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -H, halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;Q and Z are joined to form a heterocyclyl and substituted with oxo; and wherein the heterocycle may be further optionally substituted;R7is -H, -Ci-ealkyl or halo;R8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl; andwherein the disease or disorder is cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder, muscle inflammation, sarcopenia or bone density loss, non-alcoholic331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder.

[0006] In embodiments of the methods disclosed herein the compound of Formula (A) is a compound is of Formula (A-l):(A-l)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof,whereinring A is heteroaryl or aryl, wherein the heteroaryl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -NR8R9, -CN, -CI-6 alkyl, -Ci-ehaloalkyl, -Ci-6 alkylene-carbocyclyl, or -Ci-6 alkylene-heterocyclyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R7is -H, -Ci-ealkyl or halo;R8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl; andR5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.

[0007] In embodiments, the compound of Formula (A-l) is a compound of Formula (III):331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof wherein: ring A, R1, R2, n, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0008] In embodiments, the compound of Formula (I) is a compound of Formula (III-A):(in-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, R3, R4, R5A, R5B, R6A, R6B, R7, X1and X2are defined herein.

[0009] In embodiments, the compound of Formula (III) is a compound of Formula (III-B):(III-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0010] In embodiments, the compound of Formula (III) is a compound of Formula (III-C):4331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(III-C)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, R3, R4, R5A, R5B, R6A, R6B, R7, X1and X2are defined herein.

[0011] In embodiments, the compound of Formula (III) is a compound of Formula (III-D):(III-D)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0012] In embodiments, the compound of Formula (A-l) is a compound of Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: ring A, R1, R2, m, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0013] In embodiments, the compound of Formula (IV) is a compound of Formula (IV-A):5331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(IV-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, m, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0014] In embodiments, the compound of Formula (IV) is a compound of Formula (IV-B):(IV-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein: R1, R2, m, R3, R4, R5A, R5B, R6A, R6B, and R7are defined herein.

[0015] In embodiments, the lipid disorder is hyperlipidemia or dyslipidemia.

[0016] In embodiments, the cardiovascular disorder is pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A shows fasting blood glucose in ZDF rats treated with Compound 1 or vehicle control throughout the study disclosed in Example 19. All comparisons after day 0: p<0.001 by T-test.6331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0018] FIG. IB shows HbAlc (%) in ZDF rats treated with Compound 1 or vehicle control throughout the study disclosed in Example 19. All comparisons after day 0: p<0.001 by T-test.

[0019] FIG. 1C shows fasting plasma insulin in ZDF rats treated with Compound 1 or vehicle control throughout the study disclosed in Example 19. All comparisons after day 0: p<0.001 by T-test.

[0020] FIG. 2A shows water intake in ZDF rats treated with Compound 1 or vehicle control during the study disclosed in Example 19. Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0021] FIG. 2B shows body weight gain in ZDF rats treated with Compound 1 or vehicle control during the study disclosed in Example 19. Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0022] FIG. 3A shows liver mass normalized to total body mass and compared between Compound 1 treated and control groups (n=10) in the study disclosed in Example 19.Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0023] FIG. 3B shows kidney mass normalized to total body mass and compared between Compound 1 treated and control groups (n=10) in the study disclosed in Example 19.Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0024] FIG. 3C shows a molecular marker of liver injury (serum ALT) for ZDF rats treated with Compound 1 or vehicle control throughout the study described in Example 19.Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0025] FIG. 3D shows a molecular marker of kidney function (blood urea) for ZDF rats treated with Compound 1 or vehicle control throughout the study described in Example 19. Statistical significance at endpoints: p<0.001 by Student’s T-test.

[0026] FIG. 4 creatine kinase (U / L) levels for ZDF rats treated with Compound 1 or vehicle control throughout the study described in Example 19 (-32%, p<0.05, at the last day of treatment).

[0027] FIG. 5A shows body weight for 16-week-old male severely diabetic db / db mice treated with Compound 1 (50 mg / kg) or vehicle control PO QD for 28 days in the study described in Example 20.7331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0028] FIG. 5B shows glycated hemoglobin at experimental endpoint for severely diabetic db / db mice treated with Compound 1 (50 mg / kg) or vehicle control PO QD in the study described in Example 20. N= 9 mice / group. p<0.001 by T-test.

[0029] FIG. 5C shows pancreatic islet area at experimental endpoint for severely diabetic db / db mice treated with Compound 1 (50 mg / kg) or vehicle control PO QD in the study described in Example 20. N= 9 mice / group. p =0.05 by T-test.

[0030] FIG. 6A shows triglyceride levels in mice treated with Compound 1 or vehicle control PO QD in the study described in Example 20.

[0031] FIG. 6B shows LDL levels in mice treated with Compound 1 or vehicle control PO QD in the study described in Example 20.

[0032] FIG. 7A shows cardiac dynamics (end-systolic volume, ESV) for diabetic 7-week-old SDT fatty rats treated with vehicle control, Compound 1, and Semaglutide in the study described at Example 25.

[0033] FIG. 7B shows isovolumetric relaxation time (IVRT) for diabetic 7-week-old SDT fatty rats treated with vehicle control, Compound 1, and Semaglutide in the study described at Example 25.

[0034] FIG. 7C shows relative heart weight for diabetic 7-week-old SDT fatty rats treated with vehicle control, Compound 1, and Semaglutide in the study described at Example 25.DETAILED DESCRIPTIONDefinitions

[0035] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art.

[0036] The term “about” when immediately preceding a numerical value means a range of plus or minus an acceptable degree of variation in the art. In embodiments, the term “about” encompasses 10% of that value, e.g., “about 50” means 45 to 55, “about 25,000” means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is8331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein.

[0037] When a range of values is listed, it is intended to encompass each value and sub -range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs-6 alkyl.

[0038] The term “pharmaceutically acceptable salts” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0039] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0040] As used herein, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic saturated hydrocarbon. In embodiments, the alkyl is an alkyl containing one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated. In embodiments, the alkyl group is a straight chain C1-10 alkyl group. In embodiments, the alkyl group is a branched chain C1-10 alkyl group. In embodiments, the alkyl group is a straight chain C1-6 alkyl group. In embodiments, the alkyl group is a branched chain C1-6 alkyl group. In embodiments, the alkyl group is a straight chain Ci-4 alkyl group. In embodiments, the alkyl group is a branched chain Ci-4 alkyl group. For example, a Ci-4 alkyl group as used herein refers to a group selected from methyl, ethyl, / / -propyl, z-propyl, secpropyl, / / -butyl, z-butyl, sec-butyl, / -butyl, / / -pentyl, / -amyl, / / -hexyl, / / -heptyl, / / -octyl, n-nonyl, / / -decyl, / / -undecyl, and / / -dodecyl. In embodiments, “alkyl” is a straight-chain9331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0041] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical. In embodiments, the alkylene has from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0042] As used herein, the term “alkenyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds. In embodiments, the alkenyl group is a C2-6 alkenyl group. In embodiments, the alkenyl group is a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0043] As used herein, the term “alkynyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In embodiments, the alkynyl has one carboncarbon triple bond. In one embodiment, the alkynyl group is a C2-6 alkynyl group. In embodiments, the alkynyl group is a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0044] As used herein, the term “alkoxy” as used by itself or as part of another group refers to a radical of the formula ORal, wherein Ralis an alkyl, alkenyl, or alkynyl as defined herein. In embodiments, Ralis an alkyl. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0045] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon, and which is attached to the rest of the10331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062molecule by a single bond. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0046] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, spirocyclic, or bridged ring systems (e.g., fused, or bridged ring systems), having from three to twenty carbon atoms (e.g., 3-20, 3-10, 3-9 or 3-6), and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0047] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms (e.g., 3-20, 3-10, 3-9 or 3-6), preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0048] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having from 3 to 20 carbon atoms and one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyls include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0049] As used herein, the term “cycloalkoxy” as used by itself or as part of another group refers to a radical of the formula ORal, wherein Ralis a cycloalkyl as defined herein. Unless11331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062stated otherwise specifically in the specification, a cycloalkoxy group can be optionally substituted.

[0050] As used herein, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a Ci-io haloalkyl group. In embodiments, the haloalkyl group is a Ci-6 haloalkyl group. In embodiments, the haloalkyl group is a Ci-4 haloalkyl group. Unless otherwise stated specifically in the specification, a haloalkyl group can be optionally substituted.

[0051] “Heterocyclyl” or “heterocyclic” or “heterocycle” as used by itself or as part of another group refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is on the heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.12331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, andthianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Unless otherwise stated specifically in the specification, a heterocyclyl can be optionally substituted.

[0052] “Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In embodiments, an aryl group has ten ring carbon atoms (“Cioaryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise stated specifically in the specification, an aryl can be optionally substituted.

[0053] “Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of13331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

[0054] “Heteroaryl” as used by itself or as part of another group refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, / .<?., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadi azolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-14331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Unless otherwise stated specifically in the specification, a heteroaryl can be optionally substituted.

[0055] “Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0056] An “optionally substituted” group as used herein means any of the above groups, such as an optionally substituted alkyl, optionally substituted alkylene, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted carbocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted haloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable. Two of the optional substituents can join to form an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle. Typically, substitution herein does not result in an O-O, O-N, S-S, S-N (except SO2-N bond),15331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062heteroatom-halogen, or -C(O)-S bond or three or more consecutive heteroatoms, with the exception of O-SO2-O, O-SO2-N, and N-SO2-N, except that some of such bonds or connections may be allowed if in a stable aromatic system.

[0057] In embodiments, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate.

[0058] Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, — OH, hydroxyalkyl, haloalkyl, — O-alkyl, — O-haloalkyl, -alkylene-O-alkyl, — O-aryl, — O-alkylene-aryl, acyl, — C(O)-aryl, halo, — NO2, — CN, — SFs, — C(O)OH, — C(O)O-alkyl, — C(O)O-aryl, — C(O)O— alkylene-aryl, — S(O)-alkyl, — S(O)2-alkyl, — S(O)-aryl, — S(O)2-aryl, — S(O)-heteroaryl, — S(O)2-heteroaryl, — S-alkyl, — S-aryl, — S-heteroaryl, — S-alkylene-aryl, — S-alkylene-heteroaryl, — S(O)2-alkylene-aryl, — S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, — O — C(O)-alkyl, — O — C(O)-aryl, — O — C(O)-cycloalkyl, — C(=N— CN)— NH2, — C(=NH)— NH2, — C(=NH)— NH(alkyl), — N(YI)(Y2), -alkyl ene-N(Yi)(Y2), — C(O)N(YI)(Y2), and — S(O)2N(YI)(Y2), wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0059] Some examples of suitable substituents include, but not limited to, (Ci-Cs)alkyl groups, (C2-Cs)alkenyl groups, (C2-Cs)alkynyl groups, (C3-Cio)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (Ci-Cs)alkyl groups (for example but not limited to — CF3), — O — (Ci-Cs)alkyl groups, — OH, — S — (Ci-Cs)alkyl groups, — SH, — NH(Ci-Cs)alkyl16331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062groups, — N((Ci-Cs)alkyl)2 groups, — NH2, — C(0)NH2, — C(O)NH(Ci-Cs)alkyl groups, — C(O)N((Ci-C8)alkyl)2, — NHC(O)H, — NHC(O) (Ci-C8)alkyl groups, — NHC(O) (C3-C8)cycloalkyl groups, — N((Ci-C8)alkyl)C(O)H, — N((Ci-C8)alkyl)C(O)(Ci-C8)alkyl groups, — NHC(O)NH2, — NHC(O)NH(Ci-C8)alkyl groups, — N((Ci-C8)alkyl)C(O)NH2groups, — NHC(O)N((Ci-C8)alkyl)2groups, — N((Ci-C8)alkyl)C(O)N((Ci-C8)alkyl)2groups, — N((Ci-C8)alkyl)C(O)NH((Ci-C8)alkyl), — C(O)H, — C(O)(Ci-C8)alkyl groups, — CN, — NO2, — S(O)(Ci-C8)alkyl groups, — S(O)2(Ci-C8)alkyl groups, — S(O)2N((Ci-C8)alkyl)2 groups, — S(O)2NH(Ci-C8)alkyl groups, — S(O)2NH(C3-C8)cycloalkyl groups, — S(O)2NH2 groups, — NHS(O)2(Ci-C8)alkyl groups, — N((Ci-C8)alkyl)S(O)2(Ci-C8)alkyl groups, — (Ci-C8)alkyl-O— (Ci-C8)alkyl groups, — O— (Ci-C8)alkyl-O— (Ci-C8)alkyl groups, — C(O)OH, — C(O)O(Ci-C8)alkyl groups, NHOH, NHO(Ci-C8)alkyl groups, — O-halogenated (Ci-C8)alkyl groups (for example but not limited to — OCF3), — S(O)2-halogenated (Ci-C8)alkyl groups (for example but not limited to — S(O)2CF3), — S-halogenated (Ci-C8)alkyl groups (for example but not limited to — SCF3), — (Ci-Ce) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), — (Ci-Ce) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, — NHC(O)O — (Ci-C6)alkyl groups, — N((Ci-C6)alkyl)C(O)O— (Ci-C6)alkyl groups, — C(=NH)— (Ci-C6)alkyl groups, — C(=NOH) — (Ci-Ce)alkyl groups, or — C(=N — O — (Ci-C6)alkyl)-(Ci-Ce)alkyl groups.

[0060] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -NH2, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -SH, -SC1-6 alkyl, -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci 6 alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(CI-6 alkyl), -NHC(=O)(CI-6 alkyl), -N(CI-6 alkyl)C(=O)( Ci^ alkyl), -NHCO2(CI 6 alkyl), -NHC(=O)N(Ci 6 alkyl)2, -NHC(=O)NH(CI-6 alkyl), -NHC(=0)NH2, -NHSO2(CI 6 alkyl), -SO2N(Ci-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2 -SO2C1-6 alkyl, -SO2OC1 6 alkyl, -OSO2C1 6 alkyl, -SOCi 6 alkyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-1017331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062membered heterocyclyl, 5-10 membered heteroaryl, or two geminal substituents can be joined to form =0.

[0061] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, Ci-io alkyl, Ci-io haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tertButyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-m ethoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

[0062] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., those forming silyl ethers,18331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062such as trimethyl silyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, di chloroacetate, tri chloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

[0063] Unless expressly stated to the contrary, combinations of substituents and / or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0064] In some embodiments, the “optionally substituted” alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable), NH2, protected amino, NH(CI-4 alkyl) or a protected derivative thereof, N(Ci-4alkyl((Ci-4 alkyl), Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Ci-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable), Ci-4 alkyl, fluoro- substituted Ci-4 alkyl (e.g., CF3), Ci-4 alkoxy, and fluoro-substituted Ci-4 alkoxy.

[0065] In embodiments, the “optionally substituted” aryl or heteroaryl group herein can be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, -CN, NH2, protected amino, NH(CI-4 alkyl) or a protected derivative thereof, N(CI-4 alkyl((C 1-4 alkyl), -S(=O)(C 1-4 alkyl), -SO2(Ci-4 alkyl), Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Ci-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents19331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062independently selected from F, -OH, oxo (as applicable), Ci-4 alkyl, fluoro- substituted Ci-4 alkyl, Ci-4 alkoxy and fluoro- substituted Ci-4 alkoxy.

[0066] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.

[0067] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or isomers can be prepared by asymmetric syntheses. See, for example, Jacques etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen el al., Tetrahedron 332 25 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures.

[0068] Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to2H,3H,13C,14C,15N,18O,32P,35S,18F,36C1, and125I. Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention.

[0069] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature,20331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062solvent, and pH. Tautomerizations ( / .<?., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0070] The term “treating” means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.

[0071] The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.Compounds

[0072] The compounds of the present disclosure are useful for inhibiting aldehyde dehydrogenase (e.g., ALDHla3) and can be used for treating various diseases and disorders, such as cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder, muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder.Compounds of Formula (A)

[0073] In embodiments, provided herein is a compound of Formula (A):wherein:ring A is an optionally substituted heteroaryl, an optionally substituted heterocyclyl or an optionally substituted aryl;RAis -H or -Ci-ealkyl;21331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062IJis CR4orN;12is CR3or N;13is CR7or N;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -H, halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;Q and Z are joined to form a heterocyclyl and substituted with oxo; and wherein the heterocycle may be further optionally substituted;R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0074] In embodiments, the compound of Formula (A) is a compound of Formula (A-l):(A-l)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof,whereinring A is heteroaryl or aryl, wherein the heteroaryl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -NR8R9, -CN, -C1-6 alkyl, -Ci-ehaloalkyl, -C1-6 alkylene-carbocyclyl, or -C1-6 alkylene-heterocyclyl;R3is -H, halo, -C1-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -Ci-ehaloalkyl, - C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2; andR5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring;R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.Compounds of Formula (I)

[0075] In embodiments, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;n is 1 or 2;R3is -H, halo, -C1-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;23331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0076] In embodiments of the compounds of Formula (I), the compound is not:(i) 5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-, having the structure:(ii) 5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-; having the structure:(iii) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:(iv) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20624-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:

[0077] In embodiments of the compounds of Formula (I), ring A is heteroaryl.

[0078] In embodiments of the compounds of Formula (I), ring A is heteroaryl comprising at least one nitrogen atom.

[0079] In embodiments of the compounds of Formula (I), ring A is a monocyclic heteroaryl.

[0080] In embodiments of the compounds of Formula (I), ring A is a monocyclic heteroaryl comprising at least one nitrogen atom.

[0081] In embodiments of the compounds of Formula (I), ring A is a 5- or 6-membered heteroaryl.

[0082] In embodiments of the compounds of Formula (I), ring A is not an isothiazole.

[0083] In embodiments of the compounds of Formula (I), ring A is a heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or more heteroatoms independently selected from N and O.

[0084] In embodiments of the compounds of Formula (I), ring A is a heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments of the compounds of Formula (I), ring A is a monocyclic heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments of the compounds of Formula (I), ring A is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or two heteroatoms independently selected from N and O.25331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0085] In embodiments of the compounds of Formula (I), ring A is a heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (I), ring A is a monocyclic heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (I), ring A is a 5- or 6-membered heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (I), ring A is a 6-membered heteroaryl having one or two N atoms.

[0086] In embodiments of the compounds of Formula (I), ring A is a heteroaryl having one N atom. In embodiments of the compounds of Formula (I), ring A is a monocyclic heteroaryl having one N atom. In embodiments of the compounds of Formula (I), ring A is a 5- or 6-membered heteroaryl having one N atom.

[0087] In embodiments of the compounds of Formula (I), ring A is a 6-membered heteroaryl.

[0088] In embodiments of the compounds of Formula (I), ring A is 6-membered heteroaryl comprising at least one nitrogen atom.

[0089] In embodiments of the compounds of Formula (I), ring A is 6-membered heteroaryl comprising one or two nitrogen atoms.

[0090] In embodiments of the compounds of Formula (I), ring A is pyridyl.

[0091] In embodiments of the compounds of Formula (I), ring A is aryl.

[0092] In embodiments of the compounds of Formula (I), ring A is a phenyl.

[0093] In embodiments of the compounds of Formula (I), n is 1 or 2.

[0094] In embodiments of the compounds of Formula (I), n is 1.

[0095] In embodiments of the compounds of Formula (I), n is 2.

[0096] In embodiments, provided herein is a compound of Formula (I-A):(I-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form26331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062thereof;wherein:X1and X2are each independently CH or N;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0097] In embodiments of Formula (I- A), X1is CH and X2is N.

[0098] In embodiments of Formula (I- A), X1is N and X2is CH.

[0099] In embodiments of Formula (I- A), X1is CH and X2is CH.

[0100] In embodiments of Formula (I- A), X1is N and X2is N.

[0101] In embodiments, provided herein is a compound of Formula (I-B):(I-B)331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereofwherein:R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0102] In embodiments of the compounds of Formula (I-A) or (I-B), the compound is not:(i) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(ii) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(iii) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8- methyl-2-oxo-6-quinolinyl)-.

