Methods for treating obesity and increasing weight loss

Abstract

The present disclosure relates to methods for treating obesity and / or methods for reducing and maintaining body weight and / or body fat in a patient in need thereof.

Description

METHODS FOR TREATING OBESITY AND INCREASING WEIGHT LOSSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 563,238, filed March 8, 2024, and the benefit of International Patent Application Number PCT / CN2024 / 080896, filed on March 11, 2024, each of which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to methods for treating obesity and / or methods for reducing and maintaining body weight and / or body fat in a patient in need thereof.BACKGROUND

[0003] Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. Apelin, a peptide hormone, exerts its effect by binding with angiotensin II protein J receptor (APJ) and is considered to be linked with diabetes and obesity. Apelin and its receptor are widely present in the body and are involved in many physiological processes, such as glucose and lipid metabolism, homeostasis, endocrine response to stress, and angiogenesis. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies.SUMMARY

[0004] The compound 7V-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)methanesulfonamide and A-(5-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)- lH-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide, designated herein as Compound A and Compound B, respectively, have the following formulas:Compound A Compound B

[0005] Compound A and Compound B modulate APJ receptor activity. The synthesis and method of use of these compounds is described in PCT International Application Publication No. W02020 / 073011, which is incorporated by reference herein in its entirety.

[0006] In some embodiments, the present disclosure relates to a method for treating obesity and / or conditions related thereto (e.g. obesity complications) in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide- 1 (GLP-1) receptor modulator.

[0007] In some embodiments, administering to a subject in need thereof an effective amount of Compound A or Compound B, or a pharmaceutically acceptable salt thereof, in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator, increases total weight loss when compared to tire GLP-1 receptor modulator alone, normalizes body composition to levels observed in lean controls, and / or decreases fed glucose levels without an appreciable decrease in calorie intake.

[0008] In some embodiments, the present disclosure relates to a method for inducing weight loss, maintaining body weight, maintaining muscle mass, treating obesity, inducing fat loss, and / or reducing fat mass while retaining muscle mass, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B:Compound A Compound Bor a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide- 1 (GLP-1) receptor modulator.

[0009] In some embodiments, weight loss refers to muscle-sparing weight loss. In some embodiments, the weight loss is selective weight loss (e.g., disproportionally affects fat over muscle mass).

[0010] In some embodiments, the GLP-1 receptor modulator is a GLP-1 receptor agonist. In some embodiments, the method further comprises administering a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. In some embodiments, the GLP-1 receptor agonist is not the same as the GIP receptor agonist. In some embodiments, the GLP-1 receptor modulator is a GLP-l / GIP dual agonist. In some embodiments, the GLP-1 receptor modulator is a dual glucose-dependent insulinotropic polypeptide (GIP / GLP-1). In some embodiments, the GLP-1 receptor modulator is a triple GIP / GLP- 1 / glucagon (GCG) receptor agonist.

[0011] In some embodiments, the present disclosure relates to a method for inducing weight loss, maintaining body weight, maintaining muscle mass, treating obesity, inducing fat loss, and / or reducing fat mass while retaining muscle mass, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows cumulative food intake of test subjects.

[0013] FIG. 2 shows percent of body weight loss in test subjects.

[0014] FIG. 3 shows fed blood glucose levels of test subjects.

[0015] FIG. 4 shows percent of fat mass of test subjects.DETAILED DESCRIPTIONDefinitions

[0016] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0017] As used in the present specification, the following words, phrases and symbols are generally intended to have tire meanings as set forth below, except to the extent that the context in which they arc used indicates otherwise.

[0018] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(0)NH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0019] The prefix “Cu.v” indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0020] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the tenn “about” includes the indicated amount ± 10%. In other embodiments, the tenn “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof know n to those skilled in the art.

[0021] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1.20 alkyl). 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., Ci-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g.. methyl, ethyl, propyl, isopropyl, n-butyl, sec-buty l, iso-butyl, tert-butyl, pentyl. 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, allpositional isomers having that number of carbons may be encompassed; thus, for example, ‘'butyr includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and “propyl” includes n-propyl (i.e., -(CH2)2CH3), and isopropyl (i.e., -CH(CH3)2).

[0022] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e.. C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including1.2-butadienyl, and 1,3 -butadienyl).

[0023] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2.2o alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The temr “alkynyl” also includes those groups having one triple bond and one double bond.

[0024] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively.

[0025] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g.. methoxy, ethoxy, n-propoxy, iso-propoxy. n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and1.2-dimethylbutoxy .

[0026] “Alkylthio” and “thioalkoxy” refer to the group “alkyl-S-”.

[0027] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl,2.2.2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2 -fluoropropyl, 1,2-dibromoethyl. and tire like.

[0028] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen.

[0029] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0030] “Cyanoalkyl” refers to an alkyl group as defined above, wherein one, or one or more (e.g. , 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0031] ‘ ’Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0032] ‘ ’Amido” refers to both a “C -amido” group which refers to the group -C(0)NRyRzand an “N- amido” group which refers to the group -NRyC(0)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0033] ’‘Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl. aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0034] ‘ ’Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0035] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., Ce-20 aryl), 6 to 12 carbon ring atoms (i.e., Ce-i2 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.

[0036] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -0-C(0)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(0)0Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0037] ■‘Carboxyl ester’ or '‘ester” refer to both -OC(O)RXand -C(O)ORX, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0038] ‘'Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0039] ‘ ‘Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl. cycloalkyl, heterocyclyl, ary l, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0040] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic tabic, such as fluoro, chloro, bromo, or iodo.

[0041] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any- associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0042] “Heteroalkylene” refers to a divalent heteroalkyl group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain. The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl. aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkylene groups include, e.g., -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -OCH2-, -CH(CH3)O-, -CH2CH2O-, -CH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2O-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -SCH2-, -CH(CH3)S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NRyCH2-, -CH(CH3)NRyCH2-. -CH2CH2NRyCH2-. -CH2CH2NRyCH2CH2NRyCH2-, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the tenn “heteroalkylene” does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.

[0043] “Heteroaiy 1” refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1.20 heteroaryl). 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3.8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl. oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl. phenazinyl. phthalazinyl. pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl. pyrimidinyl, pyridazinyl. quinazolinyl. quinoxalinyl. quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused- heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl,benzo [b]thienyl, indazolyl, benzo [d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a hctcroaryl regardless of the attachment to the remainder of the molecule (ie., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0044] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "‘heterocyclyf’ includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (<?.g., 1 to 3) oxo (=0) or N-oxide (-0 ) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the attachment to the remainder of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1.2,3,4-tetrahydroquinazolinyl, and 5.6.7.8-tetrahydroquinazolinyl are heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e.. C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e.. C2-10 heterocyclyl). 2 to 8 ring carbon atoms (i.e.. C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl. azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4- benzodioxanyl, benzopyranyl. benzodioxinyl, benzopyranonyl, benzofuranonyl. dioxolanyl. dihydropyranyl. hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl. pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuiy 1, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorph olinyl, thiamorpholinyl. 1-oxo-thiomorpholinyl. and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyL and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3- c]pyridinyl, indolinyl, and isoindolinyl, where tire heterocyclyl can be bound via either ring of the fused system. The term “heterocyclyl” also includes rings comprising the sulfoximine moiety of RQB(e.g., when Raand Rbof RQBis fused to the ring comprising Q1-Q5, e.g.. when Raand RQA, or Rband RQA. fonn a ring), such as, but not limited to. 3.4-dihydro-lλ6.2-thiazinc 1 -oxide. Iλ6.2-thiazinc 1 -oxide. 4,5- dihydro-3H-Iλ6-isothiazolc 1-oxide, l-(imino)tetrahydro-lH-lXb-thiophene 1-oxide, 4,5-dihydro-3H-lXb, 2-thiazepine 1-oxide, and the like. See, e.g.. Cram, et. aI, J. Org. Chem., 1973, 38(1), 20-26.

[0045] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluene sulfonyl.

[0046] “Alkylsulfonyl” refers to the group -S(O)2R, where R is alkyl.

[0047] “Alkylsulfinyl” refers to tire group -S(O)R, where R is alkyl.

[0048] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g. , 1 to 5, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0049] As used herein, the tenn “compound,” is meant to include any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0050] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0051] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, exceptthat one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,170,180,31P,32P,35S,18F,36C1,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0052] The term “isotopically enriched analogs’’ includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster. “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5( 12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0053] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F.3H.11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0054] Tire concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0055] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0056] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmacal use.

[0057] The tenn “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p- toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3, or primary, secondary, tertiary amines, such as salts derived from a N-containing heterocycle, a N-containing heteroaryl, or derived from an amine of formula N(R fi (e.g.,independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, or hctcroaryl. wherein each is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0058] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione. or combinations thereof. In some embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0059] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0060] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Tire use of such media and agents forpharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0061] A ‘‘solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0062] As used herein, when a ring is described as being “aromatic,” it means the ring has a continuous, delocalized ir-electron system. Typically, tire number of out of plane 7r-electrons corresponds to the H uckel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system comprising at least two rings is described as “aromatic,” it means the ring system comprises one or more aromatic ring(s). Accordingly, when a ring system comprising at least tw o rings is described as “non-aromatic,” none of the constituent rings of the ring system is aromatic.

[0063] As used herein, when a ring is described as being “partially unsaturated,” it means tire ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system comprising at least two rings is described as “partially unsaturated,” it means the ring system comprises one or more partially unsaturated ring(s), provided that none of the constituent rings of the ring system is aromatic.

[0064] As used herein, the term “compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of tire structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0065] The temr “tautomer” as used herein refers to compounds w hose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer.

[0066] The term “pharmaceutically acceptable” as used herein indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.

[0067] The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0068] The terms “effective amount” or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of Formula I. or a pharmaceutically acceptable salt or solvate thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0069] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in tire sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g.. Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Prefonnulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0070] The term “pharmaceutical composition” refers to a mixture of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as provided herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the artincluding, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0071] The terms '‘treat,” '‘treating,” and ‘'treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0072] The term “preventing,” as used herein, is the prevention of the onset, recurrence or spread, in whole or in part, of tire disease or condition as described herein, or a symptom thereof.

[0073] The temrs “subject,” “patient,” or “individual,” as used herein, are used interchangeably and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the tenn refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or needed. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0074] The terms “treatment regimen” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination.

[0075] The term “pharmaceutical combination,” as used herein, refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0076] The term “combination therapy” as used herein refers to a dosing regimen of two different therapeutically active agents (i.e., the components or combination partners of the combination), w herein the therapeutically active agents are administered together or separately in a maimer prescribed by a medical care taker or according to a regulatory agency as defined herein.GLP-1 Receptor Modulators

[0077] The term “GLP-1 receptor” as used herein, refers to the glucagon-like peptide-1 (GLP-1) receptor, and intended to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous, and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0078] The term “GLP-1 receptor modulator” as used herein, refers to a modulator (e.g., agonist) of the glucagon-like peptide-1 (GLP-1) receptor. A modulator can refer to any adjustment (e.g. , increase or decrease) and can include, for example agonism, partial agonism, or antagonism.

[0079] In some embodiments, the GLP-1 receptor modulator is a GLP-1 receptor agonist.

[0080] GLP-1 receptor agonists enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels, both in fasting and postprandial states; and slow gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1 RAs have been shown to treat type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, albiglutide (Tanzeum®), dulaglutide (LY2189265, Trulicity®). cfpcglcnatidc. exenatide (Byetta®. Bydureon®, Exendin-4), liraglutide (Victoza®, NN2211), lixisenatide (Lyxumia®), semaglutide (Ozempic®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0081] In some embodiments, the GLP-1 receptor modulator is a GLP-l / GIP dual receptor agonist.

[0082] Incretin metabolic honnones, including glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP), are important in the regulation of glucose homeostasis. Medicaments targeting this family of intestinal peptides, such as GLP-1 receptor modulators (e.g., agonists), have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0083] Exemplary GLP-1 receptor modulators which can be used in the methods and combinations described herein are described in include those described in W02009111700, WO2010114824, WO2018056453, W02018109607, TW201925204, WO2019239319, WO2019239371, W02020103815, WO2020184942, W02020207474, WO2020263695, W02021018023, W02021081207, WO2021096284, W02021096304, WO2021112538, WO2021154796, WO2021155841,WO2021160127, WO2021187886, WO2021197464, CN113480534, CN113493447, W02021219019, WO2021244645, CN113773310, WO2021249492, CN113801136, CN113816948, WO2021254470, CN113831337, W02022007979, WO2022017338, WO2022028572, W02022031994, W02022040600, WO2022042691, WO2022048665, WO2022052958, WO2022068772, WO2022078152, W02022078380, W02022078407, WO2022111624, CN114591308, CN1134634510, CN114591296, CN114634510, CN114716423, WO2022135572, CN114763352, WO2022165076, CN114907351, WO2022109182, WO2022192428, WO2022192430, WO2022199458, WO2022202864, WO2022199661, WO2022216094, WO2022225914, WO2022225941, WO2022235717, WO2022241287, WO2022246019, WO2022247701, WO2022253202, WO2022258805,WO2022257979, WO2022266068, WO2022268152, WO2022268029, WO2023277620, WO2023280133, WO2023284822, WO2023288313, W02023000240, W02023001237, W02023011395, W02023031741, W02023029380, WO2023049518, W02023051490, WO2023057429, WO2023057414, WO2023057427, WO2023066356, WO2023076237, WO2023098852, WO2023106310, WO2023111144, WO2023111145, WO2023116882, WO2023116879, WO2023125896, WO2023124824, WO2023130878, WO2023152698, WO2023164050, WO2023164358, WO2023182869, W02023220109, W02023220112, WO2023222084, WO2023222124, WO2023228023, WO2023246839, W02024008174, WO2024017266, WO2024018395, WO2024026338, WO2024028795, or W02024041609.

[0084] In some embodiments, the GLP-1 modulator is selected from tirzepatide (Mounjaro®, Zepbound®), exenatide (Byetta®, Bydureon®, Exendin-4), lixisenatide (Lyxumia®), liraglutide (Victoza®, NN2211), dulaglutide (LY2189265, Trulicity®), albiglutide (Tanzeum®), semaglutide (Wegovy®, Rybelsus®, Ozempic®), retatrutide (LY3437943), mazdutide (LY3305677), efpeglenatide (HM11260C). taspoglutide (R1583, BIM51077. ITM077), survodutide (BI456906). cotadutide (MEDI0382), pemvidutide (ALT-801), efmopegdutide (MK-6024), efocipegtrutide (HM15211), pegloxenatide (PEX168), pegapamodutide (LY2944876), albenatide (CJC1134PC), utreglutide (GL0034), ZP2929, NNC0113-0987, BPI-3016, TT401, SAR441255, BI-456906, ALT-801, AC-3174, SAR-425899, HM-15211, YH-25723, YH-25724, YH-22241, YH-GLP1, RPC-8844, PB-718, NN-6177, CT-388. CT-868, XW003, XW004, CJC-1134, CJC-1131, AMG133, DD-01, DD-03, DD-14 , DD-15, 1D110521156. TERN-601, MDR-0001, HPG5119, ECC5004. VK2735. orforglipron (LY3502970). danuglipron (PF06882961), lotiglipron (PF07081532), CT-996, HRS-7535, V-0219, XW014, PF- 06882961, LSN3318839, and TTP273.

[0085] In some embodiments, the GLP-1 modulator is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:Rais hydrogen, cyano, C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of halo, oxo, C1-6alkoxy, C3-6cycloalkyl, and heteroaryl, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl;Rbis C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl; or Raand Rbtaken together with the atoms to which each is attached fonn a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-3 independently selected C1-6alkyl;Ra,and Rb’ are independently selected from the group consisting of C1-6alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo; C3-6cycloalkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo; and C6-10aryl optionally substituted with from 1-3 independently selected C1-3alkyl; orRa’ and Rb’ taken together with the phosphorous atom to which each is attached forms a ring including from 5-8 ring atoms, wherein from 0-2 ring atoms (in addition to the phosphorous attached to Raand Rb) are heteroatoms each independently selected from the group consisting of: 0, S, and N, wherein the ring is optionally substituted with from 1-3 independently selected C1-6alkyl; each RQAis independently hydrogen, halo, cyano, hydroxy, -NRcRd. -C(O)NRcRd. -S(0)o-2Re, C1-6alkyl optionally substituted with 1-6 independently selected Rf, C1-6alkoxy optionally substituted with 1-6 substituents each independently selected from the group consisting of hydroxy, halo, and i e alkoxy, 3-12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of o aryl optionallysubstituted with 1-3 independently selected -C(0)(C1-6alkyl), and 5-10 membered heteroaryl optionally substituted with 1-6 independently selected Rs; or Raor Rband an adjacent RQAare taken together with the atom to which each is attached to form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 independently selected Rh; q is 0, 1, 2, 3, 4, or 5; each RAis independently halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C3.6 cycloalkyl;R3is hydrogen or C1-6alkyl optionally substituted with 1-6 substituents independently selected from the group consisting of halo, hydroxy, and C1-6alkoxy;R9is -C(O)OR9a, -C(O)NR9aR9b, 5-6 membered heteroaryl optionally substituted with 1-3 independently selected R9c, 4-6 membered heterocyclyl optionally substituted with 1-3 independently selectedX1is 0 or S;R9ais hydrogen or C 1-6 alkyl;R9bis hydrogen, C1-6alkyl, -C(O)(Ci 6 alkyl), -S(0)o-2(C1-6alkyl), or cyano; each R9cis independently hydrogen, oxo, C1-6alkyl optionally substituted with 1-6 independently selected halo and C1-6alkoxy, or -C(O)(Ci 6 alkyl); v is 0, 1, 2, or 3; each RCais independently halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or NRcRd; or a pair of RCaon the same or different ring atoms, taken together with the ring atom(s) to which each is attached, forms a carbocyclic ring including 3-8 ring atoms; each Rcand Rdare each independently hydrogen, C1-6alkyl, -C(O)(Ci e alkyl),-S(O)i-2(C3.6 cycloalkyl) are each optionally substituted with 1-6 substituents independently selected from the group consisting of hydroxy, halo, and C1-6alkoxy; each Reis independently hydrogen, C1-6alkyl, or C1-6haloalkyl;w is 0, 1, 2, or 3; each R11is independently C1-6alkyl, wherein each C1-6alkyl is independently optionally substituted with 1-6 independently selected Rf; each Rris independently halo, hydroxy. -NRcRd, C1-6alkoxy, C1-6haloalkoxy, or 3-12 membered heterocyclyl which is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxy, C1-6alkyl, and 3-12 membered heterocyclyl; each R8is independently C1-6alkyl, C1-6alkoxy, -NRcRd, or 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of Ci.6alkyl and -C(O)C1-6alkyl; and each Rhis independently halo, cyano, hydroxy, C1-6alkyl, C1-6haloalkyl, -NH2, -NH(CI-3 alkyl), -N(CI.3 alkyl)2, C1-3alkoxy, or C1-3haloalkoxy.

[0086] In some embodiments, the GLP-1 modulator is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:Q2is N or CRQA;RQBis -S(O)(NRa)Rb;Rais hydrogen, cyano, C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of halo, oxo, C1-6alkoxy, C3-6cycloalkyl, and heteroaryl, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl;Rbis C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl; or Raand Rbtaken together with the atoms to which each is attached form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-3 independently selected C1-6alkyl; each RQAis independently hydrogen, halo, cyano, hydroxy, -NRcRd. -C(O)NRcRd. -S(0)o-2Re, C1-6alkyl optionally substituted with 1-6 independently selected Rf, C1-6alkoxy optionally substituted with 1-6 substituents each independently selected from the group consisting of hydroxy, halo, and C1.6 alkoxy, 3-12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-6alkyl and -C(O)(C1-6alkyl), C6-10aryl optionally substituted with 1-3 independently selected -C(O)(C1-6alkyl), and 5-10 membered heteroaryl optionally substituted with 1-6 independently selected R6; or Raor Rband an adjacent RQAarc taken together with the atom to which each is attached to form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 independently selected Rh; q is 0, 1, 2, 3, 4, or 5; each RAis independently halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C3-6cycloalkyl;R3is hydrogen or C1-6alkyl optionally substituted with 1-6 substituents independently selected from the group consisting of halo, hydroxy, and C1-6alkoxy;R9is -C(O)OR9a, -C(O)NR9aR9b, 5-6 membered heteroaryl optionally substituted with 1-3 independently selected R9c, 4-6 membered heterocyclyl optionally substituted with 1-3 independently selectedX1is 0 or S;R9ais hydrogen or C1-6alkyl;R9bis hydrogen. C1-6alkyl, -C(O)(C1-6alkyl), -S(0)o-2(C1-6alkyl), or cyano;each R9cis independently hydrogen, oxo, C1-6alkyl optionally substituted with 1-6 independently selected halo and C1-6alkoxy, or -C(O)(Ci 6 alkyl); v is 0, 1, 2, or 3; each RCais independently halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or NRcRd; or a pair of RCaon the same or different ring atoms, taken together with the ring atom(s) to which each is attached, fonns a carbocyclic ring including 3-8 ring atoms; each Rcand Rdare each independently hydrogen, C1-6alkyl. -C(O)(Ci 6 alkyl),-S(O)i.2(C3-6cycloalkyl) are each optionally substituted with 1-6 substituents independently selected from the group consisting of hydroxy, halo, and C1-6alkoxy; each Reis independently hydrogen, C1-6alkyl, or C1-6haloalkyl; w is 0, 1, 2, or 3; each R11is independently C1-6alkyl, wherein each C1-6alkyl is independently optionally substituted with 1-6 independently selected Rf; each R1is independently halo, hydroxy, -NRcRd, C1-6alkoxy, C1-6haloalkoxy, or 3-12 membered heterocyclyl which is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxy, C1-6alkyl, and 3-12 membered heterocyclyl; each Rgis independently C1-6alkyl, C1-6alkoxy, -NRcRd, or 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-6alkyl and -C(O)C1-6alkyl; and each Rhis independently halo, cyano, hydroxy, C1-6alkyl, C1-6haloalkyl, -NH2, -NH(CI-3 alkyl), -N(CI-3 alkyl)2, C1-3alkoxy, or C 1.3 haloalkoxy .

[0087] In certain embodiments, R3is C1-6alkyl. In certain embodiments, R3is methyl. In certain embodiments, Q2is CH. In certain embodiments, RQAis hydrogen, halo, -NHCH3, or methyl; Rais methyl or ethyl; and Rbis ethyl or cyclopropyl or cyclobutyl. In certain embodiments, v is 2. In certain embodiments, v is 2; and each RCais methyl. In certain embodiments, w is 1; and each R1* is methyl. Incertain embodiments,R9cis H.