[0103] In embodiments, provided herein is a compound of Formula (I-C):(I-C)28331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:X1and X2are each independently CH or N;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0104] In embodiments of Formula (I-C), X1is CH and X2is N.

[0105] In embodiments of Formula (I-C), X1is N and X2is CH.

[0106] In embodiments of Formula (I-C), X1is CH and X2is CH.

[0107] In embodiments of Formula (I-C), X1is N and X2is N.

[0108] In embodiments, provided herein is a compound of Formula (I-D):(I-D)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form 29331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062thereofwherein:R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-6 haloalkyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-6 haloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-6 haloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0109] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C 1 -6 haloalky 1, halo, or -NR8R9.

[0110] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci -3 haloalkyl, halo, or -NR8R9.

[0111] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci -6 haloalkyl.

[0112] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci -3 haloalkyl.

[0113] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CF3, -CH2CF3, Cl, F, or -NH2.

[0114] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-6 haloalkyl or -NR8R9.

[0115] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci -3 haloalkyl or -NR8R9.30331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0116] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CF3, -CH2CF3, or -NH2.

[0117] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CF3 or -CH2CF3.

[0118] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CF3.

[0119] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CH2CF3.

[0120] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -C1-6 haloalkyl.

[0121] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is independently -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C 1-6 alkylene-heterocyclyl, or -Ci 6 haloalkyl.

[0122] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CN or -C1-6 alkyl.

[0123] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CN or -Ci-3 alkyl.

[0124] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CN, -CH3, or -CH2CH3.

[0125] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CN.

[0126] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -C1-6 alkyl.

[0127] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -Ci-3 alkyl.

[0128] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CH3.31331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0129] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R2is -CH2CH3.

[0130] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-6 haloalkyl and R2is independently -CN or -C1-6 alkyl.

[0131] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-6 haloalkyl and R2is -CN. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-3 haloalkyl and R2is -CN. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CH2CF3, and R2is -CN.

[0132] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-6 haloalkyl and R2is -C1-6 alkyl.

[0133] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is -H, halo, -C1-6 alkyl, or -C1-6 haloalkyl.

[0134] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is -H or halo.

[0135] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is -H.

[0136] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -C1-6 alkyl-CN, -C 1-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -C1-6 haloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2.

[0137] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -C1-6 alkyl-CN, -C 1-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl.

[0138] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -C1-6 alkyl-CN, -C 1-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl.32331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0139] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is halo, -CN, -Ci-ealkyl, -Ci-6 alkyl -CN, -Ci-6 haloalkyl, or carbocyclyl.

[0140] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is halo or -Ci-ealkyl.

[0141] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is -Ci-ealkyl.

[0142] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is -F or -CH3.

[0143] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R4is -CH3.

[0144] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-6 haloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -C 1-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is halo, -CN, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is halo or -Ci-ealkyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is -Ci-ealkyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is -F or -CH3. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is -CH3.

[0145] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci -6 haloalkyl, R2is -CN, R3is H, and R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl,33331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062heteroaryl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I- A), (I-B), (I-C), or (I-D), R1is -Ci-6 haloalkyl, R2is -CN, R3is H, and R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci-6 haloalkyl, R2is -CN, R3is H, and R4is halo, -CN, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, or carbocyclyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci-6 haloalkyl, R2is -CN, R3is H, and R4is halo or -Ci-ealkyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci-6 haloalkyl, R2is -CN, R3is H, and R4is -Ci-ealkyl. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -Ci-6 haloalkyl, R2is -CN, R3is H, and R4is -F or -CH3. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R3is H, and R4is -CH3. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -C1-3 haloalkyl and R2is -CN. In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R1is -CH2CF3, and R2is -CN.

[0146] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.

[0147] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 4-8 membered heterocyclic ring.

[0148] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl.

[0149] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R5A, R5B, R6A, and R6Bare -H.

[0150] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R7is -H, -Ci-ealkyl or halo.

[0151] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R7is -H or halo.34331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0152] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R7is -H or -F.

[0153] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R7is -H or -Ci-ealkyl.

[0154] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R7is -H.

[0155] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8and R9are each independently -H, -Ci-6 alkyl, aryl or heteroaryl.

[0156] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8and R9are each independently -H or -Ci-6 alkyl.

[0157] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8is -H or -Ci-ealkyl.

[0158] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8is -H.

[0159] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8is -Ci-ealkyl.

[0160] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R9is -H or -Ci-ealkyl.

[0161] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R9is -H.

[0162] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R9is -Ci-ealkyl.

[0163] In embodiments of the compounds of Formula (I), (I-A), (I-B), (I-C), or (I-D), R8and R9are -H.

[0164] In embodiments, provided herein is a compound of Formula (I), (I-A), (I-B), (I-C), or (I-D), or a pharmaceutically acceptable salt or deuterated form thereof.

[0165] In embodiments, provided herein is a compound of Formula (I), (I-A), (I-B), (I-C), or (I-D), or a pharmaceutically acceptable salt thereof.35331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0166] In embodiments, provided herein is a compound of Formula (I), (I- A), (I-B), (I-C), or (I-D).Compounds of Formula (II)

[0167] In embodiments, provided herein is a compound of Formula (II):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0168] In embodiments of the compounds of Formula (II), the compound is not:(i) 5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2, 2, 2 -tri fluoroethyl)-;331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(ii) 5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;(iii) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(iv) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(v) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0169] In embodiments of the compounds of Formula (II), ring A is heteroaryl.

[0170] In embodiments of the compounds of Formula (II), ring A is heteroaryl comprising at least one nitrogen atom.

[0171] In embodiments of the compounds of Formula (II), ring A is a monocyclic heteroaryl.

[0172] In embodiments of the compounds of Formula (II), ring A is a monocyclic heteroaryl comprising at least one nitrogen atom.

[0173] In embodiments of the compounds of Formula (II), ring A is a 5- or 6-membered heteroaryl.

[0174] In embodiments of the compounds of Formula (II), ring A is a 6-membered heteroaryl.

[0175] In embodiments of the compounds of Formula (II), ring A is 6-membered heteroaryl comprising at least one nitrogen atom.

[0176] In embodiments of the compounds of Formula (II), ring A is 6-membered heteroaryl comprising one or two nitrogen atoms.

[0177] In embodiments of the compounds of Formula (II), ring A is not an isothiazole.

[0178] In embodiments of the compounds of Formula (II), ring A is a heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or more heteroatoms independently selected from N and O.37331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0179] In embodiments of the compounds of Formula (II), ring A is a heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or two heteroatoms independently selected from N and O.

[0180] In embodiments of the compounds of Formula (II), ring A is a heteroaryl having one or two N atoms. In embodiments, ring A is a monocyclic heteroaryl having one or two N atoms. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or two N atoms. In embodiments ring A is a 6-membered heteroaryl having one or two N atoms.

[0181] In embodiments of the compounds of Formula (II), ring A is pyridyl.

[0182] In embodiments of the compounds of Formula (II), ring A is aryl.

[0183] In embodiments of the compounds of Formula (II), ring A is a phenyl.

[0184] In embodiments, provided herein is a compound of Formula (II-A):(II-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0185] In embodiments of the compounds of Formula (II-A), the compound is not(i) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(ii) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(iii) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0186] In embodiments, provided herein is a compound of Formula (II-B):(II-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -C1-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -C1-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; or331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0187] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -C1-6 haloalkyl, halo or -NR8R9.

[0188] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -C1-6 haloalkyl or -NR8R9.

[0189] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -C1-3 haloalkyl or -NR8R9.

[0190] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -CF3, -CH2CF3, or -NH2.

[0191] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -C1-6 haloalkyl.

[0192] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is -C1-3 haloalkyl.

[0193] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R1is R1is -CH2CF3.

[0194] In embodiments of the compounds of Formula (II), (II-A), or (II-B), m is 0, 1 or 2.

[0195] In embodiments of the compounds of Formula (II), (II-A), or (II-B), m is 0.

[0196] In embodiments of the compounds of Formula (II), (II-A), or (II-B), m is 1.

[0197] In embodiments of the compounds of Formula (II), (II-A), or (II-B), m is 2.

[0198] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -C1-6 haloalkyl.

[0199] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R2is independently halo, -CN, -C1-6 alkyl, or -C1-6 haloalkyl.

[0200] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R3is -H, -C1-6 alkyl, or -C1-6 haloalkyl.40331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0201] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R3is -H.

[0202] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl.

[0203] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is -F, -CN, -OH, -Ci-6 alkyl-CN, -OCi-6 alkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, or heteroaryl.

[0204] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is -F, -CN, OCi-6 alkyl, or -C(O)N(R8R9)2.

[0205] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is a 5-6 membered heteroaryl. In embodiments, the heteroaryl is a 5-membered heteroaryl containing two nitrogen atoms.

[0206] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is -F, -CN, -

[0207] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R4is -F, -CN, -

[0208] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl, or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.

[0209] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl, or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 4-8 membered heterocyclic ring.

[0210] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl.331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0211] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R5A, R5B, R6A, and R6Bare -H.

[0212] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R7is -H, -Ci-ealkyl or halo.

[0213] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R7is -H or halo.

[0214] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R7is -H or -F.

[0215] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R7is -H or -Ci-ealkyl.

[0216] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R7is -H.

[0217] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8and R9are each independently -H, -Ci-6 alkyl, aryl or heteroaryl.

[0218] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8and R9are each independently -H or -Ci-6 alkyl.

[0219] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8is -H or -Ci-ealkyl.

[0220] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8is -H.

[0221] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8is -Ci-ealkyl.

[0222] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R9is -H or -Ci-ealkyl.

[0223] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R9is -H.

[0224] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R9is -Ci-ealkyl.

[0225] In embodiments of the compounds of Formula (II), (II-A), or (II-B), R8and R9are -H.

[0226] In embodiments, provided herein is a compound of Formula (II), (II-A), or (II-B), or a pharmaceutically acceptable salt or deuterated form thereof.

[0227] In embodiments, provided herein is a compound of Formula (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof.

[0228] In embodiments, provided herein is a compound of Formula (II), (II-A), or (II-B).42331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Compounds of Formula (III)

[0229] In embodiments, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;n is 1 or 2;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0230] In embodiments of the compounds of Formula (III), the compound is not:(i) 5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-, having the structure:43331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(ii) 5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-; having the structure:(iii) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:(iv) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; having the structure:

[0231] In embodiments of the compounds of Formula (III), ring A is heteroaryl.44331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0232] In embodiments of the compounds of Formula (III), ring A is heteroaryl comprising at least one nitrogen atom.

[0233] In embodiments of the compounds of Formula (III), ring A is a monocyclic heteroaryl.

[0234] In embodiments of the compounds of Formula (III), ring A is a monocyclic heteroaryl comprising at least one nitrogen atom.

[0235] In embodiments of the compounds of Formula (III), ring A is a 5- or 6-membered heteroaryl.

[0236] In embodiments of the compounds of Formula (III), ring A is not an isothiazole.

[0237] In embodiments of the compounds of Formula (III), ring A is a heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or more heteroatoms independently selected from N and O.

[0238] In embodiments of the compounds of Formula (III), ring A is a heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments of the compounds of Formula (1-1), ring A is a monocyclic heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments of the compounds of Formula (1-1), ring A is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or two heteroatoms independently selected from N and O.

[0239] In embodiments of the compounds of Formula (III), ring A is a heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (III), ring A is a monocyclic heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (III), ring A is a 5- or 6-membered heteroaryl having one or two N atoms. In embodiments of the compounds of Formula (III), ring A is a 6-membered heteroaryl having one or two N atoms.

[0240] In embodiments of the compounds of Formula (III), ring A is a heteroaryl having one N atom. In embodiments of the compounds of Formula (III), ring A is a monocyclic heteroaryl having one N atom. In embodiments of the compounds of Formula (III), ring A is a 5- or 6-membered heteroaryl having one N atom.45331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0241] In embodiments of the compounds of Formula (III), ring A is a 6-membered heteroaryl.

[0242] In embodiments of the compounds of Formula (III), ring A is 6-membered heteroaryl comprising at least one nitrogen atom.

[0243] In embodiments of the compounds of Formula (III), ring A is 6-membered heteroaryl comprising one or two nitrogen atoms.

[0244] In embodiments of the compounds of Formula (III), ring A is pyridyl.

[0245] In embodiments of the compounds of Formula (III), ring A is aryl.

[0246] In embodiments of the compounds of Formula (III), ring A is a phenyl.

[0247] In embodiments of the compounds of Formula (III), n is 1 or 2.

[0248] In embodiments of the compounds of Formula (III), n is 1.

[0249] In embodiments of the compounds of Formula (III), n is 2.

[0250] In embodiments, provided herein is a compound of Formula (III-A):(in-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:X1and X2are each independently CH or N;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R346331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0251] In embodiments of Formula (III-A), X1is CH and X2is N.

[0252] In embodiments of Formula (III-A), X1is N and X2is CH.

[0253] In embodiments of Formula (III-A), X1is CH and X2is CH.

[0254] In embodiments of Formula (III-A), X1is N and X2is N.

[0255] In embodiments, provided herein is a compound of Formula (III-B):(III-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereofwherein:R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;R3is -H, halo, -C1-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be47331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0256] In embodiments of the compounds of Formula (III-A) or (III-B), the compound is not: (i) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(ii) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(iii) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0257] In embodiments, provided herein is a compound of Formula (III-C):(III-C)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:X1and X2are each independently CH or N;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0258] In embodiments of Formula (III-C), X1is CH and X2is N.

[0259] In embodiments of Formula (III-C), X1is N and X2is CH.

[0260] In embodiments of Formula (III-C), X1is CH and X2is CH.

[0261] In embodiments of Formula (III-C), X1is N and X2is N.

[0262] In embodiments, provided herein is a compound of Formula (III-D):(in-D)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereofwherein:R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R3is -H, halo, -Ci-6 alkyl, or -Ci-6 haloalkyl;R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-6 haloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl.

[0263] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R1is -Ci-ehaloalkyl, halo, or -NR8R9.

[0264] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R1is -Ci-3haloalkyl, halo, or -NR8R9.

[0265] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R1is -Ci-ehaloalkyl.

[0266] In embodiments of the compounds of (III), (III-A), (III-B), (III-C), or (III-D), R1is -Ci -3 haloalkyl.

[0267] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -CF3, -CH2CF3, Cl, F, or -NH2.

[0268] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -C 1-6 haloalkyl or -NR8R9.

[0269] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -C1-3 haloalkyl or -NR8R9.

[0270] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -CF3, -CH2CF3, or -NH2.

[0271] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -CF3 or -CH2CF3.50331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0272] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R1is -CF3.

[0273] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R1is -CH2CF3.

[0274] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is independently halo, -CN, -C1-6 alkyl, -C1-6 alkylene-carbocyclyl, -C1-6 alkylene-heterocyclyl, or -C1-6 haloalkyl.

[0275] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is independently -CN, -C1-6 alkyl, -C 1-6 alkylene-carbocyclyl, -Ci-ealkylene-heterocyclyl, or -C1-6 haloalkyl.

[0276] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CN or -C1-6 alkyl.

[0277] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CN or -C1-3 alkyl.

[0278] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CN, -CH3, or -CH2CH3.

[0279] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CN.

[0280] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -C1-6 alkyl.

[0281] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -C1-3 alkyl.

[0282] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CH3.

[0283] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R2is -CH2CH3.

[0284] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -C1-6 haloalkyl and R2is independently -CN or -C1-6 alkyl.51331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0285] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D),), R1is -C 1-6 haloalky 1 and R2is -CN.

[0286] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R1is -Ci-6 haloalkyl and R2is -Ci-6 alkyl.

[0287] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R3is -H, halo, -Ci-6 alkyl, or -Ci-6 haloalkyl.

[0288] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R3is -H or halo.

[0289] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R3is -H.

[0290] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo.

[0291] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-6 haloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2.

[0292] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl.

[0293] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R4is halo, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl, -C1-6 alkyl-CN, -C 1-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl.

[0294] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R4is halo, -CN, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, or carbocyclyl.52331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0295] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R4is halo or -Ci-ealkyl.

[0296] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R4is -Ci-ealkyl.

[0297] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), is -F or -CH3.

[0298] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R4is -CH3.

[0299] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D),

[0300] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.

[0301] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 4-8 membered heterocyclic ring.

[0302] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl.

[0303] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R5A, R5B, R6A, and R6Bare -H.

[0304] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R7is -H, -Ci-ealkyl or halo.

[0305] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R7is -H or halo.331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0306] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R7is -H or -F.

[0307] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R7is -H or -Ci-ealkyl.

[0308] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R7is -H.

[0309] In embodiments of the compounds of Formula (III), (III- A), (III-B), (III-C), or (III-D), R8and R9are each independently -H, -Ci-6 alkyl, aryl or heteroaryl.

[0310] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R8and R9are each independently -H or -Ci-6 alkyl.

[0311] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R8is -H or -Ci-ealkyl.

[0312] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R8is -H.

[0313] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R8is -Ci-ealkyl.

[0314] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R9is -H or -Ci-ealkyl.

[0315] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R9is -H.

[0316] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R9is -Ci-ealkyl.

[0317] In embodiments of the compounds of Formula (III), (III-A), (III-B), (III-C), or (III-D), R8and R9are -H.

[0318] In embodiments, provided herein is a compound of Formula (III), (III-A), (III-B), (III-C), or (III-D), or a pharmaceutically acceptable salt or deuterated form thereof.

[0319] In embodiments, provided herein is a compound of Formula (III), (III-A), (III-B), (III-C), or (III-D), or a pharmaceutically acceptable salt thereof.54331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0320] In embodiments, provided herein is a compound of Formula (III), (III-A), (III-B), (III-C), or (in-D).Compounds of Formula (IV)

[0321] In embodiments, provided herein is a compound of Formula (IV’):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, -halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -Ci-6alkyl, -CN, -OH, -O-Ci-6alkyl, -Ci-6alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0322] In embodiments of the compounds of Formula (IV’), the compound is not:55331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(i) 5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;(ii) 5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;(iii) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(iv) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(v) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0323] In embodiments, provided herein is a compound of Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;56331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0324] In embodiments of the compounds of Formula (IV), the compound is not:(i) 5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2, 2, 2-tri fluoroethyl)-;(ii) 5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2, 2, 2-tri fluoroethyl)-;(iii) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(iv) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(v) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0325] In embodiments of the compounds of Formula (IV’) or (IV), ring A is heteroaryl.

[0326] In embodiments of the compounds of Formula (IV’) or (IV), ring A is heteroaryl comprising at least one nitrogen atom.

[0327] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a monocyclic heteroaryl.

[0328] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a monocyclic heteroaryl comprising at least one nitrogen atom.

[0329] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a 5- or 6-membered heteroaryl.

[0330] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a 6-membered heteroaryl.57331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0331] In embodiments of the compounds of Formula (IV’) or (IV), ring A is 6-membered heteroaryl comprising at least one nitrogen atom.

[0332] In embodiments of the compounds of Formula (IV’) or (IV), ring A is 6-membered heteroaryl comprising one or two nitrogen atoms.

[0333] In embodiments of the compounds of Formula (IV’) or (IV), ring A is not an isothiazole.

[0334] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or more heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or more heteroatoms independently selected from N and O.

[0335] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a monocyclic heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N and O. In embodiments, ring A is a 6-membered heteroaryl having one or two heteroatoms independently selected from N and O.

[0336] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a heteroaryl having one or two N atoms. In embodiments, ring A is a monocyclic heteroaryl having one or two N atoms. In embodiments, ring A is a 5- or 6-membered heteroaryl having one or two N atoms. In embodiments ring A is a 6-membered heteroaryl having one or two N atoms.

[0337] In embodiments of the compounds of Formula (IV’) or (IV), ring A is pyridyl.

[0338] In embodiments of the compounds of Formula (IV’) or (IV), ring A is aryl.

[0339] In embodiments of the compounds of Formula (IV’) or (IV), ring A is a phenyl.