[0088] In some embodiments, the GLP-1 modulator is a compound of Formula IB:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:Q2is N or CRQA;RQBis -P(O)RaRb;Rais hydrogen, cyano, C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of halo, oxo, C1-6alkoxy, C3-6cycloalkyl, and heteroaryl, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1.3 alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl;Rbis C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from tire group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1.3 alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl; or Raand Rbtaken together with the atoms to which each is attached form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-3 independently selected Ci.6alkyl; each RQAis independently hydrogen, halo, cyano, hydroxy, -NRcRd, -C(O)NRcRd, -S(0)o-2Re, Ci -6 alkyl optionally substituted with 1-6 independently selected Rf, C1-6alkoxy optionally substitutedwith 1-6 substituents each independently selected from the group consisting of hydroxy, halo, and C1-6alkoxy, 3-12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-6alkyl and -C(O)(Ci s alkyl), Cs-io aryl optionally substituted with 1-3 independently selected -C(O)(C1-6alkyl), and 5-10 membered heteroaryl optionally substituted with 1-6 independently selected R8; q is 0, 1, 2, 3, 4, or 5; each RAis independently halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C3-6cycloalkyl;R3is hydrogen or C1-6alkyl optionally substituted with 1-6 substituents independently selected from the group consisting of halo, hydroxy, and Ci.6alkoxy;-6 membered hetcroaryl optionally substituted with 1-3 independently selected R9c, 4-6 membered heterocyclyl optionally substituted with 1-3 independently selectedX1is 0 or S; se eap y y g y y-S(O)i.2(C3-6 cycloalkyl) are each optionally substituted with 1-6 substituents independently selected from the group consisting of hydroxy, halo, and C1-6alkoxy; each Reis independently hydrogen, C1.6 alkyl, or C1-6haloalkyl;w is 0, 1, 2, or 3; each R11is independently C1-6alkyl, wherein each C1-6alkyl is independently optionally substituted with 1-6 independently selected Rf; each Rris independently halo, hydroxy. -NRcRd, C1-6alkoxy, C1-6haloalkoxy, or 3-12 membered heterocyclyl which is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxy, Ci.6alkyl, and 3-12 membered heterocyclyl; each R8is independently C1-6alkyl, C1-6alkoxy, -NRcRd, or 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of Ci.6alkyl and -C(O)C1-6alkyl; and each Rhis independently halo, cyano, hydroxy, C1-6alkyl, C1-6haloalkyl, -NH2, -NH(CI-3 alkyl), -N(CI.3 alkyl)2, C1-3alkoxy, or C1-3haloalkoxy.

[0089] In some embodiments, the GLP-1 modulator is selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.Table 1or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0090] The compounds provided herein encompass stereochemical forms of the compounds, for example, optical isomers, such as enantiomers, diastereomers, as well as mixtures thereof, e.g., mixtures of enantiomers and / or diastereomers, including racemic mixtures, as well as equal or non-cqual mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are contemplated in this disclosure. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0091] It will further be appreciated that the compounds or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure. Forexample, compounds and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.Treatment Methods and Use

[0092] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in tire clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein maybe suited are described below or will become apparent to those skilled in tire art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0093] Improvements in any of the foregoing response criteria are specifically provided by the methods of the present disclosure.

[0094] In some embodiments, provided is a method for reducing and maintaining body weight, and / or body fat, comprising administering to a subject in need thereof, such as e.g. in an overweight or obese subject, an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator.

[0095] In some embodiments, the subject has diabetes (e.g., a type 2 diabetes subject being obese or overweight).

[0096] In some embodiments, the subject does not have diabetes, but is obese or overweight.

[0097] In some embodiments, the present disclosure relates to a method for inducing body weight loss comprising administering to a subject in need thereof, an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator.

[0098] In some embodiments, the present disclosure relates to a method for inducing weight loss, maintaining body weight, maintaining muscle mass, treating obesity, inducing fat loss, and / or reducing fat mass while retaining muscle mass, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator.

[0099] In some embodiments, the present disclosure relates to a method for inducing weight loss, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B. or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon- like peptide-1 (GLP-1) receptor modulator.

[0100] In some embodiments, the present disclosure relates to a method for maintaining body weight, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B, or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon- like peptide-1 (GLP-1) receptor modulator. In some embodiments, the subject has been administered a GLP-1 receptor modulator prior to performing the methods disclosed herein.

[0101] In some embodiments, the present disclosure relates to a method for preventing body weight and / or body fat gain or controlling, stabilizing or maintaining a reduced body weight, and / or body fat followed discontinuation of weight reducing treatment (such as e.g. diet, exercise and / or treatment with an anti-obesity or body weight reducing agent), particularly after discontinuation of treatment with a GLP-1 receptor agonist, the method comprising administering to a subject in need thereof an effective amount of Compound A or Compound B, or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator.

[0102] In some embodiments, the present disclosure relates to a method for delaying body weight and / or body fat gain, and / or maintaining reduction in body weight, and / or body fat in a subject (particularly an obese patient with or without diabetes), the method comprising administering to a subject in need thereof an effective amount of Compound A or Compound B. or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator. In some embodiments, the method is subsequent to cessation of, or withdrawn from, body weight reducing and / or fat reducing treatment.

[0103] In some embodiments, the present disclosure relates to a method of delaying body weight, and / or body fat gain and / or maintaining body weight, and / or body fat loss, induced by treatment with a GLP-1 receptor agonist in a subject, said method comprising cessation of GLP-1 receptor agonist treatment and transferring the subject from GLP-1 receptor agonist to. the method comprising administering to a subject in need thereof an effective amount of Compound A or Compound B, or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator. In some embodiments, the GLP-1 receptor modulator is not the same GLP-1 receptor modulator previously administered.

[0104] In some embodiments, the methods disclosed herein decrease or eliminate the severity, duration, and / or presence of one or more side effects attributable to the GLP-1 receptor modulator, such as. but not limited to, nausea, vomiting, and / or diarrhea.

[0105] In some embodiments, the present disclosure relates to a method for reducing, maintaining loss of or delaying increase of body weight and / or body fat in a subject being in condition of actively puttingon weight and / or increasing body weight through the deposition of fat, such as e.g. after withdrawing a weight loss treatment or under a treatment associated with weight gain (e.g. through the action of sulphonylureas, glinides, insulin and / or thiazolidinediones, the use of w hich is associated w ith weight gain).

[0106] In some embodiments, the present disclosure relates to a method for reducing intra-myocellular fat and / or hepatic fat in a patient in need thereof, such as e.g. in an overweight or obesity patient with or without diabetes (e.g., type 2 diabetic patient being obese or overweight).

[0107] In some embodiments, the subject has not previously been treated with an antidiabetic drug (drug -naive patients). Thus, in an embodiment, the therapies described herein may be used in naive patients. In another embodiment, diabetes patients may include patients with advanced or late stage type 2 diabetes mellitus (including patients with failure to conventional antidiabetic therapy), such as e.g. patients with inadequate glycemic control on one, two, or more conventional oral and / or non-oral antidiabetic drugs, such as e.g. patients with insufficient glycemic control despite (mono-)therapy with metfonnin, a thiazolidinedione (particularly pioglitazone). a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue, insulin or insulin analogue, or an a-glucosidase inhibitor, or despite dual combination therapy with metformin / sulphonylurea, metformin / thiazolidinedione (particularly pioglitazone). metformin / insulin, pioglitazone / sulphonylurea, pioglitazone / insulin, or sulphonylurea / insulin.

[0108] Thus, in some embodiments, the therapies described herein may be used in subjects experienced with therapy, e.g. with conventional oral and / or non-oral antidiabetic mono- or dual or triple combination medication as mentioned herein. A further embodiment of diabetic patients refers to patients ineligible for metformin therapy including, but not limited to, patients for whom metformin therapy is contraindicated, e.g. patients having one or more contraindications against metfonnin therapy according to label, such as for example patients with at least one contraindication selected from one or more of: renal disease, renal impairment or renal dysfunction (e.g., as specified by product information of locally approved metformin); dehydration; unstable or acute congestive heart failure; acute or chronic metabolic acidosis; or hereditary' galactose intolerance; and / or patients who suffer from one or more intolerable side effects attributed to metformin, particularly gastrointestinal side effects associated with metfonnin, such as for example patients suffering from one or more gastrointestinal side, such as nausea, vomiting, diarrhea, intestinal gas, or severe abdominal discomfort.

[0109] In some embodiments, the diabetic patients which may be amenable to the methods of this disclosure may include, but not limited to. diabetic patients for whom normal metformin therapy is not appropriate, such as e.g. diabetic patients who need reduced dose metformin therapy due to reducedtolerability, intolerability, or contraindication against metformin or due to (mildly) impaired / reduced renal function (including elderly patients, such as e.g. > 60-65 years).Treatment Regimens

[0110] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Proper dosage for a particular situation can be determined by one skilled in the medical arts. In some cases, the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.[OHl] In some embodiments, the GLP-1 receptor modulator is administered at a dose from about 0.01 to about 1000 mg per day. For example, from about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount and is the daily dose.

[0112] In some embodiments. Compound A or Compound B. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered at a dose from about 0.01 to about 1000 mg. For example, from about 0. 1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg. about 600 mg to about 900 mg. or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount and is the daily dose.

[0113] In some embodiments, Compound A or Compound B. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered at a single dose from 2 mg to 600 mg, and at doses from 75 mg to 500 mg, once daily dosing for seven days, with no SAEs reported.

[0114] In some embodiments, the GLP-1 receptor modulator is administered at a dosage of from about 0.0002 mg / Kg to about 100 mg / Kg (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg; from about 0.0002 mg / Kg to about 5 mg / Kg; from about 0.0002 mg / Kg to about 1 mg / Kg; from about 0.0002 mg / Kg to about 0.5 mg / Kg; from about 0.0002 mg / Kg to about 0. 1 mg / Kg; from about 0.001 mg / Kg to about 50 mg / Kg; from about 0.001 mg / Kg to about 25 mg / Kg; from about 0.001 mg / Kg to about 10 mg / Kg; from about 0.001 mg / Kg to about 5 mg / Kg; from about 0.001 mg / Kg to about 1 mg / Kg; from about 0.001 mg / Kg to about 0.5 mg / Kg; from about 0.001 mg / Kg to about 0. 1 mg / Kg; from about 0.01 mg / Kg toabout 50 mg / Kg; from about 0.01 mg / Kg to about 25 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0. 1 mg / Kg to about 50 mg / Kg; from about 0. 1 mg / Kg to about 25 mg / Kg; from about 0.1 mg / Kg to about 10 mg / Kg; from about 0.1 mg / Kg to about 5 mg / Kg; from about 0.1 mg / Kg to about 1 mg / Kg; from about 0.1 mg / Kg to about 0.5 mg / Kg). Each of the dosages are per day.

[0115] In some embodiments, the GLP-1 receptor modulator is administered as a dosage of about 100 mg / Kg per day.

[0116] In some embodiments, Compound A or Compound B. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered at a dosage of from about 0.0002 mg / Kg to about 100 mg / Kg (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg; from about 0.0002 mg / Kg to about 5 mg / Kg; from about 0.0002 mg / Kg to about 1 mg / Kg; from about 0.0002 mg / Kg to about 0.5 mg / Kg; from about 0.0002 mg / Kg to about 0. 1 mg / Kg; from about 0.001 mg / Kg to about 50 mg / Kg; from about 0.001 mg / Kg to about 25 mg / Kg; from about 0.001 mg / Kg to about 10 mg / Kg; from about 0.001 mg / Kg to about 5 mg / Kg; from about 0.001 mg / Kg to about 1 mg / Kg; from about 0.001 mg / Kg to about 0.5 mg / Kg; from about 0.001 mg / Kg to about 0.1 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 25 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0. 1 mg / Kg to about 25 mg / Kg; from about 0. 1 mg / Kg to about 10 mg / Kg; from about 0.1 mg / Kg to about 5 mg / Kg; from about 0.1 mg / Kg to about 1 mg / Kg; from about 0. 1 mg / Kg to about 0.5 mg / Kg). Each of the doses are the daily dose.

[0117] In some embodiments. Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrag thereof is administered as a dosage of about 100 mg / Kg per day.

[0118] In some embodiments, the GLP-1 receptor modulator is administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every’ three days, once weekly, twice weeks, once every two weeks, once a month).