[0340] In embodiments, provided herein is a compound of Formula (IV-A):58331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(IV-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein:R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0341] In embodiments of the compounds of Formula (IV-A), the compound is not(i) 4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;(ii) 5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or(iii) 4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

[0342] In embodiments, provided herein is a compound of Formula (IV-B):59331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(IV-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; wherein:R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; andR7is -H or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroaryl.

[0343] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -C 1 -6 haloalky 1, halo or -NR8R9.

[0344] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -Ci-ehaloalkyl or -NR8R9.

[0345] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -Ci -3 haloalky 1 or -NR8R9.

[0346] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -CF3, -CH2CF3, or -NH2.331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0347] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -Ci -6 haloalkyl.

[0348] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is -Ci -3 haloalkyl.

[0349] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R1is R1is -CH2CF3.

[0350] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), m is 0, 1 or 2.

[0351] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), m is 0.

[0352] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), m is 1.

[0353] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), m is 2.

[0354] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R2is independently halo, -CN, -C1-6 alkyl, -Ci-ealkylene-carbocyclyl, -Ci-ealkylene-heterocyclyl, or -C1-6 haloalkyl.

[0355] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R2is independently halo, -CN, -C1-6 alkyl, or -C1-6 haloalkyl.

[0356] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R3is -H, -C1-6 alkyl, or -C1-6 haloalkyl.

[0357] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R3is -H.

[0358] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R4is -F, -CN, -OH, -O-Ci-6alkyl, -C1-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl.

[0359] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R4is -F, -CN, -OH, -C1-6 alkyl-CN, -OC1-6 alkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, or heteroaryl.

[0360] In embodiments of the compounds of Formula(IV’), (IV), (IV-A), or (IV-B), R4is -F, -CN, OC1-6 alkyl, or -C(O)N(R8R9)2.61331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0361] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R4is a 5-6 membered heteroaryl. In embodiments, the heteroaryl is a 5-membered heteroaryl containing two nitrogen atoms.

[0362] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R4is ->

[0363] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R4is -

[0364] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl, or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.

[0365] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl, or one of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 4-8 membered heterocyclic ring.

[0366] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl.

[0367] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R5A, R5B, R6A, and R6Bare -H.

[0368] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R7is -H, -Ci-ealkyl or halo.

[0369] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R7is -H or halo.

[0370] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R7is -H or -F.62331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0371] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R7is -H or -Ci-ealkyl.

[0372] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R7is -H.

[0373] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8and R9are each independently -H, -Ci-6 alkyl, aryl or heteroaryl.

[0374] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8and R9are each independently -H or -Ci-6 alkyl.

[0375] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8is -H or -Ci-ealkyl.

[0376] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8is -H.

[0377] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8is -Ci-ealkyl.

[0378] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R9is -H or -Ci-ealkyl.

[0379] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R9is -H.

[0380] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R9is -Ci-ealkyl.

[0381] In embodiments of the compounds of Formula (IV’), (IV), (IV-A), or (IV-B), R8and R9are -H.

[0382] In embodiments, provided herein is a compound of Formula (IV’), (IV), (IV-A), or (IV-B), or a pharmaceutically acceptable salt or deuterated form thereof.

[0383] In embodiments, provided herein is a compound of Formula (IV’), (IV), (IV-A), or (IV-B), or a pharmaceutically acceptable salt thereof.

[0384] In embodiments, provided herein is a compound of Formula (IV’), (IV), (IV-A), or (IV-B).63331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0385] In embodiments, provided herein is one or more compounds of Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.

[0386] In embodiments, provided herein is one or more compounds of Table 1, or a pharmaceutically acceptable salt or deuterated form thereof.

[0387] In embodiments, provided herein is one or more compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0388] In embodiments, provided herein is one or more compounds of Table 1.Table 1. Compounds64331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206265 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206267 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Compositions

[0389] In embodiments, the present disclosure provides pharmaceutical compositions for modulating (e.g., inhibiting) aldehyde dehydrogenase (e.g., ALDHla3) in a subject. In some embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (I- A), (I-B), (I-C), (I-D), (II), (II- A), (n-B), (III), (III-A), (ni-B), (III-C), (IILD), (IV’), (IV), (IV-A), or (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof).68331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0390] In embodiments, a pharmaceutical composition comprises one or more compounds of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (III-C), or (IILD), (IV’), (IV), (IV-A), or (IV-B), or Table 1 or a pharmaceutically acceptable salt or deuterated form thereof.

[0391] In embodiments, a pharmaceutical composition comprises one or more compounds of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (III-C), or (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt thereof.

[0392] In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (III-C), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) and a pharmaceutically acceptable carrier.

[0393] In embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable carrier.

[0394] In embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0395] In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof and a pharmaceutically acceptable carrier.

[0396] In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable carrier.69331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0397] In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0398] In embodiments of the present disclosure, a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (I-A), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof), and a pharmaceutically acceptable excipient or adjuvant is provided. The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0399] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, transdermally, buccally, sublingually, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

[0400] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.70331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0401] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion.

[0402] In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler.

[0403] Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, When used in combination with one or more additional therapeutic agents, compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure can be included in a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.

[0404] In some embodiments, compounds of the present disclosure can also be used for treating type 2 diabetes in combination with one or more additional therapeutic agents useful for treating type 2 diabetes, e.g., metformin, recombinant insulin, liraglutide, semaglutide, empagliflozin etc.

[0405] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.Therapeutic Use

[0406] The compounds of the present disclosure find use in any number of methods. For example, in embodiments, the compounds of the present disclosure are useful in methods for inhibiting ALDHla3 . Accordingly, in some embodiments, the present disclosure provides the 71331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062use of any one of the foregoing compounds of (e.g., a compound of Formula (A), (A-I), (I), (I-A), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) for inhibiting ALDHla3 activity. For example, in some embodiments, inhibiting ALDHla3 activity is in a mammalian cell. In embodiments, inhibiting ALDHla3 activity can be in a subject in need thereof (e.g., a mammalian subject, such as a human) and for treatment of any of the described conditions or diseases.

[0407] In some embodiments, inhibiting ALDHla3 activity is binding aldehyde dehydrogenase e.g., ALDHla3 . In embodiments, ALDHla3 is selectively inhibited. In embodiments, the compound of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) exhibits selectivity for ALDH1A3 over ALDH1A2. In embodiments, the compound of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) is an ALDH1 A3 isoform selective inhibitor.

[0408] In some embodiments, the present disclosure provides methods of treating a disease or disorder that is treatable by administration of an aldehyde dehydrogenase inhibitor (e.g., an aldehyde dehydrogenase isoform la3 (ALDHla3), the method comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (LA), (LB), (LC), (LD), (II), (ILA), (ILB), (III), (IILA), (IILB), (IILC), (IILD), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof).

[0409] In some embodiments, the disease or disorder is associated with aldehyde dehydrogenase (e.g., an aldehyde dehydrogenase isoform la3 (ALDHla3)). In embodiments, the disease or disorder is associated with aldehyde dehydrogenase isoform la3 (ALDHla3) in the subject. For example, in some embodiments, the disease or disorder is type 2 diabetes, other embodiments, the disease or disorder is a lipid disorder such as hyperlipidemia or dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Metabolic Dysfunction- Associated Steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia. In other embodiments, the disorder is a 72331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062cardiovascular disorder, such as pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease. In other embodiments, the disease is a kidney disease caused by or associated with type 2 diabetes or cardiometabolic syndrome. In other embodiments, the disease is sarcopenia or bone density loss due to cardiometabolic disease. In embodiments, the disease or disorder is cardiometabolic syndrome. In embodiments, the disease or disorder is a diabetic kidney disease. In embodiments, the disease or disorder is a lipid disorder, such as hyperlipidemia or dyslipidemia. In embodiments, the disease or disorder is muscle inflammation. In embodiments, the disease or disorder is sarcopenia or bone density loss. In embodiments, the disease or disorder is non-alcoholic fatty liver disease (NAFLD). In embodiments, the disease or disorder is non-alcoholic steatohepatitis (NASH). In embodiments, the disease or disorder is metabolic dysfunction-associated steatohepatitis (MASH). In embodiments, the disease or disorder is hypercholesterolemia. In embodiments, the disease or disorder is hypertriglyceridemia. In embodiments, the disease or disorder is familial cholesterolemia. In embodiments, the disease or disorder is familial triglyceridemia. In embodiments, the disease or disorder is a cardiovascular disorder, such as pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease. In other embodiments, the disease or disorder is a proliferative disease or disorder. In embodiments, the disease or disorder is cancer such as breast cancer, lung cancer, gastric cancer, prostate cancer, sarcoma, melanoma, leukemia, lymphoma, thyroid cancer.

[0410] In embodiments, the present disclosure provides methods of treating a cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder (e.g., hyperlipidemia or dyslipidemia), muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder (e.g., pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease) comprising administering a compound (e.g., a compound of Formula (A), (A-I), (I), (I-A), (I-B), (I-C), (I-D), (II), (ILA), (ILB), (III), (IILA), (IILB), (III-C), (HI-73331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062D), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) or pharmaceutical composition of the present disclosure

[0411] In embodiments, the present disclosure provides methods for the treatment of a cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder (e.g., hyperlipidemia or dyslipidemia), muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder (e.g., pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease) in a subject in need thereof, comprising administering one or more compounds disclosed in US 2021 / 0155602, US 2023 / 0128402, US 2024 / 0132469 or PCT / US2023 / 077659, each of which is incorporated by reference herein.

[0412] In embodiments, the subject suffers from a disease or disorder associated with aldehyde dehydrogenase, for example, a disease or disorder associated with aldehyde dehydrogenase isoform la3 (ALDHla3). In embodiments, the subject suffers from a disease or disorder associated with aldehyde dehydrogenase isoform la3 (ADDHla3). In embodiments, the subject suffers from type 2 diabetes.

[0413] In embodiments, compounds of the present disclosure (e.g., a compound of Formula (A), (A-I), (I), (I-A), (I-B), (I-C), (I-D), (II), (II-A), (II-B), (III), (III-A), (III-B), (III-C), (III-D), (IV’), (IV), (IV-A), (IV-B), or Table 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof) are used for the treatment of diseases or disorders that are associated with aldehyde dehydrogenase, such as a disease or disorder associated with ADDHla3. In embodiments, compounds of the present disclosure are used for the treatment of diseases or disorders that are associated with ADDHla3.

[0414] In embodiments, compounds of the present disclosure are used for the treatment of diseases or disorders that are associated with ADDHla3.

[0415] In embodiments, compounds of the present disclosure are used for the treatment and / or prophylaxis of type 2 diabetes. In embodiments, treating type 2 diabetes comprises treating74331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062type 2 diabetes-associated dyslipidemia. In embodiments prophylaxis of type 2 diabetes comprises prophylaxis of type 2 diabetes-associated dyslipidemia.

[0416] In embodiments, the compounds of the present disclosure are used for the treatment of one or more of the diseases or disorders disclosed herein. In embodiments, the compounds of the present disclosure are used for the prophylaxis (or prevention) of one or more of the diseases or disorders disclosed herein.

[0417] As discussed herein, metabolic diseases such as type 2 diabetes are associated with a pathology driven by ALDHla3 activities. In some embodiments, the method further comprises administering to the subject an effective amount of an additional anti-metabolic diseases agents, such as anti-type 2 diabetes agent. Suitable additional anti-metabolic diseases agents include without limitation an incretin mimic, recombinant insulin, a biguanide, SGLT2 inhibitors, a therapeutic antibody, etc. Any of the known Type 2 Diabetes treatments can be used in combination with the compounds of the present disclosure, for example, for treating Type 2 Diabetes (e.g., described herein) or treating or preventing other metabolic syndromes.

[0418] In embodiments, the compound of the present disclosure recited in the methods herein is a compound of the present disclosure having an IC50 value of less than 250 nM (e.g., in particular embodiments, less than 100 nM, such as about 1-100 nM, about 10-100 nM, about 10-50 nM, about 20-100 nM, about 20-50 nM, etc.) in inhibiting ALDHla3 when measured by the method described herein in example 16.

[0419] In embodiments, the compound of the present disclosure recited in the methods herein has at least about a 2-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 3-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 4-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 5-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 6-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 7-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about an 8-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 9-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 10-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 11-75331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, the compound has at least about a 12-fold selectivity for inhibiting ALDHla3 over ALDHla2. In embodiments, inhibiting ALDHla3 or ALDHla2 is measured by the methods described herein in example 16.NUMBERED EMBODIMENTS #11. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of:(i) a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof; or(ii) a pharmaceutical composition comprising a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof, and a pharmaceutically acceptable carrier:wherein:ring A is an optionally substituted heteroaryl, an optionally substituted heterocyclyl or an optionally substituted aryl;RAis -H or -Ci-ealkyl;IJis CR4orN;12is CR3or N;13is CR7or N;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -H, halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo;Q and Z are joined to form a heterocyclyl and substituted with oxo; and wherein the heterocycle may be further optionally substituted;R7is -H, -Ci-ealkyl or halo;76331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062R8and R9are each independently -H, -Ci-6 alkyl, aryl or heteroaryl; and wherein the disease or disorder is cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder, muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder.2. The method of embodiment 1, wherein the compound is of Formula (A-l):(A-l)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof,whereinring A is heteroaryl or aryl, wherein the heteroaryl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -NR8R9, -CN, -CI-6 alkyl, -Ci-ehaloalkyl, -Ci-6 alkylene-carbocyclyl, or -Ci-6 alkylene-heterocyclyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo; andR5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring.3. The method of embodiment 2, wherein the compound is of Formula (I):77331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereofwherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl; andn is 1 or 2.4. The method of embodiment 3, wherein the compound is of Formula (I-A):(I-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein X1and X2are each independently CH or N.5. The method of embodiment 4, wherein the compound is of Formula (I-B):78331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(LB)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.6. The method of any one of embodiments 3-5, wherein R1is -Ci-6 haloalkyl.7. The method of any one of embodiments 3-5, wherein R1is -C1-3 haloalkyl, halo, or - NR8R9.8. The method of embodiment 7, wherein R1is -C1-3 haloalkyl.9. The method of embodiment 7, wherein R1is -CF3, -CH2CF3, Cl, F, or -NH2.10. The method of embodiment 7, wherein R1is -CF3 or -CH2CF3.11. The method of any one of embodiments 3-10, wherein R2is -CN or -C1-6 alkyl.12. The method of embodiment 11, wherein R2is -CN or -C1-3 alkyl.13. The method of embodiment 12, wherein R2is -CN, -CH3, or -CH2CH3.14. The method of any one of embodiments 3-13, wherein R3is -H or halo.15. The method of embodiment 14, wherein R3is -H.16. The method of any one of embodiments 3-15, wherein R4is halo, -CN, -OH, -O-Ci- ealkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, - NR8R9, -C(O)OH, -C(O)OCI-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl.17. The method of embodiment 16, wherein R4is halo, -CN, -Ci-ealkyl, -C1-6 alkyl-CN, - Ci -6 haloalkyl, or carbocyclyl.18. The method of embodiment 17, wherein R4is halo or -Ci-ealkyl.19. The method of embodiment 18, wherein R4is -F or -CH3.20. The method of embodiment 19, wherein R4is -CH3.21. The method of any one of embodiments 3-20, wherein R5A, R5B, R6A, and R6Bare -H.79331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206222. The method of any one of embodiments 3-21, wherein R7is -H or -Ci-ealkyl.23. The method of any one of embodiments 3-22, wherein R8is -H or -Ci-ealkyl.24. The method of embodiment 1, wherein the compound is selected from the group consisting of:80331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.25. The method of embodiment 1 or 2, wherein the compound is of Formula (II):81331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl; andR4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl.26. The method of embodiment 25, wherein ring A is heteroaryl.27. The method of embodiment 25 or 26, wherein ring A is a 6-membered heteroaryl.28. The method of any one of embodiments 25-27, wherein the compound of Formula (II) is a compound of Formula (II-A):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.82331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206229. The method of any one of embodiments 25-28, wherein the compound of Formula (II- A) is a compound of Formula (II-B):(II-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.30. The method of any one of embodiments 25-29, wherein R1is -C1-3 haloalkyl.31. The method of embodiment 30, wherein R1is -CH2CF3.32. The method of any one of embodiments 25-31, wherein m is 0.33. The method of any one of embodiments 25-32, wherein R3is -H.34. The method of any one of embodiments 25-33, wherein R4is -F, -CN, -OH, -C1-6 alkyl-CN, -OC1-6 alkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, - C(O)OCi-6 alkyl, heterocyclyl, or heteroaryl.35. The method of any one of embodiments 25-34, wherein R4is -F, -CN, OC1-6 alkyl, or -C(O)N(R8R9)2.36. The method of any one of embodiments 25-34, wherein R4is a 5-6 membered heteroaryl.37. The method of embodiment 36, wherein the heteroaryl is a 5-membered heteroaryl containing two nitrogen atoms.83331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206238. The method of any one of embodiments 25-34, wherein R4is -F, -CN, -OCH3, -&39. The method of any one of embodiments 25-38, wherein R5A, R5B, R6A, and R6Bare - H.40. The method of any one of embodiments 25-39, wherein R7is -H or -Ci-ealkyl.41. The method of any one of embodiments 25-40, wherein R8is -H or -Ci-ealkyl.42. The method of embodiment 1, wherein the compound is selected from the group consisting of:84331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206285 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.43. The method of embodiment 1, wherein a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof is administered.44. The method of embodiment 1, wherein a pharmaceutical composition comprising a compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof, and a pharmaceutically acceptable carrier is administered.45. The method of any one of embodiments 1-44, wherein the lipid disorder is86331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062hyperlipidemia or dyslipidemia.46. The method of any one of embodiments 1-44 wherein the cardiovascular disorder is pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease.NUMBERED EMBODIMENTS #2or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;n is 1 or 2;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl; and87331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062provided the compound is not:5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.2. The compound of embodiment 1, wherein the compound is of Formula (III-A):(in-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein X1and X2are each independently CH or N.3. The compound of embodiment 2, wherein the compound is of Formula (III-B):(III-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form 88331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062thereof.4. The compound of any one of embodiments 1-3, wherein R1is -Ci-6 haloalkyl.5. The compound of any one of embodiments 1-3, wherein R1is -C1-3 haloalkyl, halo, or -NR8R9.6. The compound of embodiment 5, wherein R1is -C1-3 haloalkyl.7. The compound of embodiment 5, wherein R1is -CF3, -CH2CF3, Cl, F, or -NH2.8. The compound of embodiment 5, wherein R1is -CF3 or -CH2CF3.9. The compound of any one of embodiments 1-8, wherein R2is -CN or -C1-6 alkyl.10. The compound of embodiment 9, wherein R2is -CN or -C1-3 alkyl.11. The compound of embodiment 10, wherein R2is -CN, -CH3, or -CH2CH3.12. The compound of any one of embodiments 1-11, wherein R3is -H or halo.13. The compound of embodiment 12, wherein R3is -H.14. The compound of any one of embodiments 1-13, wherein R4is halo, -CN, -OH, -O- Ci-6alkyl, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, -C(O)OCI-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl.15. The compound of embodiment 14, wherein R4is halo, -CN, -Ci-ealkyl, -C1-6 alkyl-CN, -C1-6 haloalkyl, or carbocyclyl.16. The compound of embodiment 15, wherein R4is halo or -Ci-ealkyl.17. The compound of embodiment 16, wherein R4is -F or -CH3.18. The compound of embodiment 17, wherein R4is -CH3.19. The compound of any one of embodiments 1-18, wherein R5A, R5B, R6A, and R6Bare - H.20. The compound of any one of embodiments 1-19, wherein R7is -H or -Ci-ealkyl.89331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062 21. The compound of any one of embodiments 1-20, wherein R8is -H or -Ci-ealkyl.22. The compound of embodiment 1 selected from the group consisting of:90331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.23. A compound of Formula (IV):91331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;m is 0, 1 or 2;R3is -H, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is -F, -CN, -OH, -O-Ci-6alkyl, -Ci-6 alkyl-CN, -C(O)NR8R9, -C(O)OR8, -NR8R9, -NR8C(O)R9, heterocyclyl, or heteroaryl;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -Ci-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -Ci-ealkyl, aryl, or heteroarylprovided the compound is not:5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;4-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or92331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20624-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.24. The compound of embodiment 23, wherein ring A is heteroaryl.25. The compound of embodiment 23 or 24, wherein ring A is a 6-membered heteroaryl.26. The compound of any one of embodiments 23-25, wherein the compound of Formula (IV) is a compound of Formula (IV-A):(IV-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.27. The compound of any one of embodiments 23-26, wherein the compound of Formula (IV-A) is a compound of Formula (IV-B):(IV-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.28. The compound of any one of embodiments 23-27, wherein R1is -C1-3 haloalkyl.29. The compound of embodiment 28, wherein R1is -CH2CF3.93331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206230. The compound of any one of embodiments 23-29, wherein m is 0.31. The compound of any one of embodiments 23-30, wherein R3is -H.32. The compound of any one of embodiments 23-31, wherein R4is -F, -CN, -OH, -Ci-6 alkyl-CN, -OCi-6 alkyl, -C(O)NR8R9, -NR8C(O)CI-6 alkyl, -NR8R9, -C(O)OH, - C(O)OCi-6 alkyl, heterocyclyl, or heteroaryl.33. The compound of any one of embodiments 23-32, wherein R4is -F, -CN, OCi-6 alkyl, or -C(O)N(R8R9)2.34. The compound of any one of embodiments 23-32, wherein R4is a 5-6 membered heteroaryl.35. The compound of embodiment 34, wherein the heteroaryl is a 5-membered heteroaryl containing two nitrogen atoms.36. The compound of any one of embodiments 23-32, wherein R4is -F, -CN, -OCH3, -37. The compound of any one of embodiments 23-36, wherein R5A, R5B, R6A, and R6Bare -H.38. The compound of any one of embodiments 23-37, wherein R7is -H or -Ci-ealkyl.39. The compound of any one of embodiments 23-38, wherein R8is -H or -Ci-ealkyl.40. A compound is selected from the group consisting of:94331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206295 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206296 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.41. A pharmaceutical composition comprising the compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof, and a pharmaceutically acceptable carrier.42. A method for treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of embodiments 1-40 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41.43. The method of embodiment 42, wherein treating type 2 diabetes comprises treating type 2 diabetes-associated dyslipidemia.44. A method of treating a disease or disorder associated with aldehyde dehydrogenase in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41.45. The method of embodiment 44, wherein the disease or disorder is associated with aldehyde dehydrogenase isoform la3 (ALDHla3).46. A method of inhibiting an aldehyde dehydrogenase in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-40 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41.47. The method of embodiment 46, wherein aldehyde dehydrogenase isoform la3 (ALDHla3) is selectively inhibited.97331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062EXAMPLESExample 1: Synthesis of 2-methyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-5- (2,2,2-trifluoroethyl)isonicotinamide (Compound 1)