[0119] In some embodiments, Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g, everyother day, every two days, even1three days, once weekly, twice weeks, once every two weeks, once a month).

[0120] In some embodiments, the period of administration of the GLP-1 receptor modulator is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, a period of during which administration is stopped is for 1 day, 2 days. 3 days, 4 days, 5 days, 6 days, 7 days. 8 days. 9 days, 10 days, 1 1 days. 12 days, 13 days. 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0121] In some embodiments, the period of administration of Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months. 8 months, 9 months, 10 months, 11 months. 12 months, or more. In some embodiments, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0122] In some embodiments, the GLP-1 receptor modulator is administered to a patient for a period of time followed by a separate period of time where administration of Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered.

[0123] In some embodiments, Compound A or Compound B. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered to a patient for a period of time followed by a separate period of time where administration of, the GLP-1 receptor modulator, is administered.

[0124] In some embodiments, the GLP-1 receptor modulator is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the GLP-1 receptor modulator is started and then a fourth period following the third period where administration is stopped. For example, the period of administration ofthe GLP-1 receptor modulator followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In some embodiments, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months. 6 months, 7 months, 8 months, 9 months, 10 months. 11 months, 12 months, or more. In some embodiments, a period of during which administration is stopped is for 1 day, 2 days. 3 days. 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0125] In some embodiments, the dose is raised, or “up-titrated,” until an effective and / or maximum dose has been achieved or side effects occur. In one embodiment, the dose is started and the dose is increased after each month of treatment until the optimal dose is achieved. In one embodiment, the maximal dose is achieved after 1, 2, 3. or 4 months of treatment.

[0126] In some embodiments. Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is started and then a fourth period following the third period where administration is stopped. For example, the period of administration of Compound A or Compound B, or a pharmacally acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In some embodiments, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months. 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0127] In some embodiments, the GLP-1 receptor modulator is administered by parenteral administration to the patient weekly.

[0128] In some embodiments, the GLP-1 receptor modulator is administered orally to the patient on a daily basis (e.g. , as a single dose or as two or more divided doses) or non-daily basis (e.g. , every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0129] In some embodiments, the GLP-1 receptor modulator is administered as an oral tablet or capsule.

[0130] In some embodiments, Compound A or Compound B, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered orally to the patient on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).Regimens

[0131] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every tw o days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0132] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days. 5 days. 6 days. 7 days, 8 days, 9 days, 10 days. 1 1 days. 12 days, 13 days. 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks. 6 weeks, 7 weeks, 8 weeks. 9 w eeks, 10 weeks, 1 1 w eeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, w ith administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks. 6 weeks. 7 weeks, 8 weeks. 9 weeks. 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.Combination Therapies

[0133] In one embodiment, the methods disclosed herein may be used in combination with one or more additional therapeutic agent that are being used and / or developed to treat the diseases and disorders discussed above.

[0134] In some embodiments, the methods further comprise administering an additional therapy or therapeutic agent to the patient. In some embodiments, the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an anti -obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), anti -emetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combinations thereof. In some embodiments, tire antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose linked transporter 2 (SGLT2) inhibitor, aglitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (GIP), an insulin or insulin analogue, an alpha glucosidase inhibitor, a sodium-glucose linked transporter 1 (SGLT1) inhibitor, or any combinations thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a famesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion. phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combinations thereof. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combinations thereof. In some embodiments, the agent to treat NASH is selected from the group consisting of an FXR agonist, PF-05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21) agonist, a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, anileal bile acid transporter (IBAT) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, or any combinations thereof. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrag thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order.

[0135] Representative additional therapeutic agents include, but are not limited to, anti -obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, antiinflammatory drags, antithrombotic agents, anti-oxidants, therapeutic agents for osteoporosis, vitamins, antidementia drags, erectile dysfunction drags, therapeutic drags for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria and anti -emetic agents.

[0136] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulator, GABA modulator (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK- 1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, l l|3-hydroxy steroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat). (33 agonists (e.g.. N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturated enzyme inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., piragliatin, AZD-1656, AZD6370, TTP-355, compounds described in W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821, W0008 / 136428 and W0008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving drags, CNTF (ciliary’ neurotrophic factor), BDNF (brain-dcrivcd neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide. AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339. TM-30335), oxyntomodulin(OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), human proislet peptide (HIP), famesoid X receptor (FXR) agonist, phentennine, zonisamide, norepinephrine / dopamine reuptake inhibitor, GDF-15 analog, methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulator, and AMP-activated protein kinase (AMPK) activator.

[0137] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-diabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS- 1), oral insulin preparation, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metfonnin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., any of glucagon analogs described, e.g.. in WO 2010 / 011439), agents which antagonize the actions of or reduce secretion of glucagon, sulfonylurea agents (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide), thiazolidinedione agents (e.g., rosiglitazone or pioglitazone), a-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, such as prandial glucose regulators (sometimes called "‘short-acting secretagogues”). e.g., meglitinides (e.g.. repaglinide and nateglinide), cholinesterase inhibitors (e.g.. donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-l / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, abiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513. PF-00734200, PHX1149, SK-0403, ALS2-0426. TA-6666, TS- 021. KRP-104, trelagliptin).

[0138] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21), a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acctyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an apoptosis signal -regulating kinase 1 (ASK1) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, glycyrrhizin. Schisandra extract, ascorbic acid, glutathione,silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B-complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, anti-virals, and anti-oxidants.

[0139] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat. epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factor and increasing agents thereof (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WOOl / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-l-imidazolyl)-5-[3-(2- methylphenoxyl)propyl]oxazole), compounds described in W02004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO- 226, pyridorin, pyridoxamine), serotonin and noradrenalin reuptake inhibitors (e.g., duloxetine). sodium channel inhibitors (e.g., lacosamide), active oxygen scavengers (e.g. , thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal regulating kinase- 1 (ASK-1) inhibitors.

[0140] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)- l-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2- oxo- l,2,3,5-tetrahydro-4, l-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g.. bezafibrate. clofibrate. simfibrate. clinofibrate). anion exchange resin (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma oryzanol (y-oryzanol)), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib) and u>-3 fatty acid preparations (e.g., co-3-fatty acid ethyl esters 90).

[0141] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-hypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan. losartan, losartan potassium, eprosartan, valsartan, telmisartan. irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and [3-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0142] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide. polythiazide, methyclothiazide). antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g.. acetazolamide) and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[0143] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivative, picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL) such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colonystimulating factor, erythropoietin).

[0144] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-thrombotic agents. Non-limiting examples include heparins (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium) warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., aragatroban, dabigatran) FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betnxaban, YM150, compounds descnbed in W002 / 06234, W02004 / 048363, W02005 / 030740, W02005 / 058823, and W02005 / 113504) thrombolytic agents (e.g. , urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel. E5555. SHC530348, cilostazol, ethyl icosapentate. beraprost sodium, and sarpogrelate hydrochloride).

[0145] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitrioL elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Suitable examples of vitamins include vitamin Bl and vitamin B12. Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Suitable examples of therapeutic agents for urinary frequency or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride and propiverine hydrochloride. Suitable examples of therapeutic agents for dysuria include acetylcholine esterase inhibitors (e.g., distigmine). Suitable examples of antiinflammatory agents include nonsteroidal anti-inflammatory- drugs such as aspirin, acetaminophen, indomethacin.

[0146] Other exemplary additional therapeutic agents include agents that modulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat the complications of prolonged hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications related to micro-angiopathies, anti-dyslipidemia agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cholesterol-lowering agents, bile acid sequestrants (e.g.. cholestyramine), cholesterol absorption inhibitors (e.g, plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), bile acid binding resins, nicotinic acid (niacin) and analogues thereof, anti-oxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, including adrenergic receptor antagonists, such as beta blockers (e.g. , atenolol), alpha blockers (e.g. , doxazosin), and mixed alpha / beta blockers (e.g. , labetalol), adrenergic receptor agonists, including alpha-2 agonists (e.g.. clonidine), angiotensin converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone), centrally acting adrenergic drugs, such as central alpha agonists (e.g., clonidine), diuretic agents (e.g., furosemide), haemostasis modulators, including antithrombotics (e.g., activators of fibrinolysis), thrombin antagonists, factor Vila inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and low molecular weight analogues thereof, factor Xa inhibitors, and direct thrombin inhibitors (e.g. , argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacyl glycerolacyltransferase (DGAT) inhibitors, feeding behavior modifying agents, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission-modulating agents, such as selective serotonin reuptake inhibitors (SSRI) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARI), noradrenaline-serotonin reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAGI) (e.g., toloxatone and amiflamine), compounds described in W0007 / 013694, W02007 / 018314, WG2008 / 093639 and W02008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, compounds described in W02004 / 041266, W02004 / 106276. W02005 / 063729, W02005 / 063725, W02005 / 087710. W02005 / 095338, W02007 / 013689 and W02008 / 001931), SGLT1 inhibitors, adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-ameliorating agents, such as a cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents,agents for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormones, IGF-1, antibodies against a cachexia-inducing factor TNF-a, LIF, IL-6, and oncostatin M, metabolism-modifying proteins or peptides such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor a (PPARa), MC4r agonists, insulin receptor agonist, PDE 5 inhibitors, glycation inhibitors (e.g., ALT-711). nerve regeneration-promoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g, desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), a2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), antianxiety drugs (e.g., benzothiazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T- cell receptor and IL-2 receptor-specific antibodies), B cell depleting therapies (e.g., anti-CD20 antibody (e.g., rituxan), i-BLyS antibody), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibody (e.g., tysabri), drags that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin), interferons (e.g., IFN-P), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosupressants (e.g., my cophenolate), and metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, chiglitazar, lobeglitazone, PLX-204. PN-2034, GFT- 505. THR-0921. exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donating agents (e.g., organonitrates), and NO promoting agents (e.g., phosphodiesterase inhibitors).

[0147] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-emetic agents. As used herein, an “anti-emetic” agent refers to any agent that counteracts (e.g., reduces or removes) nausea or emesis (vomiting). It is to be understood that when referring to a therapeutically effective amount of an anti-emetic agent, the amount administered is an amount needed to counteract (e.g. , reduce or remove) nausea or emesis (vomiting). While not wishing to be bound by theory, it is believed that administering one or more anti -emetic agents in combination with the formula (I) compounds described herein may allow higher dosages of the formula (I) compounds to be administered, e.g., because the patient may be able to have a normal food intake and thereby respond faster to the treatment.

[0148] Non-limiting examples of anti-emetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), ncurolcptics / anti-psychotics, antihistamines, anticholinergic agents, steroids (e.g., corticosteroids), NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists), antidopaminergic agents / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0149] For example, the antiemetic agent can be selected from the group consisting of: neuroleptics, antihistamines, anti-cholinergic agents, steroids, 5HT-3-receptor antagonists, NK1 -receptor antagonists, anti- dopaminergic agents / dopamine receptor antagonists, benzodiazepines and non- psychoactive cannabinoids.

[0150] In some embodiments, the anti -emetic agent is a 5HT3-receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 -receptor antagonists (serotonin receptor antagonists) include: Granisetron (Kytril), Dolasetron. Ondansetron (Zofran), Tropisetron. Ramosetron, Palonosetron. Alosetron. azasetron, Bemesetron. Zatisetron, Batanopirde, MDL-73147EF: Metoclopramide. N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,l]non-7-yl-l H- indazole-3 -carboxamide dihydrochloride), Y- 25130 hydrochloride, MDL 72222, Tropanyl-3,5-dimethylbenzoate, 3-(4-Allylpiperazin-l-yl)-2- quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Other non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant). quetiapine, qamosetron, ramosteron, ricasetron, risperidone, ziprasidone. and zatosetron.