[0420] Step 1:

[0421] To a solution of 6-methylpyridine-3-carbaldehyde (5 g, 41.28 mmol, 1 eq) and TBAF (1 M, 41.28 mL, 1 eq) in THF (90 mL) was added TMSCF3 (6.46 g, 45.40 mmol, 1.1 eq) at 0°C. The mixture was stirred at 25°C for 1 hr. TLC indicated 6-methylpyridine-3-carbaldehyde was consumed completely and one new spot formed. To the mixture was added water (50 ml). The reaction liquid was extracted by EtOAc (100ml), then the organic liquid was washed with brine (10 ml * 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=15 / l to 5 / 1). Compound 2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethanol (3.43 g, 17.94 mmol, 21.74% yield) was obtained.JH NMR (400 MHz, CHLOR.OFOR.M-t / ) 8 ppm 7.45 - 7.56 (m, 2H), 7.25 - 7.31 (m, 1H), 7.05 (d, J= 5.6 Hz, 1H), 7.34 - 7.42 (m, 1H), 2.34 (s ,1H).

[0422] Step 2:98331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0423] A mixture of 2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethanol (5 g, 26.16 mmol, 1 eq), TEA (7.94 g, 78.47 mmol, 10.92 mL, 3 eq) in DCM (100 mL) was degassed and purged with N2 for 3 times at 0°C. To the mixture was added 4-methylbenzenesulfonyl chloride (6.48 g, 34.00 mmol, 1.3 eq) in DCM (15 mL) at 0°C. Then the mixture was stirred at 20°C for 12 hr under N2 atmosphere. LC-MS showed 2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethanol was consumed completely and one main peak with desired m / z was detected. To the mixture was added water (50 mL), the reaction liquid was washed by DCM (100ml), then the organic liquid was washed with brine (5 mL* 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate= 10 / 1 to 4 / 1). Compound [2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethyl] 4-methylbenzenesulfonate (4.8 g, 13.48 mmol, 51.54% yield) was obtained.

[0424] Step 3:

[0425] To the bottle was added Pd / C (0.5 g, 10% purity) under Ar. Then to the mixture was added [2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethyl] 4-methylbenzenesulfonate (3 g, 8.69 mmol, 1 eq) in MeOH (100 mL). The suspension was degassed under vacuum and purged with H2 3 times. The mixture was stirred under H2 (50 psi) at 50°C for 2 hours. LC-MS showed [2,2,2-trifluoro-l-(6-methyl-3-pyridyl)ethyl] 4-methylbenzenesulfonate was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and the filtrate was concentrated. To the mixture was added sat. NaHCCh (50 mL). The aqueous phase was extracted with DCM (20 mL* 3). The combined organic phase was washed with brine (30 mL), dried with Na2SC>4, filtered and concentrated in vacuum. 2-methyl-5-(2,2,2-trifluoroethyl)pyridine (1.5 g, 8.56 mmol, 98.58% yield) was obtained.

[0426] Step 4:

[0427] To the solution of 2-methyl-5-(2,2,2-trifluoroethyl)pyridine (1.5 g, 8.56 mmol, 1 eq) in DCM (30 mL) was added m-CPBA (2.09 g, 10.28 mmol, 85% purity, 1.2 eq) in portions at 0 °C. The mixture was stirred at 20 °C for 12 hr. LC-MS showed 2-methyl-5-(2,2,2-trifluoroethyl)pyridine was consumed completely and one main peak with desired m / z was detected. To the mixture was added to sat. Na2SOs (50 mL). The mixture was stirred at 20 °C for 0.5 hr. The aqueous phase was extracted with DCM (50 mL*3). The combined organic phase was washed with brine (20 mL), dried with Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica99331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 80 mL / min). 2-methyl-l-oxido-5-(2,2,2-trifluoroethyl)pyridin-l-ium (1 g, 5.23 mmol, 61.09% yield) was obtained. 'H NMR (400 MHz, CHLOROFORM- ) 6 ppm 8.25 (s, 1H), 7.26 (d, J= 8.0 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 3.25 - 3.40 (m, 2H), 2.52 (s, 3H).

[0428] Step 5:

[0429] The mixture of 2-methyl-l-oxido-5-(2,2,2-trifluoroethyl)pyridin-l-ium (1 g, 5.23 mmol, 1 eq) in EtI (8.16 g, 52.31 mmol, 4.18 mL, 10 eq) was stirred at 50 °C for 1 hr. LC-MS showed ~30.8% of 2-methyl-l-oxido-5-(2,2,2-trifluoroethyl)pyridin-l-ium remained. Several new peaks were shown on LC-MS and ~28.9% of desired compound was detected. The mixture was cooled to 20 °C. To the mixture was added Petroleum ether (20 mL). The mixture was stirred at 20 °C for 20 min. The mixture was filtered. The filter cake was concentrated in vacuum. l-ethoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyridin-l-ium (1.1 g, 3.17 mmol, 60.58% yield) was obtained.

[0430] Step 6:

[0431] To a 100 mL three neck bottle was added l-ethoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyridin-l-ium (1.1 g, 3.17 mmol, 1 eq, I-) in H2O (20 mL). Then to the mixture was added the solution of NaCN (200 mg, 4.08 mmol, 1.29 eq) in H2O (2 mL) dropwise at 50 °C. The mixture was stirred at 50 °C for 1 h. LC-MS showed 1 -ethoxy -2-methyl-5-(2, 2,2-trifluoroethyl)pyridin-l-ium was consumed completely and two peaks with desired m / z was detected. The mixture was cooled to 25 °C and adjusted the pH to 9-10 by sat. NaOH. The aqueous phase was extracted with ethyl acetate (20 mL* 3). The combined organic phases were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiCh, Petroleum ether: Ethyl acetate = 2:1). 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carbonitrile (90 mg, 449.64 pmol, 14.18% yield) was obtained.XH NMR (400 MHz, CHLOROFORM- ) 8 ppm 8.68 (s, 1H), 7.45 (s, 1H), 3.55 - 3.70 (m, 2H), 2.65 (s, 3H).

[0432] Step 7:

[0433] The mixture of 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carbonitrile (30 mg, 149.88 pmol, 1 eq) in HBr (1.55 g, 9.21 mmol, 1.04 mL, 48% purity, 61.43 eq) was stirred at 130 °C for 12 hr. LC-MS showed 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carbonitrile was consumed completely and one main peak with desired m / z was detected. The mixture was 100331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062concentrated in vacuum. 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (40 mg, crude, HBr) was obtained. 'HNMR (400 MHz, METHANOLS) 8 ppm 8.93 (s, 1H), 8.36 (s, 1H), 4.20 - 4.30 (m, 2H), 2.85 (s, 3H).

[0434] Step 8:

[0435] To the mixture of 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (35 mg, 198.62 umol, 1 eq) and 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (65.56 mg, 218.48 umol, 1.1 eq, HBr) in Py. (1 mL) was added EDCI (57.11 mg, 297.93 umol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. LC-MS showed 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one was consumed completely and one main peak with desired m / z was detected. The mixture was concentrated in vacuum. Combined with another batch (18.84 mg). The combined crude product was purified by prep-TLC (SiCh, Petroleum ether: Ethyl acetate= 0: 1). 2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-5-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (30 mg, 31.1% yield) was obtained. (M+H)+: 378.1. 'H NMR (400 MHz, METHANOL-A) 6 ppm 8.53 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 3.80 - 3.95 (m, 2H), 2.98 (t, J= 8.0 Hz, 2H), 2.55 - 2.65 (m, 5H), 2.3 (s, 3H).Example 2: Synthesis of 6-methyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3- (2,2,2-trifluoroethyl)picolinamide (Compound 2)

[0436] Step 1:

[0437] To a 100 mL three neck bottle was added l-ethoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyridin-l-ium (1.1 g, 3.17 mmol, 1 eq, I-) in H2O (20 mL). Then to the mixture was added the solution of NaCN (200 mg, 4.08 mmol, 1.29 eq) in H2O (2 mL) dropwise at 50 °C. The mixture was stirred at 50 °C for 1 h. LC-MS showed 1 -ethoxy -2-methyl-5-(2, 2,2-trifluoroethyl)pyridin-l-ium was consumed completely and two peaks with desired m / z was detected. The mixture was cooled to 25 °C and adjusted to pH= 9~10 by sat. NaOH. The aqueous phase was extracted with ethyl acetate (20 mL* 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum.101331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062The residue was purified by prep-TLC (SiCh, Petroleum ether: Ethyl acetate = 2:1). 6-methyl-3-(2,2,2-trifluoroethyl)pyridine-2-carbonitrile (30 mg, 149.88 pmol, 4.73% yield) was obtained. 'HNMR (400 MHz, CHLOROFORM- ) 8 ppm 7.73 (d, J= 12.0 Hz, 1H), 7.41 (d, J= 12.0 Hz, 1H), 3.60 - 3.70 (m, 2H), 2.63 (s, 3H).

[0438] Step 2:

[0439] The mixture of 6-methyl-3-(2,2,2-trifluoroethyl)pyridine-2-carbonitrile (30.00 mg, 149.88 pmol, 1 eq) in HBr (745.00 mg, 4.42 mmol, 500.00 pL, 48% purity, 29.49 eq was stirred at 130 °C for 12 hr. LC-MS showed 6-methyl-3-(2,2,2-trifluoroethyl)pyridine-2-carbonitrile was consumed completely and one main peak with desired m / z was detected. The mixture was concentrated in vacuum. 6-methyl-3-(2,2,2-trifluoroethyl)pyridine-2-carboxylic acid (38 mg, 126.64 pmol, 84.49% yield, HBr) was obtained.

[0440] Step 3:

[0441] To the mixture of 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (20 mg, 113.50 pmol, 1 eq) and 6-methyl-3-(2,2,2-trifluoroethyl)pyridine-2-carboxylic acid (38 mg, 126.64 pmol, 1.12 eq, HBr) in Py (2 mL) was added EDCI (32.64 mg, 170.25 pmol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. LC-MS showed 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one was consumed completely and one main peak with desired m / z was detected. The mixture was concentrated in vacuum. The residue was purified by prep-TLC (SiCh, Petroleum ether: Ethyl acetate = 0:1). 6-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-2-carboxamide (9 mg, 23.85 pmol, 21.01% yield) was obtained. (M+H)+: 378.1. 'H NMR (400 MHz, METHANOLS) 6 ppm 7.81 (d, J= 8.0 Hz, 1H), 7.40 - 7.50 (m, 3H), 4.19 - 4.31 (m, 2H), 2.97 (t, J = 8.0 Hz, 2H), 2.50 - 2.65 (m, 5H), 2.29 (s, 3H).102331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 3: Synthesis of 5-ethyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-2- (trifluoromethyl)isonicotinamide (Compound 3)<

[0442] Step 1:

[0443] A mixture of methyl 5-bromo-2-(trifluoromethyl)pyridine-4-carboxylate (2 g, 7.04 mmol, 1 eq , 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.14 g, 7.39 mmol, 1.25 mL, 1.05 eq , K2CO3 (1.95 g, 14.08 mmol, 2 eq), Pd(dppf)C12 (515.23 mg, 704.15 umol, 0.1 eq in dioxane (20 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hr under N2 atmosphere. TLC indicated the reaction consumed completely. The reaction mixture was diluted with H2O 20 mL and extracted with EtOAc 40 mL (20 mL * 2). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 10 / 1). Methyl 2-(trifluoromethyl)-5-vinyl-pyridine-4-carboxylate (1 g, 4.33 mmol, 61% yield) was obtained. 'HNMR (400 MHz, CHLOROFORM- ) 8 ppm 8.97 (s, 1 H), 8.09 (s, 1 H), 7.40 - 7.48 (m, 1 H), 5.87 (d, J= 17.6 Hz, 1 H), 5.62 (d, J= 11.2 Hz, 1 H), 3.99 (s, 3 H).

[0444] Step 2:

[0445] To a solution of Pd / C (0.1 g, 2.16 mmol, 10% purity) in MeOH (5 mL) was added methyl 2-(trifluoromethyl)-5-vinyl-pyridine-4-carboxylate (0.5 g, 2.16 mmol, 1 eq under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 2 hr. LCMS showed the reaction was consumed103331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062completely. The mixture was filtered and the filtrate was concentrated in vacuum. Methyl 5-ethyl-2-(trifluoromethyl)pyridine-4-carboxylate (0.5 g, crude) was obtained.

[0446] Step 3:

[0447] To a solution of methyl 5-ethyl-2-(trifluoromethyl)pyridine-4-carboxylate (400 mg, 1.72 mmol, 1 eq) in THF (4 mL) was added LiOH.TbO (143.97 mg, 3.43 mmol, 2 eq) in H2O (4 mL). The mixture was stirred at 20 °C for 2 hr. TLC indicated the reaction was consumed completely. The reaction mixture was diluted with H2O 10 mL and extracted with EtOAc 10 mL (5 mL * 2). The water layer was adjusted to pH=2 by addition of IN HC1. The mixture was filtered and the filter cake concentrated in vacuum without further purification. 5-ethyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (0.4 g, 85% yield) was obtained.

[0448] Step 4:

[0449] To a solution of 5-ethyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (70 mg, 319.40 pmol, 1 eq) and 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (61.91 mg, 351.34 pmol, 1.1 eq) in Py (1 mL) was added EDCI (91.84 mg, 479.10 pmol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. TLC indicated the reaction was consumed completely. The reaction mixture was concentrated in vacuum. The residue was purified by prep-TLC (SiCh, Ethyl acetate: MeOH=20: 1). 5-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2- (trifluoromethyl)pyridine-4-carboxamide (52 mg, 48% yield) was obtained. (M+H)+: 378.1. ‘HNMR (400 MHz, DMSO-tL) 6 ppm 10.49 (s, 1 H), 9.46 (s, 1 H), 8.79 (s, 1 H), 7.93 (s, 1 H), 7.35 (d, J= 29.2 Hz, 2 H), 2.77 - 2.90 (m, 4 H), 2.39 - 2.46 (m, 2 H), 2.21 (s, 3 H), 1.20 (t, J= 7.6 Hz, 3 H).104331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 4: Synthesis of 5-ethyl-N-(8-fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-2- (trifluoromethyl)isonicotinamide (Compound 4)

[0450] Step 1:

[0451] To a solution of Pd / C (200 mg, 6.13 mmol, 10% purity) in AcOH (20 mL) was added 8-fluoro-lH-quinolin-2-one (2 g, 6.13 mmol, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 2 times. The mixture was stirred under H2 (50 Psi.) at 80 °C for 5 hr. LCMS showed 8-fluoro-lH-quinolin-2-one was consumed completely. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 8-fluoro-3, 4-dihydro-lH-quinolin-2-one (1.4 g, crude) was obtained.

[0452] Step 2:

[0453] To a 100 mL three neck bottle was added the solution of 8-fluoro-3,4-dihydro-lH-quinolin-2-one (0.7 g, 4.24 mmol, 1 eq) in H2SO4 (5 mL). Then to the mixture was added KNO3 (660 mg, 6.53 mmol, 1.54 eq) in protions at 0 °C. The mixture was stirred at 0 °C for 1 hr. TLC indicated 8-fluoro-3,4-dihydro-lH-quinolin-2-one was consumed completely and two new spots formed. The mixture was poured into ice (15 mL) slowly. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. Compound 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (0.8 g, crude) was obtained.

[0454] Step 3:

[0455] To a solution of Pd / C (20 mg, 10% purity) in MeOH (10 mL) was added 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (0.8 g, 3.81 mmol, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15105331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Psi.) at 20 °C for 2 hr. TLC indicated 8-fluoro-6-nitro-3, 4-dihydro-lH-quinolin-2-one was consumed completely and three new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, Petroleum ether / Ethyl acetate = 0:1).

[0456] Compound 6-amino-8-fluoro-3, 4-dihydro-lH-quinolin-2-one (0.5 g, 2.22 mmol, 58.32% yield) was obtained. (M+H)+:181.2. 'HNMR (400 MHz, CHLOROFORM-d) 8 ppm 7.5 (br s, 1H), 6.30 - 6.36 (m, 2H), 3.60 (s, 2H), 2.90 (t, J= 7.2 Hz, 2H), 2.61 (t, J= 7.2 Hz, 2H).