[0151] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron. bemesetron, zatisetron. batanopirde, MDL-73147EF, metoclopramide, N-3389, Y- 25130 hydrochloride, MDL 72222, Tropanyl-3,5- dimethylbenzoate 3-(4-AIIyI- piperazin- l-yl)-2 -quinoxalinecarbonitrile maleate, zacopride hydrochloride and mirtazepine.

[0152] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0153] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron and ondansetron.

[0154] In certain embodiments, the 5HT-3 -receptor antagonist is granisetron.

[0155] In certain embodiments, the 5HT-3-receptor antagonist is ondansetron.

[0156] In some embodiments, the anti-emetic agent is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; Dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0157] In some embodiments, the anti-emetic agent is an anticholinergic agent (Inhibitors of the acetylcholine receptors). Non-limiting examples of anticholinergic agents include: atropine,scopolamine, glycopyrron, hyoscine, artane (trihexy-5 trihexyphenidyl hydrochloride), cogentin (benztropine mesylate), akineton (biperiden hydrochloride), disipal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Kemadrin (procyclidine hydrochloride).

[0158] In some embodiments, the anti-emetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, Prednisone®, and Trimethobenzamide (Tigan).

[0159] In some embodiments, the anti-emetic agent is an NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists). Non-limiting examples of NK1 -receptor antagonists include: aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0160] Other non-limiting examples ofNKl -receptor antagonists include: MPC-4505. GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A. CGP 60829, SR 140333 (Nolpitantium besilate / chlonde). LY 303870 (Lanepitant). MDL-105172A, MDL- 103896, MEN-11149, MEN-11467, DNK 333A, YM- 49244, YM-44778, ZM-274773, MEN-10930, S- 19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK- 33A, 6b-l, CJ-11974 j . Bcnscrazidc and carbidopa k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromcthyl)bcnzyl]- 8,9,10,l l-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l ,4]diazocino[2,l-g] [1 ,7]naphthyridine-6, 13- dione], PD 154075, ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)- NHCH(CH3) Ph). FK888. and (D- Pro4, D- Trp7,9,10, Phel 1)SP4-11.

[0161] In some embodiments, the anti-emetic agent is an anti- dopaminergic agents / dopamine receptor antagonist (e.g., dopamine receptor antagonist, e.g., D2 or D3 antagonists). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine,); benzamides (e.g., Metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0162] In some embodiments, the anti -emetic agent is a non-psychoactive cannabinoids (e.g., Cannabidiol (CBD), Cannabidiol dimethylheptyl (CBD-DMH), Tetra-hydro-cannabinol (THC). Cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist). Dronabinol (Marinol®), and Nabilone (Cesamet)).

[0163] Other exemplary anti-emetic agents include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / anti-psychotics (e.g., dixyrazine, haloperidol, and Prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose(Nauzene); orthophosphoricacid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0164] Still other exemplary anti-emetic agents include those disclosed in US 20120101089A1; US 10,071,088 B2; US 6,673,792 Bl; US 6,197,329 Bl; US 10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO 2009080351 Al; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated by reference in its entirety.

[0165] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contacting with or administering the compounds and pharmacal compositions (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[0166] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as contacting with or administering the compounds and pharmacal compositions. By way of example, the additional therapeutic agent or regimen and the compounds and pharmaceutical compositions arc provided to the patient simultaneously in the same dosage fonn. As another example, the additional therapeutic agent or regimen and the compounds and pharmacal compositions are provided to the patient concurrently in separate dosage fonns.Synthesis of the Compounds

[0167] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods, and procedures. It will be appreciated that where certain process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the reactants or solvent used, but such conditions can be detennined by one skilled in the art by routine optimization procedures.

[0168] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0169] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0170] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany), or Millipore Sigma (Burlington MA USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Suppiementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5thEdition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0171] Scheme I illustrates a general method which can be employed for the synthesis of certain compounds described herein, where each Rlf, Q2, R3, R9, RCa, RQA, RQB, RA, w, v, and q are each independently as defined herein, and LG is a suitable leaving group, such as halo (e.g. , hydroxy, alkoxy, halo, etc.).Scheme I

[0172] Compounds of Formula I can be provided by coupling compound 1-A with compound 1-B under suitable coupling reaction conditions, such as amide bond forming reaction conditions ornucleophilic substitution reaction conditions reaction conditions. Further derivatization can be performed of the resulting product via methods and chemical transformations which are known to those of skill in the art can provide alternative compounds of Formula I. For example, when the leaving group is an electrophile, such as an aldehyde, the coupling reaction conditions may comprise reductive amination reaction conditions. Ulus, tire conversion may comprise more than one reaction or set of reactants.

[0173] Upon reaction completion, compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. In certain embodiments, when control of stereochemistry is desired, proper control of reaction conditions and selection of substituents for the reagents can at least partially dictate or preserve the formation of the various stereoisomers.

[0174] In some embodiments, the various substituents of compound 1-A or 1-B are as defined herein. However, derivatization thereof prior to reacting in any step, and / or further derivatization of the resulting reaction product, provides various compounds of Formula I. Appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of this disclosure are within the skill of the art.General Synthesis

[0175] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.EXAMPLES

[0176] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.Example A8 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[(S)-methyl(methylazanylidene)(oxo)- λ6-sulfanyl]phenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyri din-5- yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2-methylcyclopropyl]-4H,5H-l,2,4- oxadiazol-5-one and3- [( 1 S,2S)- 1 -(2- { [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l- {4- [(R)- methyl(methylazanylidene)(oxo)-k6-sulfanyl]phenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2- methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (Compounds 112 and 121)7-2bSecond eluting enantiomer

[0177] Step A tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4- [methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 8-la

[0178] To a solution of tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4- [azanylidene(methyl)(oxo)-Z6-sulfanyl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 7-2a (80 mg, 0.135 mmol) in DMF (5 mL) was added NaH (10.8 mg, 0.269 mmol. 60% in oil) at rt. After being stirred at rt for 0.5 h, then iodomethane (0.025 mL. 0.404 mmol) was added. The resulting mixture was stirred at rt for another 16 h. The mixture was poured into water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine, dried over ISfeSCL, filtered and the residue was concentrated to obtain tert-butyl (4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-(3-{4-[methyl(methylazanylidene)(oxo)-Z6-sulfanyl]phenyl}-2- oxoimidazol-l-yl)-4-methyl-4,5,6.7-tetrahydropyrazolo[4.3-c]pyridine-5-carboxylate 8-la (80 mg, 97.7% yield). LC-MS: m / z 609.3 (M+H)+.

[0179] Step B l-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-3-yl]-3-{4-[methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl}-2,3-dihydro-lH-imidazol- 2-one hydrochloride salt 8-2a

[0180] The mixture of tert-butyl (4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-(3-{4- [methyl(methylazanylidene)(oxo)-Xt’-sulfanyl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 8-la (40 mg, 0.066 mmol) and 4 M HC1 (gas) in 1,4- dioxane solution (0.2 mL) in DCM (1 mL) was stirred at rt for 16 h. The mixture was concentrated to obtain l-(4-(N, dimcthylsulfonimidoyl)phcnyl)-3-((S)-2-(4-fluoro-3,5-dimcthylphcnyl)-4-mcthyl-4,5,6,7- tetrahydro-2H-pyrazolo[4.3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride salt 8-2a (35 mg, 97.7% yield). LC-MS: m / z 509.2 (M+H)1.

[0181] Step C 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4- [methyl(methylazanylidene)(oxo)-L6-sulfanyl]phenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2- methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (enantiomer 1) (Compound 112)

[0182] The mixture of l-(4-(N, dimethylsulfonimidoyl)phenyl)-3-((S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol- 2-one hydrochloride salt 8-2a (70 mg, 0.128 mmol), l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-lH-indole-2 -carboxylic acid (49.2 mg, 0.128 mmol), HATU (97.6 mg, 0.257 mmol) and DIPEA (49.7 mg, 0.385 mmol) in DMF (2 mL) was stirred atrt for 12 h. The mixture was purified by prep. HPLC (Column: XBridge C18 19*250mm* 10pm; Mobile Phase A: Water (0.05% NH3.H20), B: CH3CN; Flow rate: 20 mL / min; Gradient: 27% B to 34% B;Retention Time: 8.85 - 10.03 min) to obtain 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l- {4-[-methyl(methylazanylidene)(oxo)-λ6-sulfanyl ]phenyl }-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo [4,3 -c]pyridin-5 -yl]carbonyl } -5 -(3.4,5 ,6-tetrahydro-2H-pyran-4-yl)indol- 1 -y 1) -2- methylcyclopropyl]-4H.5H-1.2.4-oxadiazol-5-one (enantiomer 1) (51.5 mg. 45.9% yield). LC-MS: m / z 874.4 (M+H)+. 'H NMR (400 MHz, DMSO-J6) 8 8.02 - 7.92 (m, 3H), 7.85 (s, 1H), 7.56 - 7.35 (m, 3H), 7.28 - 7.06 (m, 4H), 6.98 - 6.79 (m, 1H), 6.59 - 6.50 (m, 1H), 5.71 - 5.56 (m, 1H), 4.44 - 4.32 (m, 1H), 4.02 - 3.92 (m, 2H), 3.65 - 3.50 (m, 1H), 3.47 - 3.39 (m, 3H), 3.14 (s, 3H), 3.10 - 3.08 (m, 1H), 2.91 - 2.79 (m, 2H), 2.48 (s, 3H), 2.19 (s, 6H), 1.83 - 1.70 (m, 4H), 1.65 - 1.56 (m, 1H), 1.40 - 1.32 (m, 1H), 1.25 - 1.05 (m, 7H).

[0183] Step D tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4- [methyl(methylazanylidene)(oxo)-L6-sulfanyl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4, 5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

[0184] The mixture of tert-butyl (4S)-2-(4-fluoro-3.5-dimcthylphcnyl)-3-(3-j4-|- azanylidene(methyl)(oxo)-λ6-sulfanyl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4.5.6.7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 7-2b (50 mg, 0.084 mmol) in DMF (4 mL) was added NaH (4.0 mg, 0.101 mmol, 60 % in oil) and Mel (11.93 mg, 0.084 mmol). The reaction mixture was stirred at rt for 16 h under N?. Then reaction was quenched with water (50 ml), extracted with EtOAc (50 ml). Hie organic layer was washed with brine, dried over NaiSOi and concentrated to afford tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4-[methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl}-2- oxoimidazol-l-yl)-4-methyl-4,5,6.7-tetrahydropyrazolo[4.3-c]pyridine-5-carboxylate 8- lb (67 mg, crude). LC-MS: m / z 609.0 (M+H)+.

[0185] Step E l-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-3-yl]-3-{4-[methyl(methylazanylidene)(oxo)-X.6-sulfanyl]phenyl}-2,3-dihydro-lH-imidazol- 2-one hydrochloride salt 8-2b

[0186] The mixture of tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4- [methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl]-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 8-lb (67 mg, 0.110 mmol) in DCM (4 mL) was added 4 M HC1 (gas) in dioxane (0.27 mL). The reaction mixture was stirred rt for 4 h under N2. The reaction mixture was concentrated to afford l-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-{4-[methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl}-2,3- dihydro- lH-imidazol-2 -one hydrochloride salt 8-2b (67 mg, crude). LC-MS: m / z 509.0 (M+H)+.

[0187] Step F 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4- [methyl(methylazanylidene)(oxo)-λ6-sulfanyl]phenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2- methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (enantiomer 2)

[0188] To a solution of l-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7- tetrahydropyrazolo [4,3 -c]pyridin-3 -yl] -3 - { 4-| methyl (mcthylazanyl idcnc)(oxo)-Z"-sulfanyl Iphcnyl [ -2,3 - dihydro- lH-imidazol-2 -one hydrochloride salt 8-2b (67 mg. 0.132 mmol) in DMF (2 mL) was added 1- [(lS,2S)-2-methyl-l-(5-oxo-4H-1.2.4-oxadiazol-3-yl)cyclopropyl]-5-(3.4.5.6-tetrahydro-2H-pyran-4- yl)indole-2 -carboxylic acid (76 mg, 0.198 mmol), DIPEA (85 mg, 0.659 mmol), HATU (75 mg, 0.198 mmol). The reaction mixture was stirred at rt for 2 h under N2. The reaction mixture was purified using prep. HPLC (Column: Sunfire C 18 19*250mm* 10pm; Mobile Phase A: Water (0.1% formic acid), B: CH3CN; Flow rate: 20 mL / min; Gradient: 31% B to 41% B; Retention Time: 8.0 - 9.5 min) to afford 3- [(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[(R)-methyl(methylazanylidene)(oxo)-λ6- sulfanyl]phenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6.7-tetrahydropyrazolo[4.3-c]pyridin-5-yl]carbonyl[- 5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2-methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (enantiomer 2) (11.3 mg, 9.8% yield). LC-MS: m / z 874.5 (M+H)+. ’H NMR (400 MHz, DMSO-r / 6) 3 8.01 - 7.91 (m, 3 H), 7.85 - 7.76 (m, 1 H), 7.51 - 7.40 (m, 2 H), 7.41 (d, J= 8.0 Hz, 1 H), 7.29 - 7.23 (m, 1 H), 7.17 - 7.09 (m, 3 H). 6.98 - 6.82 (m, 1 H), 5.63 - 5.56 (m, 1 H), 4.46 - 4.32 (m, 1 H), 3.97 (d, J= 8.0 Hz, 2 H), 3.71 - 3.53 (m, 1 H), 3.50 - 3.36 (m, 3 H), 3.13 - 3.09 (m, 3 H), 2.94 - 2.84 (m, 2 H), 2.12 (s, 6 H), 1.80 - 1.65 (m, 7 H). 1.65 - 1.56 (m. 1 H). 1.41 - 1.37 (m, 2 H), 1.31 - 1.27 (m, 1 H). 1.17 - 1.01 (m. 3 H).

[0189] Example compounds 144. 149 and 151 were synthesized using a similar procedure described in the Example A8 above using the appropriate materials, e.g., in step D.Example A10(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-({l-[(lS,2S)-2-methyl-l-(5-oxo-4H-l,2,4-oxadiazol-3- yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-3-(3-{4-[(lS)-l-oxo-lλ6- 4H,3H,5H-l,2-thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- cjpyridine and (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4-[(lR)-l-oxo-lλ6-4H,3H,5H-l,2-thiazol- l-yl]phenyl}-2-oxoimidazol-l-yl)-5-({l-[(lS,2S)-2-methyl-l-(5-oxo-4H-l,2,4-oxadiazol-3- yl)cyclopropyl]-5-(3, 4,5, 6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-4-methyl-4, 5,6,7- tetrahydropyrazolo[4,3-c]pyridine (Compounds 142 and 143)

[0190] Step A (4-bromophenyl)(3-chloropropyl)(oxo)-Z6-sulfanimine

[0191] To a solution of (4-bromophenyl)(3-chloropropyl)sulfane (3.78 g, 14.214 mmol) in MeOH (45 mL) was added PhI(OAc)2 (13.73 g. 42.641 mmol) and H2NCO2NH4 (4.43 g, 56.855 mmol). The reaction mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was poured into sat. aq. sodium bicarbonate solution (20 mL), extracted with EtOAc (20 mL x 3). The residue was purified by flash silica gel chromatography (Silica Flash Column, Eluent of 0-50%EtOAc / PE gradient) to afford (4- bromophenyl)(3-chloropropyl)(oxo)- λ6-sulfanimine (3.50 g, 83.1% yield). LC-MS: m / z 296.0 (M+H)+.

[0192] Step B l-(4-bromophenyl)- λ6-5H,4H,3H-l,2-thiazol-l-one

[0193] A mixture of (4-bromophenyl)(3-chloropropyl)(oxo)-Z6-sulfanimine (3.503 g, 11.877 mmol) in 0.1% aq. NH3 H2O (72 mL) was stirred at 80 °C for 2 h under N2 in a sealed tube. After cooling, the mixture was poured into water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, Eluent of 0-50%EtOAc / PE gradient) to affordl-(4-bromophenyl)-lZ6-5H,4H,3H-l,2-thiazol-l-one (1.43 g, 46.2% yield). LC-MS: m / z 260.1 (M+H)+.

[0194] Step C tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-{2-oxo-3-[4-(l-oxo-lZ6- 4H,5H,3H-l,2-thiazol-l-yl)phenyl]imidazol-l-yl}-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate

[0195] To a solution of l-(4-bromophenyl)-lλ6-5H,4H,3H-L2-thiazol-l-one (1.43 g, 5.485 mmol) and tert-butyl (4S)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-3-(2-oxo-3H-imidazol-l-yl)-4, 5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (2.20 g, 4.987 mmol) in NMP (30 mL) was added methyl[(lS,2S)-2-(methylamino)cyclohexyl]amine (1.06 g, 7.480 mmol), potassium carbonate (1.38 g, 9.973 mmol) , and Cui (1.14 g, 5.984 mmol). The reaction mixture was stirred at 120 °C for 4 h under N2. After cooling, the mixture was poured into water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash silica gel chromatography (Silica Flash Column, Eluent of 0-50%EtOAc / PE gradient) to afford the tert-butyl (4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-3-{2-oxo-3-[4-( 1-oxo- lL6-4H,5H,3H-l,2-thiazol-l-yl)phenyl]imidazol-l-yl}-4.5.6.7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (3.12 g, 91.7% yield). LC-MS: m / z 621.4 (M+H)+.

[0196] Step D tert-butyl (4S)-2-(4-fluoro-3.5-dimethylphenyl)-3-(3-{4-[l-oxo-lλ6-4H,5H,3H-l,2- thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4.5.6.7-tetrahydropyrazolo[4.3-c]pyridine-5- carboxylate 10-5a (first eluting enantiomer) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4- [l-oxo-lλ6-4H,5H,3H-l,2-thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 10-5b (second eluting enantiomer)

[0197] The compound mixture tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-{2-oxo-3- [4-(l-oxo-lZ6-4H,5H,3H-l,2-thiazol-l-yl)phenyl]imidazol-l-yl}-4,5,6,7-tetrahydropyrazolo[4,3- c] pyridine -5 -carboxylate (4.20 g, 6.774 mmol) was separated by SFC (Column: REGIS (S,S)WHELK-O1 250*25 mm 10 pm, Mobile phase A (Supercritical CO2), Mobile phase B (MeOH (0.1% 7.0 M ammonia in MeOH)), Gradient: A / B = 65 / 35, Flow rate: 70 mL / min) to afford tert-butyl (4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3 - {4-[- 1 -oxo- 1 / .' -4H.5 H.3 H- 1 ,2-thiazol- 1 -yl]phenyl } -2-oxoimidazol- 1 -yl)-4-m ethyl -4.5.6.7-tctrahydropyrazolo[4,3-c]pyridinc-5-carboxylatc 10-5a (first eluting enantiomer) (2.00 g, 47.6% yield) as the fast eluent (Rt = 1.95 min), LC-MS: m / z 621.4 (M+H)+. And tert-butyl (4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-{4-[-l-oxo-lλ6-4H,5H,3H-l,2-thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)-4-methyl-4.5.6.7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 10-5b (second eluting enantiomer) (2.20 g, 52.4% yield) as the slow eluent (Rt = 2.74 min), LC-MS: m / z 621.4 (M+H)+.

[0198] Step E (4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-({ l-[(lS,2S)-2-methyl-l-(5-oxo-4H-L2,4- oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-3-(3-{4-[l-oxo- IL -4H.3H.5H- 1 ,2-thiazol- 1 -yl Iphcnyl j -2-oxoimidazol- 1 -yl)-4-methyl-4.5.6.7-tetrahydropyrazolo|4.3- c]pyridine and (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4-[l-oxo-lZ6-4H,3H,5H-l,2-thiazol-l- yl]phenyl}-2-oxoimidazol-l-yl)-5-({ l-[(lS,2S)-2-methyl-l-(5-oxo-4H-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridine (Compounds 142 and 143).Compound 142 Compound 143 enantiomer 1 enantiomer 2

[0199] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-({ l-[(lS,2S)-2-methyl-l-(5-oxo-4H-l,2,4-oxadiazol-3- yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-3-(3-{4-[l-oxo-lλ6-4H,3H,5H- 1 ,2-thiazol- 1 -yl]phenyl } -2-oxoimidazol- 1 -yl)-4-methyl-4.5 ,6, 7 -tetrahydropyrazolo [4,3 -c]pyridine (Compound 142) (enantiomer 1) and (4S)-2-(4-fluoro-3.5-dimethylphenyl)-3-(3-{4-[l-oxo-lXfi- 4H,3H,5H-l,2-thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)-5-({ l-[(lS,2S)-2-methyl-l-(5-oxo-4H-l,2,4- oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-2-yl}carbonyl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine (Compound 143) (enantiomer 2) were synthesized according to the procedures described for the preparation of Example A7 (step C to F) by using tert-butyl (4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-(3-{4-[l-oxo-lλ6-4H,5H,3H-l,2-thiazol-l-yl]phenyl}-2-oxoimidazol-l-yl)- 4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 10-5a (first eluting enantiomer) in step C and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-{4-[l-oxo-lXb-4H,5H,3H-l,2-thiazol-l- yl]phenyl]-2-oxoimidazol-l-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 10-5b (second eluting enantiomer) in step E.

[0200] Compound 142: LC-MS: m / z 886.4 (M+H)+.1H NMR (400 MHz, DMSO-r / 6) 3 7.95 - 7.88 (m, 4H), 7.49 (s, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.32 (m, 1H), 7.23 (d, J= 8.4 Hz. 1H), 7.17 - 7.15 (m, 2H), 6.98 (m, 1H), 6.77 (m, 1H), 5.55 (m, 1H), 4.39 (m, 1H), 4.00 - 3.97 (m, 2H), 3.86 - 3.81 (m, 1H), 3.72 - 3.69 (m. 1H), 3.52 - 3.46 (m, 2H). 3.40 - 3.32 (m, 2H), 2.90 - 2.83 (m. 3H), 2.33 - 2.26 (m, 3H). 2.22 (s, 6H). 1.76 - 1.69 (m. 5H), 1.65 (m. 2H), 1.39 (s, 3H), 1.20 (s, 3H).

[0201] Compound 143: LC-MS: m / z 886.4 (M+H)1.!H NMR (400 MHz, DMSO-c / 6) 8 11.59 (brs, 1H), 7.95 - 7.91 (m, 4 H), 7.53 (s, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.37 (m, 1 H), 7.28 (d, J=8.4 Hz, 1H), 7.16 - 7.14 (m, 2H), 6.96 (m, 1H), 6.88 (m, 1H), 5.57 (m, 1H), 4.50 (m, 1H), 4.00 - 3.97 (m, 2H), 3.89 - 3.84 (m, 1H), 3.77 - 3.72 (m, 1H), 3.53 - 3.46 (m, 4H), 2.92 - 2.86 (m, 2H), 2.36 - 2.28 (m, 3H), 2.22 (s, 6H), 2.05 - 2.02 (m, 1H), 1.78 - 1.73 (m, 6H), 1.66 (m, 1H), 1.43 (s, 3H), 1.17 (s, 3H).