[0457] Step 4:

[0458] To a solution of 6-amino-8-fluoro-3,4-dihydro-lH-quinolin-2-one (50 mg, 277.50 pmol, 1.1 eq) and 5-ethyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (55.29 mg, 252.27 pmol, 1 eq) in Py (1 mL) was added EDCI (72.54 mg, 378.41 pmol, 1.5 eq). The mixture was stirred at 45 °C for 1 h. LC-MS showed 6-amino-8-fluoro-3,4-dihydro-lH-quinolin-2-one was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 1). Compound 5-ethyl-N-(8-fluoro-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2-(trifluoromethyl)pyridine-4-carboxamide (40 mg, 99.97 pmol, 39.63% yield) was obtained. (M+H)+:382.1. 1HNMR (400 MHz, METHANOL-d4) 6 ppm 8.73 (s, 1H) 7.86 (s, 1H) 7.56 (dd, J= 12.0, 2.0 Hz, 1H), 7.26 - 7.29 (m, 1H), 3.02 (t, J= 7.2 Hz, 2H) 2.92 (q, J= 7.6 Hz, 2H) 2.58 - 2.66 (m, 2H) 1.30 (t, J = 8.0 Hz, 3H).106331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 5: Synthesis of 5-methyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-2-(2,2,2-trifluoroethyl)benzamide (Compound 5)

[0459] Step 1:

[0460] To the solution of i-PrMgBr (3 M, 4.44 mL, 1.2 eq) in THF (25 mL) was added n-BuLi (2.5 M, 11.10 mL, 2.5 eq) dropwise at 0 °C. Then the mixture was cooled to -70 °C. To the mxiture was added 2-bromo-N,N-diethyl-5-methyl-benzamide (3 g, 11.10 mmol, 1 eq) in THF (15 mL) drop-wise at -70 °C. The mixture was stirred at -70 °C for 1 hr. Then to the mixture was added DMF (3.25 g, 44.42 mmol, 3.42 mL, 4 eq) dropwise at -70 °C. The mixture was stirred at -70 °C for 3 hr under N2. TLC indicated -10% of 2-bromo-N,N-diethyl-5-methyl-benzamide was remained, and one major new spot with larger polarity was detected. To the mixture was added sat. NH4Q (50 mL) dropwise at -20 °C. The aqueous phase was extracted with ethyl acetate (30 mL* 4). The combined organic phases were washed with brine (30 mL* 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 2 / 1). Compound N,N-diethyl-2-formyl-5-methyl-benzamide (1.2 g, 4.49 mmol, 40.41% yield) was obtained. 'H NMR (400 MHz, CHLOROFORM-d) 8 ppm 10.00 (s, 1H), 7.84 (d, J= 8.0 Hz,107331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20621H), 7.34 (d, J= 8.0 Hz, 1H), 7.16 (s, 1H), 3.55 - 3.65 (m, 2H), 3.05 - 3.20 (m, 2H), 2.45 (s, 3H), 1.32 (t, J= 8.0 Hz, 3H), 1.04 (t, J= 8.0 Hz, 3H).

[0461] Step 2:

[0462] To a solution of N,N-diethyl-2-formyl-5-methyl-benzamide (600 mg, 2.74 mmol, 1 eq and TMSCF3 (583.62 mg, 4.10 mmol, 1.5 eq) in THF (5 mL) was added CsF (207.82 mg, 1.37 mmol, 50.44 pL, 0.5 eq in THF (1 mL) at 0°C under N2 atmosphere. The mixture was stirred at 20 °C for 2 hr under N2 atmosphere. TLC indicated 10% of N,N-diethyl-2-formyl-5-methyl-benzamide was remained, and one major new spot with lower polarity was detected. The residue was diluted with H2O 5 mL and extracted with EtOAc 30 mL (10 mL* 3). The combined organic layers were washed with brine 15 mL (5 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound N,N-diethyl-5-methyl-2-(2,2,2-trifluoro-l-trimethylsilyloxy-ethyl)benzamide (900 mg, crude) was obtained.

[0463] Step 3:

[0464] To a solution of N,N-diethyl-5-methyl-2-(2,2,2-trifluoro-l -trimethylsilyloxy -ethyl)benzamide (900 mg, 2.49 mmol, 1 eq in THF (6 mL) was added HC1 (2 M, 6.00 mL, 4.82 eq . The mixture was stirred at 20 °C for 0.5 hr under N2 atmosphere. TLC indicated 10% of N,N-diethyl-5-methyl-2-(2,2,2-trifluoro-l-trimethylsilyloxy-ethyl)benzamide was remained, and two new spots with larger polarity was detected. The residue was diluted with H2O 10 mL and extracted with DCM 30 mL (10 mL * 3). The combined organic layers were washed with brine 15 mL (5 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 2 / 1). Compound 6-methyl-3-(trifluoromethyl)-3H-isobenzofuran-l-one (200 mg, 925.26 pmol, 37.16% yield) was obtained.

[0465] Step 4:

[0466] A mixture of 6-methyl-3-(trifluoromethyl)-3H-isobenzofuran-l-one (200 mg, 925.26 pmol, 1 eq), 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (146.74 mg, 832.73 pmol, 0.9 eq and Al(CHs)3 (2 M, 601.42 pL, 1.3 eq in Tol. (8 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 hr under N2 atmosphere. LC-MS showed 4.6% of 6-methyl-3-(trifluoromethyl)-3H-isobenzofuran-l-one was remained. Several new peaks were shown on LC-MS and 79.4% of desired compound was detected. The reaction mixture was quenched by poured into 10 mL H2O and stirred at 0 °C and extracted with EtOAC 108331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, DCM: MeOH = 1 :0 to 20 / 1). Compound 5-methyl-N-(8-methyl-2-oxo-3,4-dihydro- lH-quinolin-6-yl)-2-(2, 2, 2-tri fluoro- 1-hydroxy-ethyl)benzamide (320 mg, 815.55 pmol, 88.14% yield) was obtained.

[0467] Step 5:

[0468] To a solution of 5-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2-(2,2,2-trifluoro-l-hydroxy-ethyl)benzamide (320 mg, 815.55 pmol, 1 eq), DMAP (9.96 mg, 81.56 pmol, 0.1 eq) and TEA (247.58 mg, 2.45 mmol, 340.54 pL, 3 eq in DCM (8 mL) was added 4-methylbenzenesulfonyl chloride (310.97 mg, 1.63 mmol, 2 eq in DCM (2 mL) at 0 °C. The mixture was stirred at 20°C for 2 hr under N2 atmosphere. LC-MS showed 4.4% of 5-methyl-N-(8-methyl-2-oxo-3,4-dihydro- lH-quinolin-6-yl)-2-(2, 2, 2-tri fluoro- 1-hydroxy-ethyl)benzamide remained. Several new peaks were shown on LC-MS and 84.2% of desired compound was detected. The residue was diluted with H2O 10 mL and extracted with DCM 45 mL (15 mL * 3). The combined organic layers were washed with brine 30 mL (10 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1). Compound [2,2,2-trifluoro-l-[4-methyl-2-[(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)carbamoyl]phenyl]ethyl] 4-methylbenzenesulfonate (300 mg, 548.89 pmol, 67.30% yield) was obtained. 'H NMR (400 MHz, CHLOROFORM-d) 8 ppm 7.75 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 1H), 7.20 - 7.40 (m, 7H), 6.55 - 6.65 (m, 1H), 3.01 (t, J= 8.0 Hz, 2H), 2.60 -2.70 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 2.05 (s, 2H).

[0469] Step 6:

[0470] To a solution of [2,2,2-trifluoro-l-[4-methyl-2-[(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)carbamoyl]phenyl]ethyl] 4-methylbenzenesulfonate (300 mg, 548.89 pmol, 1 eq and TEA (166.63 mg, 1.65 mmol, 229.20 pL, 3 eq in MeOH (10 mL) was added Pd / C (30 mg, 10% purity). The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (45 Psi) at 30 °C for 2 hr. LC-MS showed 34.1% of [2,2,2-trifluoro-l-[4-methyl-2-[(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)carbamoyl]phenyl]ethyl] 4-methylbenzenesulfonate remained. Several new peaks were shown on LC-MS and 36.2% of desired compound was detected. The reaction mixture was filtered and filter liquor was109331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, DCM: MeOH = 20:1). Compound 5-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2-(2,2,2-trifluoroethyl)benzamide (44 mg, 110.48 pmol, 20.13% yield) was obtained. (M+H)+: 377.2. 'HNMR (400 MHz, METHANOL-d4) 8 ppm 7.43 (s, 1H), 7.39 (s, 1H), 7.34 (t, J= 12.0 Hz, 3H), 3.75 - 7.85 (m, 2H), 2.96 (t, J= 4.0 Hz, 2H), 2.50 - 2.60 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H).Example 6: Synthesis of 3-ethyl-5-fluoro-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin- 6-yl)isonicotinamide (Compound 6)

[0471] Step 1:

[0472] To a solution LDA (2 M, 17.05 mL, 1.2 eq) in THF (100 mL) was added 3-bromo-5-fluoro-pyridine (5 g, 28.41 mmol, 1 eq) in THF (30 mL) dropwise at -70 °C. Then the reaction mixture was stirred at -70 °C for 1 hr. Then to the mixture was added (Boc)2O (12.40 g, 56.82 mmol, 13.05 mL, 2 eq) in THF (30 mL) dropwise at -10 °C. The final mixture was stirred at -10 °C for 2 hr. LC-MS showed 3-bromo-5-fluoro-pyridine was consumed completely. TLC indicated 3-bromo-5-fluoro-pyridine was consumed completely and one new spot formed. Combined with another batch (5 g scale). The reaction mixture was quenched by addition H2O 200 mL at 0°C, and then diluted with H2O 50 mL and extracted with EtOAc (200 mL* 2). The combined organic layers were washed with brine (100 mL* 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column110331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062chromatography (SiCh, Petroleum ether / Ethyl acetate= 100 / 1 to 10 / 1). Compound tert-butyl 3-bromo-5-fluoro-pyridine-4-carboxylate (3.6 g, 13.04 mmol) was obtained.

[0473] Step 2:

[0474] To the mixture of tert-butyl 3-bromo-5-fluoro-pyridine-4-carboxylate (500 mg, 1.81 mmol, 1 eq and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (334.69 mg, 2.17 mmol, 368.60 pL, 1.2 eq) inlfcO (0.5 mL) and dioxane (5 mL) was added CS2CO3 (1.77 g, 5.43 mmol, 3 eq) and Pd(dppf)C12 (132.51 mg, 181.09 pmol, 0.1 eq) at 20 °C. Then the reaction mixture was stirred at 90 °C for 2 hr. TLC indicated tert-butyl 3-bromo-5-fluoro-pyridine-4-carboxylate was consumed completely and one new spot formed. The reaction mixture was diluted with H2O 50 mL and extracted with ethyl acetate (10 mL* 3). The combined organic layers were washed with brine 15 mL (5 mL* 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 9 / 1). Compound tert-butyl 3-fluoro-5-vinyl-pyridine-4-carboxylate (230 mg, 1.03 mmol, 56.89% yield) was obtained.JH NMR (400 MHz, CHLOROFORM-d) 8 ppm 8.62 (s, 1H), 8.42 (s, 1H), 6.75 - 6.85 (m, 1H), 5.87 (d, J= 16.0 Hz, 1H), 5.54 (d, J= 12.0 Hz, 1H), 1.62 (s, 9H).

[0475] Step 3:

[0476] To a solution of tert-butyl 3-fluoro-5-vinyl-pyridine-4-carboxylate (200 mg, 895.89 pmol, 1 eq in MeOH (10 mL) was added Pd / C (20 mg, 10% purity) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 2 hr. LC-MS showed tert-butyl 3-fluoro-5-vinyl-pyridine-4-carboxylatewas consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue. Compound tert-butyl 3-ethyl-5-fluoro-pyridine-4-carboxylate (200 mg, 887.87 pmol, 99.11% yield) was obtained.

[0477] Step 4:

[0478] A mixture of tert-butyl 3-ethyl-5-fluoro-pyridine-4-carboxylate (100 mg, 443.93 pmol, 1 eq) and TFA (50.62 mg, 443.93 pmol, 32.87 pL, 1 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times. Then the reaction mixture was stirred at 20 °C for 5 hr. LC-MS showed tert-butyl 3-ethyl-5-fluoro-pyridine-4-carboxylate was consumed completely and one main peak with desired m / z was detected. The reaction mixture was concentrated under 111331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062reduced pressure to give a residue. Compound 3-ethyl-5-fluoro-pyridine-4-carboxylic acid (80 mg, crude, TFA) was obtained.

[0479] Step 5:

[0480] To the mixture of 3-ethyl-5-fluoro-pyridine-4-carboxylic acid (70 mg, 247.20 pmol, 1.05 eq, TFA) and 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (41.49 mg, 235.43 pmol, 1 eq) in Py (3 mL) was added EDCI (54.16 mg, 282.51 pmol, 1.2 eq) at 20 °C. Then the reaction mixture was stirred at 45 °C for 1 hr. LC-MS showed 3-ethyl-5-fluoro-pyridine-4-carboxylic acid was consumed completely. Several new peaks were shown on LC-MS and 8% of desired compound was detected. The reaction mixture was filtered and filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether: ethyl acetate = 0: 1). Compound 3-ethyl-5-fluoro-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl) pyridine-4-carboxamide (15 mg, 45.36 pmol, 19.27% yield) was obtained. (M+H)+: 328.2. 'H NMR (400 MHz, METHANOL-d4) 8 ppm 8.43 (d, J= 8.0 Hz, 2H), 7.41 (s, 1H), 7.33 (t, J= 8.0 Hz, 1H), 2.96 (t, J= 8.0 Hz, 2H), 2.75 - 2.85 (m, 2H), 2.58 (t, J= 8.0 Hz, 2H), 2.28 (s, 3H), 1.29 (t, J= 8.0 Hz, 3H).112331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 7: Synthesis of 3-amino-5-ethyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin- 6-yl)isonicotinamide (Compound 8)Step4 Step5 Step6Step7

[0481] Step 1:

[0482] To the mixture of 3,5-dibromopyridine-4-carboxylic acid (14 g, 49.84 mmol, 1 eq) and K2CO3 (13.78 g, 99.68 mmol, 2 eq) in DMF (140 mL) was added Mel (8.49 g, 59.81 mmol, 3.72 mL, 1.2 eq). The mixture was stirred at 20 °C for 12 hr. LC-MS showed the starting material was consumed completely. The reaction mixture was diluted with H2O 700 mL and extracted with EtOAc (300 mL * 4). The combined organic layers were washed with brine (150 mL * 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 0 / 1). The product of methyl 3,5-dibromopyridine-4-carboxylate (12 g, 40.69 mmol, 81.64% yield) was obtained.(M+H): 295.9. 'H NMR (400 MHz, DMSO-d6) 8 ppm 8.88 (s, 2 H) 3.97 (s, 3 H)

[0483] Step 2:113331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0484] To the solution of methyl 3,5-dibromopyridine-4-carboxylate (5 g, 16.95 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.61 g, 16.95 mmol, 2.88 mL, 1 eq), CS2CO3 (11.05 g, 33.91 mmol, 2 eq) in dioxane (80 mL) and H2O (8 mL) was added Pd(dppf)C12 (1.24 g, 1.70 mmol, 0.1 eq). The mixture was stirred at 100 °C for 2 hr. LC-MS showed methyl 3,5-dibromopyridine-4-carboxylate was consumed completely. The reaction mixture was diluted with H2O 80 mL and extracted with EtOAc (50 mL * 4). The combined organic layers were washed with brine (30 mL * 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=30 / l to 0 / 1). Compound methyl 3-bromo-5-vinyl-pyridine-4-carboxylate (1.5 g, 5.70 mmol, 33.63% yield) was obtained. (M+H): 242.0. 'HNMR (400 MHz, DMSO-d6) 8 ppm 8.94 (s, 1 H), 8.77 (s, 1 H), 6.60 (m, 1 H), 6.06 (d,J= 17.6 Hz, 1 H), 5.57 (d,J= 11.2 Hz, 1 H), 3.94 (s, 3 H).

[0485] Step 3:

[0486] A mixture of methyl 3-bromo-5-vinyl-pyridine-4-carboxylate (1 g, 4.13 mmol, 1 eq), tert-butyl carbamate (967.87 mg, 8.26 mmol, 2 eq), CS2CO3 (2.69 g, 8.26 mmol, 2 eq) , Pd2(dba)3 (378.29 mg, 413.11 pmol, 0.1 eq) and Xantphos (239.03 mg, 413.11 pmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 hr under N2 atmosphere. LC-MS showed methyl 3-bromo-5-vinyl-pyridine-4-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 0 / 1). Compound methyl 3-(tert-butoxycarbonylamino)-5-vinyl-pyridine-4-carboxylate (1.5 g, 4.96 mmol, 55.20% yield) was obtained. (M+H): 279.2. 'H NMR (400 MHz, DMSO-d6) 6 ppm 9.40 (s, 1 H), 8.62 (s, 1 H), 8.45 (s, 1 H), 6.79 - 6.87 (m, 1 H), 5.89 (d, J= 17.6 Hz, 1 H), 5.45 (d,J= 11.2 Hz, 1 H), 3.79 (s, 3 H), 1.44 (s, 9 H).

[0487] Step 4:

[0488] To the solution of Pd / C (0.2 g, 10% purity) in MeOH (20 mL) was added methyl 3-(tert-butoxycarbonylamino)-5-vinyl-pyridine-4-carboxylate (1.5 g, 5.39 mmol, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 2 hours. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture114331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062was filtered and concentrated under reduced pressure to give a residue. Compound methyl 3-(tert-butoxycarbonylamino)-5-ethyl-pyridine-4-carboxylate (1.5 g, 4.71 mmol, 87.37% yield) was obtained. (M+H): 281.2. 'HNMR (400 MHz, DMSO-d6) 8 ppm 9.36 (br s, 1 H), 8.36 (s, 1 H), 8.30 (s, 1 H), 3.79 (s, 3 H), 2.62 - 2.69 (m, 2 H), 1.44 (s, 9 H), 1.13 (t, J= 7.6 Hz, 3 H).

[0489] Step 5:

[0490] To the mixture of methyl 3-(tert-butoxycarbonylamino)-5-ethyl-pyridine-4-carboxylate (1.5 g, 5.35 mmol, 1 eq) in THF (10 mL) andH2O (10 mL) was added LiOH.H2O (449.10 mg, 10.70 mmol, 2 eq). The mixture was tirred at 20 °C for 2 hr. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The reaction mixture was adjusted to pH = 7 by IN HC1 solution. The reaction mixture was filtered and filter cake concentrated under reduced pressure to give a residue. Compound 3-(tert-butoxycarbonylamino)-5-ethyl-pyridine-4-carboxylic acid (700 mg, 2.52 mmol, 47.16% yield) was obtained. (M+H):267.2. ‘HNMR (400 MHz, METHANOL-d4) 6 ppm 9.10 (s, 1 H), 8.30 (s, 1 H), 2.88 - 2.96 (m, 2 H), 1.53 (s, 9 H), 1.27 (t, J = 7.6 Hz, 3 H).

[0491] Step 6:

[0492] A mixture of 3-(tert-butoxycarbonylamino)-5-ethyl-pyridine-4-carboxylic acid (300 mg, 990.91 pmol, 1 eq, HC1), 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (174.61 mg, 990.91 pmol, 1 eq), EDCI (227.95 mg, 1.19 mmol, 1.2 eq) in Py (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 45 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=30 / l to 0 / 1). Compound tert-butyl N-[5-ethyl-4-[(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)carbamoyl]-3-pyridyl]carbamate (120 mg, 282.69 pmol, 28.53% yield) was obtained. (M+H):425.3. 1HNMR (400 MHz, METHANOL-d4) 6 ppm 8.69 (s, 1 H), 8.31 (s, 1 H), 7.42 (s, 1 H), 6.46 (s, 1 H), 2.92 - 2.98 (m, 2 H), 2.74 - 2.80 (m, 2 H), 2.57 (m, 2 H), 2.27 (s, 3 H), 1.46 (s, 9 H), 1.27 (t, J = 7.6 Hz, 3 H).