[0202] Example compound 130 and 131 was synthesized using a similar procedure described in the Example A10 above using the appropriate materials in step D.Example A253-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-4-(N-methylethylsulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH- imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l-yl)- 2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 1) (Compound 164)

[0203] Step A (4-bromo-3-fluorophenyl)(ethyl)sulfane

[0204] A mixture of l-bromo-2-fluoro-4-iodobenzene (10 g, 33.234 mmol), (ethylsulfanyl)sodium(3.35 g, 39.880 mmol), Pd2(dba)3(1.52 g, 1.662 mmol) and xantphos (1.92 g, 3.323 mmol) in dry dioxane(200 mL) was stirred at 80°C for 16 hrs. The reaction mixture was poured into water (500 mL), extracted with EA (3 X 200 mL). The organic layers were dried over Na2SC>4, and concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with PE (100%) to afford (4-bromo-3- fluorophenyl)(ethyl)sulfane (6.3 g, 80.63%) as a colorless oil. 'I I NMR (400 MHz, CDCL) <5 7.44-7.40 (m, 1H). 7.05 (dd, J = 9.2, 2.0 Hz, 1H), 6.95 (dd, J= 8.4, 2.0 Hz, 1H). 2.94 (q, J= 7.2 Hz. 2H), 1.33 (t, J = 12 Hz, 3H).

[0205] Step B (4-bromo-3-fhrorophenyl)(ethyl)(imino)- λ6-sulfanonc

[0206] To a solution of (4-bromo-3-fluorophenyl)(ethyl)sulfane (4.00 g, 17.013 mmol) in MeOH (100 mL) were added (diacetoxyiodo)benzene (16.54 g. 51.039 mmol), ammonium aminomethanoate (5.31 g, 68.052 mmol), and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (500 mL), extracted with EA (3 X 200 mL). Tire organic layers were washed with saturated NaCl solution, dried over Na2SO4. and concentrated in vacuum. The residue was purified by using silica gel column chromatography eluting with EA in PE (1 / 1) to afford both isomers.

[0207] Step C (4-bromo-3-fluorophenyl)(ethyl)(imino)- λ6-sulfanonc (enantiomer 1) and (4-bromo-3- fluorophenyl)(ethyl)(imino)- λ6-sulfanonc (enantiomer 2)4-1 4-2

[0208] (4-bromo-3-fluorophenyl)(ethyl)(imino)- λ6-SLilfanonc obtained above was separated by SFC (Column: DAICELCHIRALPAK®AS; Column size: 250 mm*40 mm, 10 pm; Mobile Phase A: Supercritical CCL; Mobile Phase B: MeOH (0.1% 7.0 M Ammonia in MeOH); Gradient: B = 10%). Flow rate: 140 mL / min, Column temp.: 25 °C) to afford (4-bromo-3-fluorophenyl)(ethyl)(imino)- λ6-sulfanonc (enantiomer 1) (1500 mg, 33.13%) as a colorless oil as the fast eluent. R.T=1.16 min. LC-MS: m / z 266.0 (M+H)+. And (4-bromo-3-fluorophenyl)(ethyl)(imino)- λ6-sulfanonc (enantiomer 2) (1500 mg, 33.13%) as the slow eluent, R.T=1.47 min. LC-MS: m / z 266.0 (M+H)+.

[0209] Step D tert-butyl (4S)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-lH- imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine- 5 -carboxylate (enantiomer 1)

[0210] To a solution of tert-butyl (S)-2-(4-fluoro-3.5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g, 4.530 mmol) in NMP (24 mL) were added copper1+) iodide (1.04 g, 5.436 mmol), potassium carbonate (1.25 g, 9.060 mmol), (4-bromo-3-fluorophenyl)(ethyl)(imino)- λ6-sulfanonc (enantiomer 1) (1.57 g, 5.889 mmol) and (1R, 2R)-N1,N2-dimethylcyclohexane-l,2-diamine (0.64 g, 4.530 mmol), and the reaction mixture was stirred at 130 °C for 4 hrs under N2. The mixture was poured into water (50 mL), extracted with EA ((3 X 30 mL), washed with brine ((3 X 20 mL). The organic layer was dried and concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with (eluting PE / EA=1 / 1) to afford tert-butyl (4S)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-lH-imidazol-l- yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (enantiomer 1) (1.75 g, 61.64%) . LC-MS: m / z 627.8 (M+H)+.

[0211] Step E tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(N- methylethylsulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetraliydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1)

[0212] To a solution of tert-butyl (4S)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (500 mg, 0.798 mmol) in DMF (10 mL) wasadded sodium hydride (19.15 mg, 0.798 mmol) at 0 °C under N2 . The reaction mixture was stirred at 0 °C for 1 hr and iodomethane (0.078 mL, 0.957 mmol) was added. The reaction mixture was stirred at room temperature for another 16 hrs. Tire mixture was poured into water (50 mL), extracted with EA (20 mL X 3). Tire combined organic layers were washed with brine (50 mL), dried over Na2SO4, fdtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with (eluting PE / EA=1 / 1) to give tert-butyl (4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(N- methylethylsulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (200 mg, 97.81%). LC-MS: m / z 641.4 (M+H)+.

[0213] Step F 1 -((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridin-3-yl)-3-(2-fluoro-4-(N-methylethylsulfonimidoyl)phenyl)-l,3-dihydro-2H-imidazol-2-one, hydrochloride salt (enantiomer 1)

[0214] A solution of tert-butyl (4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-(3-(2-fhioro-4-(N- methylethylsulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (215 mg, 0.312 mmol) in HCl / dioxane (3 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuum to afford l-((S)-2- (4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2-fluoro- 4-(N-methylethylsulfonimidoyl)phenyl)-l,3-dihydro-2H-imidazol-2-one, hydrochloride salt (enantiomer 1) (168 mg, 99.77%) which was used in the next step without further purification. LC-MS: m / z 541.2 (M+H-HC1)+.

[0215] Step G 3-((lS.2S)-l-(5-((S)-2.2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-4-(N-methylethylsulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol- l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)-!, 2, 4-oxadiazol-5(4H)-one (enantiomer 1) (Compound 164)

[0216] To a solution of 5-((S)-2,2-dimethyltetraliydro-2H-pyran-4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo- 4, 5-dihydro-L2.4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2 -carboxylic acid (114.16 mg, 0.277 mmol) in DMF (3 mL) were added HATU ( 158.25 mg, 0.416 mmol), DIPEA (143.44 mg, 1.110 mmol), and l-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)- 3-(2-fluoro-4-(N-methylethylsulfonimidoyl)phenyl)-l,3-dihydro-2H-imidazol-2-one, hydrochloride salt (enantiomer 1) (150 mg, 0.277 mmol), and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was poured into water (50 mL), extracted with EA (20 mL X 3). Tire combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 3% MeOH in DCM and then prep- HPLC (NH4HCO3) to afford 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(N-methylethylsulfonimidoyl)phenyl)-2 -oxo-2, 3-dihydro- lH-imidazol-l-yl)-4-mcthyl-4,5,6,7-tctrahydro-2H-pyrazolo[4,3-c]pyridinc-5-carbonyl)-lH-indol-l-yl)- 2-methylcyclopropyl)-l,2.4-oxadiazol-5(4H)-one (enantiomer 1) (63.60 mg, 24.24%).

[0217] LC-MS: m / z 934.2 (M+H)+.1H NMR (400 MHz, DMSOd / 6) 8 11.50 (s, 1H), 7.75-7.73 (m, 3H), 7.53 (s, 1H). 7.42 (d, J = 8.4 Hz. 1H), 7.30- 7.21 (m, 1H), 7.16 (d, J = 6.4 Hz, 2H), 7.04 (s, 1H), 6.90-6.88 (m, 2H). 5.60 (s. 1H), 4.47 (s, 1H), 3.75-3.72 (m, 2H). 3.60 (s, 1H), 3.31-3.25 (m, 2H), 2.90-2.86 (m, 1H), 2.57 (s, 3H), 2.25 (d, J =1.6 Hz, 6H), 1.76-1.71 (m, 4H), 1.66-1.63 (m, 2H), 1.62-1.58 (m, 2H), 1.45 (s, 3H), 1.30-1.29 (m, 4H), 1.20-1.13 (m, 9H).19F NMR (376 MHz, DMSO-J,.) 8 -118.55, -122.06.Example A143-[(lS,2S)-l-{5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-{[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)-λ6-sulfanyl]-2-fluorophenyl}-2- oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}indol-l-yl}-2- methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (Compound 180)

[0218] Step A 3-[(lS.2S)-l-]5-[(4S)-2.2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-] [(4S)-2-(4- fluoro-3 ,5 -dimethylphenyl)-3 -( 1 - {4-[cyclopropyl(methylazanylidene)(oxo)-λ6-sulfanyl] -2-fluorophenyl } -2-oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}indol-l-yl}-2- methylcyclopropyl]-4H,5H-l,2,4-oxadiazol-5-one (Compound 180)

[0219] To a solution of 5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l- (5-oxo-4H-l, 2, 4-oxadiazol-3-yl)cyclopropyl]indole-2 -carboxylic acid (37.23 mg, 0.090 mmol)and HATU (68.76 mg. 0.181 mmol) in N,N-dimethylmethanamide (8 mL) was added 3-[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-l-{4- [cyclopropyl(methylazanylidene)(oxo)-λ6-sulfanyl]-2-fluorophenyl}-2,3-dihydro-lH-imidazol-2-one (50 mg, 0.090 mmol) and DIEA (58.36 mg, 0.452 mmol). The mixture was stirred at rt for 2 h. After the reaction was completed, water (20 mL) was added into the mixture. The solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep. HPLC (Waters 2767 / Qda, Column: SunFire Sunfire C18, 19*250mm, 10 pm; Mobile Phase A: 0.1%FA / H2O, B: CH3CN ; flow rate: 20 mL / min; gradient: 76%-81%; Retention Time: 7.9-8.7min of 17 min) to afford 3-[(lS,2S)-l-{5- [(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2EI-pyran-4-yl]-2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4- [cyclopropyl(methylazanylidene)(oxo)-Z6-sulfanyl]-2 -fluorophenyl }-2-oxoimidazol-3-yl)-4-methyl- 4,5 ,6,7-tetrahydropyrazolo [4,3 -c]pyridin-5 -yl]carbonyl } indol- 1 -yl} -2 -methyl cyclopropyl]-4H,5H- 1,2,4- oxadiazol-5-one (39.9 mg. 46.7% yield). LC-MS: m / z 946.7 (M+H)+. 'H NMR (400 MHz, DMSO-r / 6) d 11.55 (brs, 1 H). 7.78 - 7.75 (m. 3 H), 7.51 (s, 1 H), 7.42 (d. J= 8.4 Hz, 1 H), 7.24 (d, J= 8.0 Hz, 1 H).7.16 (d, J= 6.4 Hz, 2 H), 7.04 (s, 1 H), 6.89 - 6.76 (m, 2 H), 5.54 (m, 1 H), 4.40 (m, 1 H), 3.74 (d, J= 92 Hz, 2 H), 3.51 (m, 1 H), 2.83 (m, 1 H), 2.79 (m, 1 H), 2.59 (s, 3 H), 2.24 (s, 6 H), 1.73 - 1.55 (m, 8 H), 1.44 (s, 3 H), 1.30 - 1.21 (m, 11 H), 1.10 (m, 1 H), 0.98 - 0.90 (m, 2 H).Example A12-a3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fliioro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridiiie-5-carbonyl)- lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 1) (Compound 195) and 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)- lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 2) (Compound 196)12-6a 12-6b

[0220] Step A 4-bromo-3-fluoro-2-methylbenzene-l-thiol

[0221] To a mixture of 4-bromo-3-fluoro-2 -methylaniline (2.7 g, 13.233 mmol) in H2O (10 mL) was added cone. HC1 (2.205 mL. 26.465 mmol). The reaction mixture was cooled in an ice / NaCl bath (approximately -5 to -10 °C), a solution of sodium nitrite (958.6 mg, 13.894 mmol) in H2O (10 mL) was added slowly over 10 minutes. The mixture was stirred for an additional 30 minutes with cooling.Separately, a solution of [(ethoxythioxomethyl)sulfanyl]potassium (2545.3 mg, 15.879 mmol) in H2O (30 mL) was prepared and heated to 65 °C. The cold solution of diazonium salt was then added slowly over 20 minutes to the warmed solution of potassium ethyl xanthogenate. The reaction mixture was stirred for an additional 30 minutes at 65 °C and then cooled to ambient temperature. A solution of NaOH (2646.6 mg, 66.165 mmol) in H2O (10 mL) was added, the reaction was stirred at 70 °C for 18 h. After the reaction was completed, monitored by TLC. the mixture was cooled to rt, the mixture was poured into ice (200 g), acidified with concentrated HC1 to / >H=1, the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous NazSCL, filtered and concentrated to afford 4- bromo-3-fluoro-2 -methylbenzene- 1 -thiol (3.7 g, crude), used for the next step without purification.