[0493] Step 7:

[0494] A mixture of tert-butyl N-[5-ethyl-4-[(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)carbamoyl]-3-pyridyl]carbamate (120 mg, 282.69 pmol, 1 eq) in TFA (5 mL) and DCM (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C 115331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062for 5 hr under N2 atmosphere. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 7 by saturated NaHCCh solution. The solution was extracted with EtOAc (2 mL * 3). The combined organic layers were washed with brine(l mL * 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 3-amino-5-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)pyridine-4-carboxamide (100 mg, crude) was obtained. (M+H): 325.2. 1HNMR (400 MHz, METHANOL-d4) 8 ppm 7.96 (s, 1 H), 7.78 (s, 1 H), 7.43 (s, 1 H), 7.36 (s, 1 H), 2.96 (t, J = 7.6 Hz, 2 H), 2.65 - 2.70 (m, 2 H), 2.57 (t, J= 7.6 Hz, 2 H), 2.27 (s, 3 H), 1.22 - 1.29 (m, 3 H).Example 8: Synthesis of N-(8-(l-methyl-lH-imidazol-4-yl)-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3-(2,2,2-trifluoroethyl)isonicotinamide (Compound 11)Compound 11

[0495] Step 1:

[0496] To a solution of N-(8-chloro-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3 -(2,2,2-trifluoroethyl)pyridine-4-carboxamide (100 mg, 260.59 pmol, 1 eq tributyl-(l-methylimidazol-4-yl)stannane (145.07 mg, 390.88 pmol, 1.5 eq in dioxane (3 mL) was added palladium;tritert-butylphosphane (13.32 mg, 26.06 pmol, 0.1 eq) under glovebox. The mixture was stirred at 110 °C for 12 hr. LC-MS showed starting reactant remained and desired compound was detected. The mixture was diluted with H2O 10 mL and extracted with EtOAc 20 mL (10 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, EtOAc: MeOH = 5: 1). Compound N-[8-(l-methylimidazol-4-yl)-2-oxo-3, 4-dihydro- 116331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (60 mg, 138.75 pmol, 53% yield) was obtained. 'HNMR (400 MHz, DMSO-t / 6) 6 ppm 11.75 (s, 1H), 10.60 (s, 1H), 8.68 - 8.80 (m, 2H), 7.88 (s, 1H), 7.82 - 7.86 (m, 1H), 7.63 (d, J= 4.8 Hz, 1H), 7.58 (s, 1H), 7.36 -7.42 (m, 1H), 4.01 (q, J= 11.2 Hz, 2H), 3.76 (s, 3H), 2.93 (t, J= 7.2 Hz, 2H), 2.43 - 2.50 (m, 2H). (M+H)+: 430.2.Example 9: Synthesis of methyl 2-oxo-6-(3-(2,2,2-trifluoroethyl)isonicotinamido)-l,2,3,4-tetrahydroquinoline-8-carboxylate (Compound 12) and 2-oxo-6-(3-(2,2,2-trifluoroethyl)isonicotinamido)-l,2,3,4-tetrahydroquinoline-8-carboxamide (Compound

[0497] Step 1:

[0498] Two batches in parallel. To a solution of ethyl 2 -amino- 5 -nitro-benzoate (5 g, 23.79 mmol, 1 eq) in AcOH (50 mL) was added Bn (4.94 g, 30.92 mmol, 1.59 mL, 1.3 eq). The mixture was stirred at 25 °C for 1 hr. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was poured into ice-water (100 mL) slowly, filtered and the filter cake was concentrated under reduced pressure to give a residue. Compound ethyl 2-amino-3-bromo-5-nitro-benzoate (13 g,117331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206244.97 mmol, 94.52% yield) was obtained. 'H NMR (400 MHz, METHANOL-A) 6 ppm 8.76 (d, J= 2.8 Hz, 1H), 8.49 (d, J= 2.8 Hz, 1H), 4.38 - 4.45 (m, 2H), 1.42 (t, J= 7.2 Hz, 3H).

[0499] Step 2:

[0500] To a solution of ethyl 2-amino-3-bromo-5-nitro-benzoate (3 g, 10.38 mmol, 1 eq) and ethyl (E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2-enoate (3.52 g, 15.57 mmol, 1.5 eq) in dioxane (30 mL) and H2O (3 mL) was added ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane; dichloropalladium;iron (676.36 mg, 1.04 mmol, 0.1 eq) and K2CO3 (2.87 g, 20.76 mmol, 2 eq). The mixture was stirred at 100 °C for 1 hr. LC-MS showed ethyl 2-amino-3-bromo-5-nitro-benzoate was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O 30 mL and extracted with EtOAc 150 mL (50 mL * 3). The combined organic layers were washed with brine 80 mL (40 mL * 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1). Compound ethyl 2-amino-3-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-5-nitro-benzoate (2.6 g, 8.35 mmol, 80.46% yield) was obtained.

[0501] Step 3:

[0502] To the solution of Pd / C (200 mg, 10% purity) in EtOH (30 mL) was added ethyl 2-amino-3-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-5-nitro-benzoate (2 g, 6.49 mmol, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 hr. TLC indicated the starting material was consumed completely and one new spot formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound ethyl 2, 5-diamino-3-(3-ethoxy-3-oxo-propyl) benzoate (1.6 g, 5.71 mmol, 87.98% yield) was obtained.

[0503] Step 4:

[0504] To a solution of ethyl 2, 5-diamino-3-(3-ethoxy-3-oxo-propyl) benzoate (1.6 g, 5.71 mmol, 1 eq) in Tol. (16 mL) was added TsOH (98.29 mg, 570.78 pmol, 0.1 eq). The mixture was stirred at 100 °C for Ihr. The reaction mixture was diluted with H2O 20 mL and extracted with EtOAc 120 mL (40 mL * 3). The combined organic layers were washed with brine 80 mL (40 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound ethyl 6-amino-2-oxo-3, 4-dihydro-lH-quinoline-8-carboxylate (total 1.5 g, 91% yield) was obtained. 1H NMR (400 MHz, DMSO-tL) 6 ppm 9.82 (s, 1H), 7.04 (d, J= 2.4118331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Hz, 1H), 6.70 - 6.77 (m, 1H), 5.09 (s, 2H), 4.25 - 4.35 (m, 2H), 2.82 (t, J= 7.2 Hz, 2H), 2.42 -2.47 (m, 2H), 1.29 - 1.37 (m, 3H).

[0505] Step 5:

[0506] A solution of ethyl 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxylate (200 mg, 853.79 pmol, 1 eq) in NHi / MeOH (7 M, 10.00 mL, 81.99 eq) was stirred at 90 °C for 24 hr. LC-MS showed the starting material was consumed completely and 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxamide as main peak with desired mass was detected. The mixture was cooled 25 °C and concentrated under reduced pressure to give a residue. Compound 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxamide (140 mg, 682.22 pmol, 79.91% yield) and methyl 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxylate (80 mg, 363.27 pmol, 42.55% yield) were obtained.

[0507] Step 6:

[0508] To a solution of methyl 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxylate and 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxamide (200 mg) and 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (224.80 mg, 930.50 pmol, 1.5 eq, HC1) in Py (2 mL) was added EDCI (178.38 mg, 930.50 pmol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. LC-MS showed 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carboxamide was consumed completely and 2-oxo-6-[[3-(2,2,2-trifluoroethyl)pyridine-4-carbonyl]amino]-3,4-dihydro-lH-quinoline-8-carboxamide as main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase:[H2O (10mMNH4HCO3)-ACN]; gradient: 20%-60% B over 8.0 min).

[0509] Compound 13 2-oxo-6-[[3-(2,2,2-trifluoroethyl)pyridine-4-carbonyl]amino]-3,4-dihydro-lH-quinoline-8-carboxamide (84 mg, 205.75 pmol, 33.17% yield) was obtained. 'H NMR (400 MHz, METHANOL-A) 6 ppm 8.66 - 8.75 (m, 2H), 7.96 (d, J= 2.0 Hz, 1H), 7.66 (d, J= 4.8 Hz, 1H), 7.58 - 7.63 (m, 1H), 3.90 - 4.03 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.56 -2.69 (m, 2H). (M+H)+: 393.1.

[0510] Compound 12 methyl 2-oxo-6-[[3-(2,2,2-trifluoroethyl)pyridine-4-carbonyl]amino]-3,4-dihydro-lH-quinoline-8-carboxylate (45 mg, 104.29 pmol, 16.81% yield) was obtained. 'H NMR (400 MHz, METHANOL-A) 6 ppm 8.65 - 8.74 (m, 2H), 8.25 (d, J = 2.4 Hz, 1H),119331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20627.76 - 7.83 (m, 1H), 7.65 (d, J= 4.8 Hz, 1H), 3.88 - 4.03 (m, 5H), 3.07 (t, J= 7.2 Hz, 2H), 2.63 - 2.69 (m, 2H). (M+H)+: 408.1.Example 10: Synthesis of N-(8-(4-methyl-lH-pyrazol-l-yl)-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3-(2,2,2-trifluoroethyl)isonicotinamide (Compound 14)Compound 14 Compound 14A

[0511] Solution 1: {8-bromo-lH-quinolin-2-one,l eq, 3 g} in {H2SC>4,15 mL}

[0512] Solution 2: {Fuming Nitric Acid, 1.2 eq, 1.012 g} in {H2SC>4,15 mL}.

[0513] The solution 1 was pumped by Pump 1 {SI, Pl, 2.969 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(1 / 8”) mm, 30 mL,0 °C}.

[0514] The solution 2 was pumped by Pump 2 {S2, P2, 3.031 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(1 / 8”) mm, 30 mL,0 °C}.

[0515] The residence time of flow reactor 1 was {FLR1,5 min}.120331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0516] The mixture was collected with a bottle.

[0517] The Pump 1 and Pump 2 was started at the same time. The reaction mixture was collected after running 1 min. Stop collecting the reaction mixture after 10 mins. The mixture was quenched by ice water (100 mL) and filtered. The filter cake was collected. The mixture of 8-bromo-6-nitro-lH-quinolin-2-one and 8-bromo-5-nitroquinolin-2(lH)-one (3 g, 11.15 mmol) was obtained.

[0518] Step 2:

[0519] A mixture of 8-bromo-6-nitro-lH-quinolin-2-one and 8-bromo-5-nitroquinolin-2(lH)-one (2 g, 7.43 mmol, 1 eq) was added to ths solution of 4-methyl-lH-pyrazole (4.88 g, 59.47 mmol, 4.78 mL, 8 eq) , K2CO3 (2.05 g, 14.87 mmol, 2 eq), Cui (1.42 g, 7.43 mmol, 1 eq) and L-proline (427.91 mg, 3.72 mmol, 0.5 eq) in DMSO (30 mL). The mixture was stirred at 120 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and extracted with Ethyl acetate (50 mL*3). The combined organic layers were washed with Saturated NaCl solution (20 mL*2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / l to 1 / 1). A mixture of 8-(4-methylpyrazol-l-yl)-6-nitro-lH-quinolin-2-one and 8-(4-methyl-lH-pyrazol-l-yl)-5-nitroquinolin-2(lH)-one (0.5 g, 1.85 mmol, 24.89% yield) was obtained.

[0520] Step 3:

[0521] To a solution of the mixture 8-(4-methylpyrazol-l-yl)-6-nitro-lH-quinolin-2-one (0.25 g, 925.09 pmol, 1 eq)inMeOH(50 mL) was added Pd / C (492.24 mg, 462.55 pmol, 10% purity, 0.5 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi.) at 60 °C for 12 hrs. LC-MS showed the starting material was consumed completely and two desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The mixture of 6-amino-8-(4-methylpyrazol-l-yl)-3,4-dihydro-lH-quinolin-2-one and 5-amino-8-(4-methyl-lH-pyrazol-l-yl)-3,4-dihydroquinolin-2(lH)-one (400 mg, crude) was obtained.

[0522] Step 4:

[0523] A mixture of 6-amino-8-(4-methylpyrazol-l-yl)-3,4-dihydro-lH-quinolin-2-one and 5-amino-8-(4-methyl-lH-pyrazol-l-yl)-3,4-dihydroquinolin-2(lH)-one (80 mg, 330.20 pmol, 1 eq), 3-(2,2,2-trifluoroethyl)isonicotinic acid (67.74 mg, 330.20 pmol, 1 eq), EDCI (75.96 mg,121331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062396.24 pmol, 1.2 eq) , 3-(2,2,2-trifluoroethyl) isonicotinic acid (67.74 mg, 330.20 pmol, 1 eq) and Py (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. LC-MS showed the starting material was consumed completely and two desired mass was detected. Concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD04-Welch Utimate C18 150*25*7um; mobile phase: [water (FA)-ACN]; gradient: 14%-44% B over 15 min). Two targets were obtained.

[0524] Compound 14A: (0.02 g, 44.82 pmol, 6.79% yield) was obtained. (M+H)+:430.0.JH NMR (400 MHz, DMSO-d6) 8 ppm 10.50 (s, 1 H), 10.34 (s, 1 H), 8.67 - 8.83 (m, 2 H), 8.16 (s, 1 H), 7.74 (br s, 2 H), 7.49 (br d, J = 8.4 Hz, 1 H), 7.15 (d, J= 8.8 Hz, 1 H), 4.02 (q, J = 11.2 Hz, 2 H), 2.91- 2.99 (m, 2 H), 2.27 - 2.46 (m, 2 H), 2.13 (s, 3 H).

[0525] Compound 14: (0.02 g, 45.77 pmol, 6.93% yield) was obtained. (M+H)+:430.0. 'H NMR (400 MHz, DMSO-d6) 6 ppm 10.77 (s, 1 H), 10.03 (s, 1 H), 8.70 - 8.80 (m, 2 H), 8.01 (s, 1 H), 7.71 - 7.83 (m, 2 H), 7.63 (d, J = 4.8 Hz, 1 H), 7.49 (s, 1 H), 4.00 (q, J = 11.2 Hz, 2 H), 3.00 (t, J= 7.2 Hz, 2 H), 2.50 -2.54 (m, 2 H), 2.13 (s, 3 H)Example 11: Synthesis of N-(8-fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3-(2,2,2-trifluoroethyl)isonicotinamide (Compound 15)N-4 Step 4 Compound 15

[0526] Step 1:122331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0527] To a solution of Pd / C (100 mg, 6.13 mmol, 10% purity) in AcOH (10 mL) was added 8-fluoro-lH-quinolin-2-one (1 g, 6.13 mmol, 1 eq under Ar atmosphere. The suspension was degassed and purged with H2 for 2 times. The mixture was stirred under H2 (50 Psi.) at 80 °C for 5 hr. LC-MS showed 8-fluoro-lH-quinolin-2-one was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 8-fluoro-3,4-dihydro-lH-quinolin-2-one (800 mg, crude) was obtained.

[0528] Step 2:

[0529] To a 100 mL three neck bottle was added the solution of 8-fluoro-3,4-dihydro-lH-quinolin-2-one (400 mg, 2.42 mmol, 1 eq) in H2SO4 (5 mL). Then to the mixture was added KNO3 (340 mg, 3.36 mmol, 1.39 eq in portions at 0°C. The mixture was stirred at 0 °C for 1 hr. LC-MS showed 8-fluoro-3,4-dihydro-lH-quinolin-2-one was consumed completely and one main peak with desired m / z was detected. The mixture was poured into ice (15 mL) slowly. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were washed with brine (5 mL* 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (300 mg, crude) was obtained. 'H NMR (400 MHz, DMSO-tL) 8 ppm 10.74 (s, 1H), 8.03 (t, J= 8.0 Hz, 2H), 3.09 (t, J= 8.0 Hz, 2H), 2.58 (t, J= 8.0 Hz, 2H).

[0530] Step 3:

[0531] T0 asolution of Pd / C (15 mg, 10% purity) in THF (10 mL) was added 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (150 mg, 713.74 pmol, 1 eq under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi.) at 20 °C for 2 hr. LC-MS showed 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one was consumed completely and several new peaks were shown on LC-MS and -57% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 6-amino-8-fluoro-3,4-dihydro-lH-quinolin-2-one (80 mg, crude) was obtained.

[0532] Step 4:

[0533] To a solution of 6-amino-8-fluoro-3,4-dihydro-lH-quinolin-2-one (30 mg, 166.50 pmol, 1 eq and 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (52.39 mg, 183.15 pmol, 1.1 eq, HBr) in Py (1 mL) was added EDCI (47.88 mg, 249.75 pmol, 1.5 eq . The mixture was 123331375061ATTORNEY DOCKET No.: KAYO-011 / 01 WO 347382-2062stirred at 45 °C for 2 hr. LC-MS showed 6-amino-8-fluoro-3,4-dihydro-lH-quinolin-2-one was consumed completely and several new peaks were shown on LC-MS and ~40% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, Ethyl acetate: MeOH =10: 1).Compound N-(8-fluoro-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (12 mg, 32.67 pmol, 19.62% yield) was obtained.(M+H)+: 368.0. 'H NMR (400 MHz, METHANOLS) 6 ppm 8.69 (t, J= 4.0 Hz, 2H), 7.63 (d, J= 4.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.27 (s, 1H), 3.80 - 3.90 (m, 2H), 3.02 (t, J= 8.0 Hz, 2H), 2.62 (t, J= 8.0 Hz, 2H).Example 12: Synthesis of N-(8-cyano-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3-(2,2,2-trifluoroethyl)isonicotinamide (Compound 16)BuBrettPhos Pd G3,- step3Compound 16step4

[0534] Step 1:

[0535] To a solution of 8-chloro-3,4-dihydro-lH-quinolin-2-one (500 mg, 2.75 mmol, 1 eq) in dioxane (4 mL) and H2O (3 mL) was added KO Ac (108.08 mg, 1.10 mmol, 0.4 eq) and BuBrettPhos Pd G3(235.22 mg, 275.30 umol, 0.1 eq) and ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (133.44 mg, 275.30 umol, 0.1 eq) and K4[Fe(CN)e] (811.25 mg, 2.20 mmol, 0.8 eq). The mixture was stirred at 100 °C for 4 hr. TLC indicated 8-chloro-3,4-dihydro-lH-quinolin-2-one was consumed completely and one new spot formed.124331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=10 / l to 3 / 1). Compound 2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (300 mg, 1.74 mmol, 63.29% yield) was obtained.

[0536] Step 2:

[0537] To a 100 mL three neck bottle was added the solution of 2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (300 mg, 1.74 mmol, 1 eq) in H2SO4 (3 mL) .Then to the mixture was added KNO3 (30 mg, 296.73 umol, 0.17 eq) in protions at 0°C .The mixture was stirred at 0 °C for 1 h. TLC indicated 2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile was consumed completely and one new spot formed. The mixture was poured into ice (10 mL) slowly. The reaction mixture was diluted with H2O (lOmL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine(5 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with (Petroleum ether : Ethyl acetate = 10: 1) 5 mL at 20 °C for 20 min. Compound 6-nitro-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (200 mg, 920.89 umol, 52.85% yield) was obtained.

[0538] Step 3:

[0539] To a solution of 6-nitro-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (200 mg, 920.89 umol, 1 eq) in EtOH (2 mL) and H2O (2 mL) was added Fe (257.14 mg, 4.60 mmol, 5 eq) and NH4Q (492.60 mg, 9.21 mmol, 10 eq). The mixture was stirred at 50 °C for 2 hr .TLC indicated 6-nitro-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile was consumed completely and two new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC(SiC>2, Petroleum ether / Ethyl acetate=O / l). Compound 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (100 mg, 534.19 umol, 58.01% yield) was obtained.

[0540] Step 4:

[0541] To a solution of 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile (50 mg, 267.10 umol, 1 eq) and 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (76.40 mg, 267.10 umol, 1 eq , HBr) in Py (1 mL) was added EDCI (76.80 mg, 400.65 umol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. TLC indicated 6-amino-2-oxo-3,4-dihydro-lH-quinoline-8-carbonitrile was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC 125331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(SiCh, Ethyl acetate / MeOH=20 / l). Compound N-(8-cyano-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide(20 mg, 50.64 umol, 18.96% yield) was obtained. (M+H)+:375.0. 'H NMR (400 MHz, METHANOL-d4) 8 ppm 8.65 - 8.72 (m, 2H), 7.87 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 4.8 Hz, 1H), 3.96 (q, J = 10.8 Hz, 2 H), 3.03 (t, J = 7.6 Hz, 2 H), 2.64 (t, J = 7.6 Hz, 2 H).Example 13: Synthesis of 3-chloro-5-ethyl-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)isonicotinamide (Compound 7)"step 6 Compound 7

[0542] Step 1:

[0543] To the mixture of 3-bromo-5-chloro-pyridine (5 g, 25.98 mmol, 1 eq) in THF (200 mL) at 500 mL three neck bottle was added LDA (2 M, 25.98 mL, 2 eq) drop-wise at - 78 °C under N2. The reaction mixture was stirred at -78 °C for 1 h. To the mixture was added ethyl carb onochlori date (5.63 g, 51.88 mmol, 4.94 mL, 2.00 eq) in THF (100 mL) drop-wise slowly over 1 h. The final mixture was stirred at -78 °C for 2 h. LC-MS showed 3-bromo-5-chloro- 126331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062pyridine was consumed completely. The reaction mixture was quenched by pour into 200 mL sat. NH4Q at 0 °C and diluted with H2O 50 mL and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with brine (50 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 50 / 1 to 10 / 1). Compound ethyl 3-bromo-5-chloro-pyridine-4-carboxylate (3.5 g, 13.23 mmol, 50.93% yield) was obtained. (M+H)+: 264.0, 266.0. 'H NMR (400 MHz, DMSO-de) 6 ppm 8.87 (d, J= 3.2 Hz, 1H), 8.81 (d, J= 2.4 Hz, 1H), 4.20 - 4.25 (m, 2H), 1.34 (t, J= 6.8 Hz, 3H)

[0544] Step 2:

[0545] To the mixture of ethyl 3-bromo-5-chloro-pyridine-4-carboxylate (2 g, 7.56 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.16 g, 7.56 mmol, 1.28 mL, 1 eq) in dioxane (20 mL) and H2O (2 mL) was added CS2CO3 (7.39 g, 22.68 mmol, 3 eq) and Pd(dppf)C12 (553.27 mg, 756.13 umol, 0.1 eq). Then the reaction mixture was stirred at 100 °C for 12 h. TLC indicated ethyl 3-bromo-5-chloro-pyridine-4-carboxylate was consumed completely and one new spot formed. The reaction mixture was diluted with H2O 200 mL and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1). Compound ethyl 3-chloro-5-vinyl-pyridine-4-carboxylate (1.3 g, 6.14 mmol, 81.23% yield) was obtained.

[0546] Step 3:

[0547] To a solution of ethyl 3-chloro-5-vinyl-pyridine-4-carboxylate (1.2 g, 5.67 mmol, 1 eq) in MeOH (3 mL) was added Pd / C (100 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 h. The reaction mixture was filtered and filter liquor was concentrated under reduced pressure to give a residue. Compound ethyl 3-chloro-5-ethyl-pyridine-4-carboxylate (1.1 g, 5.15 mmol, 90.80% yield) was obtained.

[0548] Step 4:

[0549] To the mixture of ethyl 3-chloro-5-ethyl-pyridine-4-carboxylate (400 mg, 1.87 mmol, 1 eq) in H2O (3 mL) and EtOH (6 mL) was added NaOH (149.76 mg, 3.74 mmol, 2 eq). The reaction mixture was stirred at 40 °C for 5 h. LC-MS showed ethyl 3-chloro-5-ethyl-pyridine- 127331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20624-carboxylate was consumed completely and desired mass was detected. The reaction mixture was filtered and filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (HCl)-ACN]; B%: l%-20%,10min). Compound 3-chloro-5-ethyl-pyridine-4-carboxylic acid (130 mg, 585.41 umol, 31.27% yield, HC1) was obtained. (M+H)+: 196.1. ‘HNMR (400 MHz, DMSO-de) 6 ppm 8.58 (s, 1H), 8.54 (s, 1H), 2.63 (q, J= 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H)

[0550] Step 5:

[0551] To the mixture of 3-chloro-5-ethyl-pyridine-4-carboxylic acid (40 mg, 180.12 umol, 1 eq, HC1 salt) in DCM (5 mL) was added oxalyl dichloride (68.59 mg, 540.37 umol, 47.30 uL, 3 eq) drop-wise at 0 °C. Then the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 3 -chi oro- 5-ethyl-pyridine-4-carbonyl chloride (30 mg, crude) was used into the next step without further purification.

[0552] Step 6:

[0553] To the mixture of 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (25.91 mg, 147.02 umol, 1 eq), TEA (44.63 mg, 441.06 umol, 61.39 uL, 3 eq) in THF (5 mL) was added 3-chloro-5-ethyl-pyridine-4-carbonyl chloride (30 mg, 147.02 umol, 1 eq) in DCM (2 mL) drop-wise at 0 °C. Then the reaction mixture was stirred at 0 °C for 2 h. LC-MS showed 3-chloro-5-ethyl-pyridine-4-carbonyl chloride was consumed completely and one main peak with desired m / z was detected. The reaction mixture was diluted with H2O 10 mL and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (3mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, Petroleum ether: Ethyl acetate = 0: 1). Compound 3-chloro-5-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)pyridine-4-carboxamide (25 mg, 70.53 umol, 47.98% yield) was obtained. (M+H)+: 344.2. 'HNMR (400 MHz, DMSO-de) 6 ppm 10.57 (s, 1H), 9.45 (s, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 7.25 - 7.37 (m, 2H), 2.85 (t, J= 7.6 Hz, 2H), 2.63 - 2.68 (m, 2H), 2.43 (t, J= 7.2 Hz, 2H), 2.21 (s, 3H), 1.20 (t, J= 7.2 Hz, 3H).128331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 14: Synthesis of 2-cyano-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-3-(2,2,2-trifluoroethyl)isonicotinamide (Compound 9)Compound 9

[0554] Step 1:

[0555] To the mixture of methyl 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (5 g, 22.8 mmol, 1 eq) in DCM (75 mL) was added m-CPBA (6.02 g, 29.6 mmol, 85% purity, 1.3 eq) in portions at 0 °C. Then the mixture was stirred at 20 °C for 12 h. To the mixture was added sat. Na2SC>3 (200 ml) and the mixture was stirred at 20 °C for 30 min. The mixture was extracted with DCM (70 mL * 3). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 3 / 1 to 2 / 1). Compound methyl l-oxido-3-(2, 2, 2-trifluoroethyl)pyridin-l-ium-4-carboxylate (4.8 g, 20.4 mmol, 89.4% yield) was obtained. (M+H)+: 236.1.

[0556] Step 2:

[0557] To a solution of methyl l-oxido-3-(2,2,2-trifluoroethyl)pyridin-l-ium-4-carboxylate (2.5 g, 10.6 mmol, 1 eq) in DCM (30 mL) was added Tri ethyl oxonium tetrafluorob orate (6.06 g, 31.8 mmol, 4.56 mL, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed -47% of desired compound was detected. The recation mixture was diluted with H2O 30 mL and extracted with DCM 10 mL * 3. The combined organic layers were washed with brine 10 mL * 3, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue.129331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 5 / 1 to 3 / 1). Compound methyl 1 -ethoxy-3 -(2, 2, 2-trifluoroethyl)pyri din- l-ium-4-carboxylate (2.4 g, 6.84 mmol, 64.3% yield, [BFT]'1) was obtained. (M+H)+: 265.1.

[0558] Step 3:

[0559] To a solution of methyl 1 -ethoxy-3 -(2, 2, 2-trifluoroethyl)pyri din- l-ium-4-carboxylate (3 g, 9.04 mmol, 1 eq, [BF4] ) in H2O (60 mL) and t-BuOH (30 mL) was added NaCN (640 mg, 13.0 mmol, 1.45 eq) in H2O (15 mL) at 30 °C. The mixture was stirred at 30 °C for 1 h. LC-MS showed methyl 1 -ethoxy-3 -(2, 2, 2-trifluoroethyl)pyri din- l-ium-4-carboxylate was consumed completely and one main peak with desired was detected. The reaction mixture was cooled to 20 °C. Then the mixture was adjusted to pH = 11 by sat.Na2CCh. The aqueous phase was extracted with ethyl acetate (40 mL * 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 3 / 1 to 2 / 1). Compound methyl 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (460 mg, 1.88 mmol, 16.4% yield) was obtained. (M+H)+: 245.1. 'HNMR (400 MHz, CHLOROFORM-d) 5 ppm 8.77 (d, J= 5.2 Hz, 1H), 7.91 (d, J= 5.2 Hz, 1H), 4.23 - 4.28 (m, 2H), 3.93 (s, 3H).

[0560] Step 4:

[0561] To a solution of ethyl 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (100 mg, 409 pmol, 1 eq) in THF (3 mL) and H2O (3 mL) was added LiOH.H2O (19.6 mg, 819,pmol, 2 eq). The mixture was stirred at 20 °C for 1 h under N2 atmosphere. LCMS showed methyl 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylate was consumed completely and one main peak with desired m / z was detected. The reaction was concentrated in vacuum to remove THF. Then the mixture was adjusted to pH = 2~3 by IN HC1. Then the mixture was filtered. The filter cake was concentrated in vacuum. Compound 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (50 mg, 217 pmol, 53.05% yield) was obtained. (M+H)+: 231.1. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 8.65 (d, J= 4.8 Hz, 1H), 7.79 (d, J= 5.2 Hz, 1H), 4.27 -4.35 (m, 2H).

[0562] Step 5:

[0563] A mixture of 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (80 mg, 300 pmol, 1 eq, HC1), 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (47.5 mg, 270 pmol, 0.9 eq), CMPI (114 mg, 450 1 pmol, 1.5 eq) and TEA (91.0 mg, 900 pmol, 125 pL, 3 eq) in THF 130331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, Petroleum ether / Ethyl acetate = 0 / 1). Compound 2-cyano-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (12 mg, 29.76 pmol, 9.92% yield) was obtained. (M+H)+: 389.1.1HNMR(400 MHz, DMSO-dd) 5 ppm 10.71 (s, 1H), 9.46 (s, 1H), 8.94 (d, J= 4.8 Hz, 1H), 7.99 (d, J= 4.8 Hz, 1H), 7.37 (s, 1H), 7.20 (s, 1H), 4.16 - 4.24 (m, 2H), 2.86 (t, . / =7 .2 Hz, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.21 (s, 3H).Example 15: Synthesis of 2-cyano-N-(8-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-5- (2,2,2-trifluoroethyl)isonicotinamide (Compound 10)

[0564] Step 1:

[0565] To a solution of methyl 2-cyano-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (100 mg, 409 pmol, 1 eq) in THF (3 mL) and H2O (3 mL) was added LiOH.H2O (19.6 mg, 819 pmol, 2 eq). The mixture was stirred at 20 °C for 1 h under N2 atmosphere. LCMS showed methyl 2-cyano-3-(2,2,2-trifluoroethyl)pyridine-4-carboxylate was consumed completely and one main peak with desired m / z was detected. The reaction was concentrated in vacuum to remove THF. Then the mixture was adjusted to pH = 2~3 by IN HC1. Then the mixture was filtered. The filter cake was concentrated in vacuum. Compound 2-cyano-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (80 mg, 782 pmol, 63.6% yield) was obtained. (M+H)+: 231.1.JH NMR (400 MHz, METHANOL-dd) 5 ppm 8.76 (s, 1H), 8.19 (s, 1H), 4.16 - 4.24 (m, 2H).

[0566] Step 2:131331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0567] A mixture of 2-cyano-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (40 mg, 150 pmol, 1 eq, HC1), 6-amino-8-methyl-3,4-dihydro-lH-quinolin-2-one (23.7 mg, 135 pmol, 0.9 eq), CMPI (57.5 mg, 225 pmol, 1.5 eq) and TEA (45.5 mg, 450 pmol, 62.6 qL, 3 eq) in THF (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 1 h under N2 atmosphere. LCMS showed no 2-cyano-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid remained. Several new peaks were shown on LCMS and -43% of desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, Petroleum ether / Ethyl acetate = 0 / 1). Compound 2-cyano-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-5-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (10 mg, 25.5 pmol, 17.0% yield) was obtained. (M+H)+: 389.1.JH NMR (400 MHz, DMSO-dd) 5 ppm 10.61 (s, 1H), 9.47 (s, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 4.06 - 4.15 (m, 2H), 2.86 (t, J= 7.6 Hz, 2H), 2.45 (t, J= 2.8 Hz, 2H), 2.21 (s, 3H).132331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 16: Synthesis of N-[8-(4-fluoropyrazol-l-yl)-2-oxo-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (Compound 22)step3Compound 22

[0568] Step l:

[0569] To a solution of 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (200 mg, 952 pmol, 1 eq) and 4-fluoro-lH-pyrazole (123 mg, 1.43 mmol, 1.5 eq) in DMF (2 mL) was added CS2CO3 (620 mg, 1.90 mmol, 2 eq). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was poured into H2O (5 mL) slowly, filtered and the filter cake concentrated under reduced pressure to give a residue. Compound 8-(4-fluoropyrazol-l-yl)-6-nitro-3,4-dihydro-lH-quinolin-2-one (80 mg, 278 pmol, 29.2% yield, 96% purity) was obtained as a yellow solid.[M+H]+: 277.0. *HNMR (400 MHz, DMSO-de) 5 ppm 10.42 (s, 1 H), 8.77 (d, J= 4.0 Hz, 1H), 8.20 - 8.30 (m, 2H), 8.06 (d, J= 4.0 Hz, 1H), 3.15 (t, J = 7.2 Hz, 2H), 2.57 - 2.64 (m, 2H).

[0570] Step 2:

[0571] To a solution of 8-(4-fluoropyrazol-l-yl)-6-nitro-3,4-dihydro-lH-quinolin-2-one (70 mg, 253 pmol, 1 eq) in EtOH (8 mL) and H2O (4 mL) was added Fe (70.8 mg, 1.27 mmol, 5 eq) and NH4Q (135 mg, 2.53 mmol, 10 eq). The mixture was stirred at 50 °C for 1 hr. The crude was combined another crude for workup (total 80 mg). The reaction mixture was filtered and then diluted with H2O 5 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were washed with brine 20 mL (10 mL * 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 6-amino-8-(4- 133331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062fluoropyrazol-l-yl)-3,4-dihydro-lH-quinolin-2-one (50 mg, 70% yield) was obtained as a yellow solid.

[0572] Step 3:

[0573] To a solution of 6-amino-8-(4-fluoropyrazol-l-yl)-3,4-dihydro-lH-quinolin-2-one (40 mg, 162 pmol, 1 eq) and 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (47.1 mg, 195 pmol, 1.2 eq, HC1) in Py (2 mL) was added EDCI (46.7 mg, 244 pmol, 1.5 eq) .The mixture was stirred at 45 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was combined to another crude for further purification (total 50 mg). The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient:20%-50% B over 8.0 min). Compound N-[8-(4-fhioropyrazol-l-yl)-2-oxo-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (100% purity, HC1) was (45 mg, 47% yield) was obtained as a yellow solid. [M+H]+: 434.1.1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.93 - 9.03 (m, 2H), 8.18 (d, J= 4.4 Hz, 1H), 8.10 - 8.15 (m, 1H), 7.77 - 7.83 (m, 2H), 7.52 - 7.57 (m, 1H), 4.04 - 4.17 (m, 2H), 3.10 (t, J= 7.2 Hz, 2H), 2.61 - 2.69 (m, 2H).134331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 17: Synthesis of N-[2-oxo-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (Compound 23)

[0574] Step l:

[0575] To a solution of 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (0.2 g, 951pmol, 1 eq and 4-(trifluoromethyl)-lH-pyrazole (155 mg, 1.14 mmol, 1.2 eq) in DMF (2 mL) was added CS2CO3 (620 mg, 1.90 mmol, 2 eq) .The mixture was stirred at 120 °C for 12 hr. The reaction was messy according to TLC. The reaction mixture was quenched by addition H2O 5 mL at 0 °C, and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (5 mL * 2), dried over Na2COs, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / 0 to 90 / 10) to give cnitro-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-2-one (0.15 g, 285 mol, 29.9% yield, 62% purity) was obtained as a white solid. 'HNMR (400 MHz, DMSO-de) 6 ppm 10.25 (s, 1H), 9.11 (s, 1H), 8.36 (d, J= 4.8 Hz, 1H), 7.98 - 8.11 (m, 1H), 7.91 (s, 1H), 3.12 - 3.22 (m, 2H), 2.57 - 2.65 (m, 2H)

[0576] Step 2:

[0577] To a solution of 6-nitro-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-2-one (0.1 g, 306 mol, 1 eq inETOH (1 mL) and H2O (0.2 mL) was added NH4Q (163 g, 3.07 mmol, 10 eq and Fe (85.6 mg, 1.53 mmol, 5 eq . The mixture was stirred at 50 °C for 1 hr.135331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was poured water (3 mL) and extracted with EtOAc (5 mL * 2). The combined organic layers were washed with brine (5 mL * 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give compound 6-amino-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-2-one (0.11 g crude) was obtained as a white solid.

[0578] Step 3:

[0579] To a solution of 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (69.2 mg, 337 pmol, 1 eq and 6-amino-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-2-one (0.1 g, 337 pmol, 1 eq) in py. (1 mL) was added EDCI (129 mg, 675 pmol, 2 eq). The mixture was stirred at 45 °C for 1 hr. LCMS showed 6-amino-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-2-one was consumed completely and one main peak with desired 484.1 m / z was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100*40mm*5 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient:25%-55% B over 8.0 min) to give compound N-[2-oxo-8-[4-(trifluoromethyl)pyrazol-l-yl]-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (99.4% purity, HC1, 33 mg) was obtained as a yellow solid. (M+H)+: 484.0JH NMR (400 MHz, DMSO-de) 8 ppm 10.82 (s, 1H), 9.61 (s, 1H), 8.86 (s, 1H), 8.78 (d, J= 4.8 Hz, 1H), 8.75 (s, 1H), 8.29 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.65 (d, J= 9.2 Hz, 1H), 4.01 (q, J= 11.2 Hz, 2H), 3.00 - 3.05 (m, 2H), 2.53 (s, 2H).136331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 18: Synthesis of N-[8-(4-cyanopyrazol-l-yl)-2-oxo-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (Compound 24)steP3 Compound 24

[0580] Step l:

[0581] To a solution of lH-pyrazole-4-carbonitrile (332 mg, 3.57 mmol, 1.5 eq) and 8-fluoro-6-nitro-3,4-dihydro-lH-quinolin-2-one (500 mg, 2.38 mmol, 1 eq) in DMF (5 mL) was added CS2CO3 (1.55 g, 4.76 mmol, 2 eq). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was poured into H2O (5 mL) slowly, filtered and the filter cake concentrated under reduced pressure to give a residue. Compound l-(6-nitro-2-oxo-3,4-dihydro-lH-quinolin-8-yl)pyrazole-4-carbonitrile (300 mg, 1.04 mmol, 43.6% yield, 98% purity) was obtained as a white solid. [M+H]+: 284.1. 'H NMR (400 MHz, DMSO-de) 6 ppm 10.08 - 10.21 (m, 1H), 9.16 (s, 1H), 8.46 (s, 1H), 8.25 - 8.35 (m, 2H), 3.16 (t, J= 7.2 Hz, 2H), 2.60 (t, J= 7.6 Hz, 2H).

[0582] Step 2:

[0583] To a solution of l-(6-nitro-2-oxo-3,4-dihydro-lH-quinolin-8-yl)pyrazole-4-carbonitrile (100 mg, 353 pmol, 1 eq) in EtOH (4 mL) and H2O (2 mL) was added Fe (98.6 mg, 1.77 mmol, 5 eq) and NH4Q (189 mg, 3.53 mmol, 10 eq). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was filtered and then diluted with H2O 5 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were washed with brine 10 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 137331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062residue. Without purification. Compound l-(6-amino-2-oxo-3,4-dihydro-lH-quinolin-8-yl)pyrazole-4-carbonitrile (80 mg, 316 pmol, 89.5% yield) was obtained as a yellow solid.[M+H]+: 254.0.

[0584] Step 3:

[0585] To a solution of l-(6-amino-2-oxo-3,4-dihydro-lH-quinolin-8-yl)pyrazole-4-carbonitrile (70 mg, 276 pmol, 1 eq) and 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (80.1 mg, 331 pmol, 1.2 eq, HC1) in Py (1 mL) was added EDCI (79.5 mg, 415 pmol, 1.5 eq) .The mixture was stirred at 45 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7um; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 10%-60% B over 8.0 min). Compound N-[8-(4-cyanopyrazol-l-yl)-2-oxo-3,4-dihydro-lH-quinolin-6-yl]-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (65 mg, 144 pmol, 52.28% yield, 97.9% purity) was obtained as a yellow solid, [M+H]+: 441.1.JH NMR (400 MHz, DMSO-de) 6 ppm 10.83 (s, 1H), 9.57 (s, 1H), 8.99 (s, 1H), 8.67 - 8.82 (m, 2H), 8.40 (s, 1H), 7.58 - 7.76 (m, 3H), 3.90 - 4.05 (m, 2H), 3.01 (J = 7.2 Hz, 2H), 2.51 - 2.55 (m, 2H).138331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 19: Synthesis of N-(8-chloro-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (Compound 25)steplCompound 25

[0586] Step l:

[0587] To a solution of 6-amino-8-chl oro-3, 4-dihydro-lH-quinolin-2-one (30 mg, 153 pmol, 1 eq) and 2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (46.8 mg, 183 pmol, 1.2 eq, HC1) in Py (1 mL) was added EDCI (43.8 mg, 229 pmol, 1.5 eq). The mixture was stirred at 45 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100*40mm*5 um;mobile phase: [H20(0.04% HCl)-ACN];gradient:15%-50% B over 8.0 min). Compound N-(8-chloro-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-2-methyl-5-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (30 mg, 69.09 pmol, 45.28% yield, 100% purity, HC1) was obtained as a yellow solid. (M+H)+: 398.1. 'H NMR (400 MHz, METHANOL-t / 4) 8 ppm 8.92 (s, 1H), 8.15 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.46 - 7.51 (m, 1H), 4.02 - 4.13 (m, 2H), 3.03 (t, J= 7.2 Hz, 2H), 2.86 (s, 3H), 2.59 - 2.66 (m, 2H).139331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 20: Synthesis of 2-cyano-6-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (Compound 26)2 step 3Compound 26

[0588] Step l:

[0589] To a solution of 2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-5-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (1 g, 2.65 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (699 mg, 3.44 mmol, 85% purity, 1.3 eq) in portions at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. To the mixture was added sat. Na2SOs (50 mL) slowly at 25 °C under N2. Then the mixture was stirred at 25 °C for 1 h. The mixture was extracted with DCM (20 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. Compound 2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-l-oxido-5-(2,2,2-trifluoroethyl)pyridin-l-ium-4-carboxamide (0.8 g, 2.03 mmol, 76.7% yield) was obtained as a white solid. (M+H)+= 394.0

[0590] Step 2:

[0591] To a solution of 2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-l-oxido-5-(2,2,2-trifluoroethyl)pyridin-l-ium-4-carboxamide (0.1 g, 254 pmol, 1 eq) in ACN (3 mL) was added trimethyloxonium;tetrafluoroborate (94.0 mg, 635 pmol, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O 20 mL and extracted with EtOAc 40 mL (20 mL * 2). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 1-methoxy-2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-5-(2,2,2- 140331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062trifluoroethyl)pyridin-l-ium-4-carboxamide (80 mg, crude) was obtained as a white solid. (M+H)+= 408.1

[0592] Step 3:

[0593] To a solution of l-methoxy-2-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-5-(2,2,2-trifluoroethyl)pyridin-l-ium-4-carboxamide (50 mg, 122.43 pmol, 1 eq) in t-BuOH (0.5 mL) and H2O (1 mL) was added dropwise NaCN (9.00 mg, 183.65 pmol, 1.5 eq) in H2O (0.2 mL) under N2 at 25 °C. The mixture was stirred at 30 °C for 1 h. The reaction mixture was cooled to 25°C. Then the mixture was adjusted to pH = 11 by sat.Na2CC>3. The aqueous phase was extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient:25%-55% B over 8.0 min). Compound 2-cyano-6-methyl-N-(8-methyl-2-oxo-3,4-dihydro-lH-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (16 mg, 36.21 pmol, 29.57% yield, 99.3% purity, HC1) was obtained as a white solid. (M+H)+= 403.1 'H NMR (400 MHz, DMSO-de) 8 ppm 10.65 (s, 1H), 9.46 (s, 1H), 7.89 (s, 1H), 7.36 (s, 1H), 7.28 (d,J= 1.6 Hz, 1H), 4.13 (q, J= 11.2 Hz, 2H), 2.86 (t, J= 6.8 Hz, 2H), 2.62 (s, 3H), 2.39 - 2.47 (m, 2H), 2.21 (s, 3H).Example 21: Aldhla3 and Aldhla2 Enzyme Inhibition Assays

[0594] Aldhla3 Enzyme Inhibition Assay

[0595] Recombinant protein extraction: pET-Aldhla3 transformed BL21-DE3 cultures induced at 20 °C for 19h with 0.3 mM IPTG rocking. Cultures were spun at 3500g for 10 min, supernatants were poured off and allowed to drain fully. Cells were resuspended in 10 mM HEPES pH 7.4, 10 mM KC1. Cells were freeze-thawed in liquid nitrogen and then a 37 °C water bath for 10 cycles followed by ultrasonication at 50% amplitude, 3 sec on, 9 sec off for 10 cycles at 4 °C. Cell extracts were spun at 16000 x g for 5 minutes.

[0596] Reaction performed at 20 °C in reaction buffer (10 mM HEPES pH 7.4, 10 mM KC1, 0.1 M Resazurin, 1 mg / mL BSA, 200 uM NAD+, diaphorase and aldehyde substrate).Recombinant enzyme and inhibitor added immediately before assay. Reaction rate measured by resorufin fluorescence.

[0597] Aldhla2 Enzyme Inhibition Assay141331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0598] Recombinant protein extraction: pET-Aldhla2 transformed BL21-DE3 cultures induced at 20 °C for 19h with 0.3 mM IPTG rocking. Cultures were spun at 3500g for 10 min, supernatants were poured off and allowed to drain fully. Cells were resuspended in 10 mM HEPES pH 7.4, 10 mM KC1. Cells were freeze-thawed in liquid nitrogen and then a 37 °C water bath for 10 cycles followed by ultrasonication at 50% amplitude, 3 sec on, 9 sec off for 10 cycles at 4 °C. Cell extracts were spun at 16000 x g for 5 minutes.

[0599] Reaction performed at 20 °C in reaction buffer (10 mM HEPES pH 7.4, 10 mM KC1, 0.1 M Resazurin, 1 mg / mL BSA, 200 uM NAD+, diaphorase and aldehyde substrate). Recombinant enzyme and inhibitor added immediately before assay. Reaction rate measured by resorufin fluorescence.

[0600] The ICso values of selected tested compounds are shown in Table 2 below. The hAldhla3:hAldhla2 ratio is based on IC50 values for hAldhla3 and hAldhla2. The designations for the hAldhla3:hAldhla2 ratio are as follows: A < 0.09; B = 0.1 - 0.2; C > 0.21 and for hAldla3 and mAldhla3 are as follows: D <100 nM; E = 100 - 200 nM; and F > 200 nM.

[0601] Control compounds A-C are disclosed in US 2024 / 0132469 which is incorporated by reference herein.(Control Compound A) (Control Compound B)(Control Compound C)Table 2. Selectivity of hALDHla3 v. hALDHlal, mALDHla3, and hALDHla3 of Selected Compounds142331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062Example 22: CYP3A4 inhibition assay

[0602] To assess the inhibition of CYP3A4 using human liver microsomes (HLM), a protocol was performed utilizing midazolam as the CYP3A4 substrate and ketoconazole as a positive control inhibitor, with both stock solutions prepared (midazolam in MeOH and ketoconazole in DMSO) and the ketoconazole working solution generated via dilution. The enzyme source was HLM, and incubations were carried out in 0.1 M phosphate buffer (pH 7.4) at 37°C. A lOx cocktail of CYP substrates, inclusive of midazolam, and a 1.27x working solution of HLM were prepared. Substrate solutions were added to appropriate wells, with phosphate buffer used for blanks, and test compound working solutions and the ketoconazole positive control were added to their respective wells, with solvent and phosphate buffer used for no-inhibitor and blank wells, respectively. Subsequently, the HLM working solution was added to all wells of the incubation plate, which was then pre-warmed at 37°C. Following preparation of the NADPH cofactor solution, the plate was pre-incubated for 10 minutes at 37°C with the test compounds or ketoconazole and HLM, after which the reaction was initiated by adding the 143331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062NADPH cofactor. After a 10-minute incubation, the reaction was quenched with a cold stop solution containing tolbutamide and labetalol in acetonitrile. The reaction mixture was then centrifuged, and the resulting supernatant was diluted with water. The diluted samples were analyzed by LC / MS / MS to quantify the formed midazolam metabolite, thus enabling the evaluation of CYP3A4 inhibition. Finally, the inhibition observed with the test compounds was compared to that of the positive control and historical data for analysis.

[0603] The Cyp3A4 % inhibition for selected test compounds of the disclosure is shown in Table 3 below. The Cyp3A4 % inhibition values are designated as follows: A > 25; B < 25 at 10pM.Table 3. CYP3A4% inhibition of selected compounds144331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062145331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062<<Example 23: Evaluation of Pharmacokinetic Profile

[0604] The pharmacokinetic profile of selected compounds was evaluated.146331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062* "BQL" was excluded in the PK parameters and mean concentration calculation.

[0605] Results:

[0606] The mean oral T’ (h) for selected test compounds of the disclosure is shown in Table 4 below.Table 4. Tl / 2 (h) for selected test compounds.147331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062

[0607] As shown in Table 4, Compound 1 of the present disclosure showed better PK characteristics for oral administration, such as significantly improved half-life (t ¥2) compared to structurally similar control compounds.Example 24: Evaluation of Compound 1 in a Pre-Type 2 Diabetes Model

[0608] The efficacy of Compound 1 in preventing type 2 diabetes onset in pre-diabetic ZDF rats was evaluated.

[0609] Protocol

[0610] Homozygous Zucker Diabetic Fatty (ZDF) male rats were screened and randomized into two groups (n = 10 / group) based on HOMA-IR, HbAlc and body weight and administered 30 mg / kg of Compound 1 or vehicle p.o. once daily with for 7 weeks.Table 5. Study treatments

[0611] Fasting blood glucose, plasma insulin and HbAlc levels were measured every two weeks and HOMA-IR was calculated for each measurement. Water and food intakes per cage and body weight per animal were measured once a week. Fasting serum chemistry was measured at initiation, midpoint and endpoint of the study. At day 48 of treatment, an intraperitoneal glucose tolerance test (ipGTT) was performed with plasma insulin and c peptide levels measured at time 0 and +30 minutes after the intraperitoneal glucose injection. At the end of treatment period, animals were fasted for 8 hours after dosing, then blood was collected to measure endpoint parameters, including clinical chemistry. Kidneys, liver, mW AT and iWAT and pancreas were collected for formalin-fixation and / or freezing.

[0612] Results

[0613] Compound 1 showed a strong anti-diabetic effect, completely preventing diabetic onset by fasting blood glucose (FIG.1A), HbAlc (FIG. IB) and insulin levels (FIG. 1C). As shown in FIG. 1A Compound 1 treatment maintained healthy fasting blood glucose levels compared to significant increase in fasting blood glucose in vehicle treated rats. Compound 1 treatment also significantly improved glucose tolerance compared to vehicle during an intraperitoneal 148331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062glucose tolerance test and resulted in increased beta cell function as measured by plasma insulin levels 30 minutes after i.p. glucose injection. This positive effect was associated with a significant reduction in %HbAlc at the end of treatment period (FIG. IB) and fasting insulin was also significantly improved by Compound 1 treatment (FIG. 1C). These results show that Compound 1 treatment was able to successfully prevent the onset of Type 2 diabetes.

[0614] Compound 1 treatment over 7 weeks also led to improved kidney function and reduced glycosuria as measured by reduced water intake (FIG. 2A) and an increase in healthy body mass gain (FIG. 2B), reflecting improved insulin sensitization.

[0615] Reduced liver (FIG.3A) and kidney weights (FIG.3B) were also observed, suggesting reduced steatosis and fibrotic content. Reduced blood urea (FIG. 3C), ALT (FIG. 3D) and water intake (FIG. 2A) strongly suggests improved liver and kidney health in Compound 1 treated animals. Animal technicians also observed that test and control animals were visually distinguishable as Compound 1 -treated animals were healthy with no outward signs of diabetic onset.

[0616] Creatine kinase was reduced overtime and significantly reduced under Compound 1 treatment, when compared to vehicle treatment at the last day of treatment (-32%, p<0.05, FIG.4) suggesting a decrease of muscle mass damage.Example 25: Evaluation of Compound 1 in a Model of Severe Type 2 Diabetes

[0617] The efficacy of Compound 1 in treating type 2 diabetes in severely diabetic db / db mice was evaluated.

[0618] Protocol

[0619] 16 and 17-week old, male, severely diabetic db / db mice were used for the study. Animals were dosed daily for 4 weeks with either vehicle control or 50 mg / kg of Compound 1 administered orally.

[0620] Results

[0621] Treatment of severely diabetic db / db mice with Compound 1 over 28 days showed an almost complete reversal of type 2 diabetes as indicated by a decrease in HbAlc levels (FIG.5B) and a recovery in pancreatic large islet ratio (FIG. 5C) without affecting food intake or body weight (Fig. 5A). Clinical chemistry demonstrated a striking 30% reduction in 149331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062triglycerides (FIG. 6A) and 17% reduction in LDLs (FIG. 6B) in the Compound 1 treated group.

[0622] These results show that Compound 1 treatment was successful in reversing diabetes in severely diabetic db / db mice.Example 26: Compound 1 v. Semaglutide in Spontaneously Diabetic Torii (STD Fatty Rat Model of Diabetic Heart Failure

[0623] The following is a head-to-head study of Compound 1 and Semaglutide in a SDT fatty rat model of diabetic heart failure.

[0624] Diabetic 7-week old SDT fatty rats were treated with vehicle, Compound 1 (30 mg / kg p.o. QD) or Semaglutide (15 nmol / kg s.c. Q3D) for 12 weeks with echocardiography used to measure cardiac dynamics (FIG. 7A). End-Systolic Volume measures degree of cardiac remodeling.

[0625] Isovolumetric relaxation time was measured as the key measure of heart failure with preserved ejection fraction (HFpEF) across each group (FIG. 7B).

[0626] At endpoint, animals were sacrificed and heart mass was collected for each group. n=10 rats / group. Error bars represent SEM (FIG. 7C).

[0627] Results

[0628] A head-to-head study of Compound 1 vs Semaglutide in this diabetic model of HFpEF demonstrates both therapies are effective in slowing the cardiac remodeling that leads to heart failure.

[0629] Compound 1 is more efficient in slowing isovolumic relaxation time (IVRT) increases.150331375061

Claims

1. ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062CLAIMS1. A compound of F ormula (III) :or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein:ring A is heteroaryl or aryl;R1is -Ci-ehaloalkyl, halo, or -NR8R9;R2is independently halo, -CN, -Ci-6 alkyl, -Ci-6 alkylene-carbocyclyl, -Ci-6 alkylene-heterocyclyl, or -Ci-ehaloalkyl;n is 1 or 2;R3is -H, halo, -Ci-6 alkyl, or -Ci-ehaloalkyl;R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-ehaloalkyl, -C(O)NR8R9, -C(0)0R8, -NR8R9, -NR8C(O)R9, heterocyclyl, heteroaryl, or carbocyclyl; or R3and R4are taken together to form heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo, -Ci-ehaloalkyl, -Ci-ealkyl, -CN, -OH, -NH2, -NH(alkyl), or -N(alkyl)2;R5A, R5B, R6A, and R6Bare each independently -H, halo, or -C1-6 alkyl; orone of R5Aand R5Bis joined with one of R6Aand R6Bto form an optionally substituted C3-8 carbocyclic ring, or an optionally substituted 3-8 membered heterocyclic ring; and R7is -H, -Ci-ealkyl or halo; andR8and R9are each independently -H, -C1-6 alkyl, aryl or heteroaryl; andprovided the compound is not:5-Isothiazolecarboxamide, 3-methyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;5-Isothiazolecarboxamide, 3-cyano-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-4-(2,2,2-trifluoroethyl)-;151331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-20624-Pyridinecarboxamide, 2-chloro-5-ethyl-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-;5H-Cyclopenta[b]pyridine-4-carboxamide, 6,6-difluoro-6,7-dihydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-; or4-Quinolinecarboxamide, 6,6-difluoro-5,6,7,8-tetrahydro-N-(l,2,3,4-tetrahydro-8-methyl-2-oxo-6-quinolinyl)-.

2. The compound of claim 1, wherein the compound is of Formula (III-A):(in-A)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof;wherein X1and X2are each independently CH or N.

3. The compound of claim 1, wherein the compound is of Formula (III-B):(III-B)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.

4. The compound of claim 1, wherein the compound is of Formula (III-D):152331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062(III-D)or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.

5. The compound of claim 4, wherein R1is -Ci-6 haloalkyl, halo, or -NR8R9.

6. The compound of claim 5, wherein R1is -Ci-6 haloalkyl.

7. The compound of claim 6, wherein R1is -CH2-CF3.

8. The compound of claim 4, wherein R2is -C1-6 alkyl, -halo, or -CN.

9. The compound of claim 4, wherein R1is -C1-6 haloalkyl and R2is -C1-6 alkyl or -CN.

10. The compound of claim 1, wherein R1is -C 1-6 haloalkyl.

11. The compound of claim 1, wherein R1is -C1-3 haloalkyl, halo, or -NR8R9.

12. The compound of claim 1, wherein R1is -C1-3 haloalkyl.

13. The compound of claim 1, wherein R1is -CF3, -CH2CF3, Cl, F, or -NH2.

14. The compound of claim 1, wherein R1is -CF3 or -CH2CF3.

15. The compound of claim 1, wherein R2is -CN or -C1-6 alkyl.

16. The compound of claim 1, wherein R2is -CN or -C1-3 alkyl.

17. The compound of claim 1, wherein R2is -CN, -CH3, or -CH2CH3.

18. The compound of claim 1, wherein R3is -H or halo.

19. The compound of claim 1, wherein R3is -H.153331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-206220. The compound of claim 1, wherein R4is halo, -CN, -OH, -O-Ci-ealkyl, -Ci-ealkyl, - Ci-6 alkyl-CN, -Ci-6 haloalkyl, -C(O)NR8R9, -NR8C(O)CI-6alkyl, -NR8R9, -C(O)OH, -C(O)OCi-6 alkyl, heterocyclyl, heteroaryl, or carbocyclyl.

21. The compound of claim 1, wherein R4is halo, -CN, -Ci-ealkyl, -Ci-6 alkyl-CN, -Ci-6 haloalkyl, or carbocyclyl.

22. The compound of claim 1, wherein R4is halo or -Ci-ealkyl.

23. The compound of claim 1, wherein R4is -F or -CH3.

24. The compound of claim 1, wherein R4is -CH3.

25. The compound of claim 1, wherein R5A, R5B, R6A, and R6Bare -H.

26. The compound of claim 1, wherein R7is -H or -Ci-ealkyl.

27. The compound of claim 1, wherein R8is -H or -Ci-ealkyl.

28. The compound of claim 1 selected from the group consisting of:154331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062155 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062156 331375061ATTORNEY DOCKET NO.: KAYO-011 / 01 WO 347382-2062or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated form thereof.

29. A method of treating disease or disorder in a subject in need thereof, the method comprising administering a compound of claim 1 to the subject, wherein the disease or disorder is cardiometabolic syndrome, a diabetic kidney disease, a lipid disorder, muscle inflammation, sarcopenia or bone density loss, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction- associated steatohepatitis (MASH), hypercholesterolemia, hypertriglyceridemia, familial cholesterolemia, familial triglyceridemia, or a cardiovascular disorder.

30. The method of claim 29, wherein the lipid disorder is hyperlipidemia or dyslipidemia.

31. The method of claim 29, wherein the cardiovascular disorder is pulmonary arterial hypertension, chronic heart failure, neointimal hyperplasia, Atherosclerotic Cardiovascular Disease (ASCVD), heart failure with preserved ejection fraction, ischemic heart disease or coronary artery disease.157331375061

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