[0222] Step B (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)sulfane

[0223] To a solution of 4-bromo-3-fluoro-2-methylbenzene-l -thiol (3.7 g, 16.735 mmol) in DMSO (60 mL) were added potassium / crt-butoxide (3.76 g, 33.471 mmol) and bromocyclopropane (10.12 g, 83.676 mmol), the reaction was stirred at 100 °C for 18 h under N2. TLC showed the reaction was completed.Tire mixture was poured into water (100 mL), extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (eluting PE 100%) to afford (4-bromo-3-fluoro-2- methylphenyl)(cyclopropyl)sulfane (2.23 g, 50.3% yield) as a colorless oil. 'H NMR (400 MHz, CDCL) 8 7.24-7.28 (m, 1 H), 7.10-7.12 (m, 1 H), 2.13 (s, 3 H), 2.01-2.05 (m, 1 H), 1.02-1.07 (m, 2 H), 0.60-0.64 (m, 2 H).

[0224] Step C (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-sulfanimine

[0225] To a solution of (4-bromo-2-fluorophenyl)(cyclopropyl)sulfane (2.2 g, 8.524 mmol) in MeOH (30 mL) was added (diacetoxyiodo)benzene (8.29 g. 25.572 mmol) and ammonium carbaminate (2.66 g, 34.095 mmol). The reaction was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). Tire combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residuewas purified by silica gel chromatography (eluting 0-50% EtOAc / PE) to afford (4-bromo-3-fluoro-2- methylphenyl)(cyclopropyl)(oxo)-λ6-sulfanimine (1.17 g, 69.2% yield). LC-MS: m / z 292.0 (M+H)+.

[0226] Step D l-(4-bromo-3-fluoro-2-methylphenyl)-l-cyclopropyl-N-methyl-l-oxo-λ6-sulfanimine

[0227] To a solution of (4-bromo-3-fluoro-2-metliylphenyl)(cyclopropyl)(oxo)-λ6-sulfanimine (3200 mg, 10.953 mmol) in dioxane (50 mL) were added cupric bis(acetate) (5967.92 mg, 32.858 mmol), Pyridine (3.543 mL. 43.810 mmol) and methylboranediol (2622.47 mg, 43.810 mmol). The reaction was stirred at 100 °C for 2 h under CL. The mixture was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluting PE / EA=10 / l) to afford l-(4-bromo- 3-fluoro-2-methylphenyl)-l-cyclopropyl-N-methyl-l-oxo-λ6-sulfanimine (2616 mg, 78.01%) as a yellow oil. LC-MS: m / z 306.2 (M+H)+.

[0228] Step E l-(4-bromo-3-fluoro-2-methylphenyl)-l-cyclopropyl-N-methyl-l-oxo-λ6-sulfanimine(enantiomer 1) and l-(4-bromo-3-fluoro-2 -methylphenyl)-! -cyclopropyl -N-methyl- l-oxo-Z6-sulfanimine(enantiomer 2)

[0371] The compound mixture l -(4-bromo-3-fluoro-2-mcthylphcnyl)- l-cyclopropyl-N-mcthyl- l -oxo-) / ’- sulfanimine (2616 mg, 8.544 mmol) was separated by SFC (system: Waters SFC 150; Column name: DAICELCHIRALPAK®IG; Column size: 250*25 mm 10 pm; Mobile Phase A: Supercritical CO?;Mobile Phase B: IPA (+0.1% 7.0 mol / L Ammonia in MeOH); Gradient: A / B = 80 / 20; Flow rate: 100 mL / min) to afford 1 -(4-bromo-3-fluoro-2 -methylphenyl)- 1 -cyclopropyl -N-methyl- 1 -oxo-L’-sulfaniminc (enantiomer 1) (1.25 g, 37.42%) as the fast eluent, R.T=1.28 min, LC-MS: m / z 306.2 (M+H)+. And l-(4- bromo-3-fluoro-2 -methylphenyl)-! -cyclopropyl -N -methyl- l-oxo-λ6-sulfanimine (enantiomer 2) (1.16 g, 34.72%) as the slow eluent, R.T=1.97 min. LC-MS: m / z 306.2 (M+H)+.Step F tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N- methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2.3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7- tetrahydro-5H-pyrazolo[4.3-c]pyridine-5-carboxylate (enantiomer 1)

[0229] To a solution of l-(4-bromo-3-fluoro-2-methylphenyl)-l-cyclopropyl-N-methyl-l -oxo-Z6- sulfanimine (enantiomer 1) (775 mg, 2.531 mmol) in NMP (15 mL) were added 2-methylpropan-2-yl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3H-imidazol-l-yl)-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (1117.51 mg, 2.531 mmol), Cui (578.46 mg. 3.037 mmol), K2CO3 (699.60 mg, 5.062 mmol) and methyl[(lR.2R)-2-(methylamino)cyclohexyl]amine (540.08 mg, 3.797 mmol), the reaction was stirred at 130 °C for 3 h under N2. The mixture was added to water (50 mL), extracted with EA (30 mL X 2), the combined organic layers were washed with brine (30 mL X 3), dried over sodium sodium sulfate, filtered and concentrated under vacuum. Tire resulting residue was purified by flash column chromatography (eluting PE / EA=l / 2), then purified by Cl 8 column chromatography (eluting 50% of ACN in water, 0.1% FA) to afford tert-butyl (4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2.3- dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (1100 mg, 65.18%) as a yellow solid. LC-MS: m / z 667.7 (M+H)+.

[0230] Step G 1 -((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridin-3-yl)-3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-l,3-dihydro-2H- imidazol-2-one, HC1 salt (enantiomer 1)

[0231] To a solution of tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N- methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (1050 mg, 1.575 mmol) in DCM (10 mL) were added HC1 (3.937 rnL, 15.747 mmol), the mixture was stirred at rt for 16 h under N2 protection. The mixture was concentrated under vacuum to afford l-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4.3-c]pyridin-3-yl)-3-(2-fluoro-3-methyl-4-(N- methylcyclopropanesulfonimidoyl)phenyl)-l,3-dihydro-2H-imidazol-2-one, HC1 salt (enantiomer 1) (893 mg, 100.0%), used for the next step with no purification. LC-MS: m / z 567.1 (M+H-HC1)+.

[0232] Step H 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH- indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 1) (Compound 195).

[0233] To a solution of 5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l- (5-oxo-4H-l, 2, 4-oxadiazol-3-yl)cyclopropyl]indole-2 -carboxylic acid (778.15 mg, 1.891 mmol) and HATU (898.25 mg, 2.364 mmol) in DMF (20 mL) was added a solution of l-((S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2-fluoro-3-methyl-4- (N-methylcyclopropanesulfonimidoyl)phenyl)-l,3-dihydro-2H-imidazol-2-one. HC1 salt (enantiomer 1) (893 mg, 1 .576 mmol) and DIPEA ( 1 .370 mL, 7.879 mmol) in DMF (5 mL), the mixture was stirred at rt for 18 h under Ar. After the reaction was completed, water (50 mL) was added. Tire mixture was extracted with EA (50 mL X 3). The combined organic layers were washed with brine (50 mL X 3), dried over sodium sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (DCM / MeOH=50 / l), then purified by Cl 8 column chromatography (48% of MeCN in water, 0.1% FA) and C18 column chromatography (50% of MeCN in water, 0.1% NH4HCO3) to afford 3-((l S,2S)-l -(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro- lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH- indol-l-yl)-2 -methylcyclopropyl)-!, 2, 4-oxadiazol-5(4H)-one (enantiomer 1) (791 mg, 51.38%). LC-MS: m / z 960.9 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) 3 11.60 (brs, 1 H), 7.76-7.74 (m, 1 H), 7.59-7.53 (m, 2 H), 7.42 (d, .7=8.4 Hz, 1 H), 7.27-7.24 (dd, Ji=8.4 Hz, J2=1.6 Hz, 1 H), 7.16 (d, .7=6,4 Hz, 2 H), 7.01 (m, 1 H), 6.86 (m, 2 H), 5.56-5.54 (m, 1 H), 4.48-4.42 (m. 1 H), 3.75-3.72 (m. 2 H), 3.61-3.51 (m, 1 H). 2.90- 2.86 (m. 2 H). 2.63 (s. 3 H), 2.57 (s. 3 H), 2.25 (s. 6 H), 1.78-1.45 (m. 11 H), 1.31-1.26 (m, 5 H), 1.20- 1.12 (m, 7 H), 0.96-0.91 (m, 1 H), 0.87-0.82 (m, 1 H).

[0234] Step I 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH- indol-l-yl)-2-metlrylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 2) (Compound 196)

[0235] 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH- indol-l-yl)-2-mcthylcyclopropyl)-l,2,4-oxadiazol-5(4H)-onc (enantiomer 2) (Compound 196) were synthesized according to the procedures described for the preparation of Compound 195) (enantiomer 1) (step F to step H). LC-MS: m / z 960.8 (M+H)1. ’HNMR (400 MHz. DMSO-t / 6) 3 11.58 (brs, 1 H), 7.75 (m, 1 H), 7.64 - 7.53 (m, 2 H). 7.41 (d, .7= 8.4 Hz, 1 H), 7.26 (d, J= 8.8 Hz, 1 H), 7.16 (d, J= 6.0 Hz, 2 H), 7.01 (m, 1 H), 6.87 (m, 2 H), 5.57 (m, 1 H), 4.43 (m, 1 H), 3.74 (d, J= 8.8 Hz, 2 H), 3.58 (m, 1 H), 3.04 - 3.01 (m, 2 H), 2.90 - 2.86 (m, 2 H), 2.63 (s, 3 H), 2.56 (s, 3 H), 2.24 (s, 6 H), 1.72-1.63 (m, 4 H), 1.62 - 1.46 (m, 6 H), 1.29 (m, 4 H), 1.20 - 1.12 (m, 7 H), 0.94 - 0.81 (m, 2 H).Example A133-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4- [cyclopropyl(methylazanylidene)(oxo)-k6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl- ,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol- l-yl)-2-methylcyclopropyl]-5H,4H-l,2,4-oxadiazol-5-one (Compound 221) (enantiomer 1) and 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)- λ6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-5-yl]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-l-yl)-2-methylcyclopropyl]-5H,4H-l,2,4-oxadiazol-5-one (Compound 222) (enantiomer 2)

[0236] Step A 4-bromo-3 -fluorobenzene- 1 -thiolBr.1 'I

[0237] To a stirred solution 4-bromo-3-fluorobenzenesulfonyl chloride (3 g, 10.969 mmol) in toluene (30 mL) was added triphenylphosphane (1 1 .51 g, 43.876 mmol). The reaction mixture was stirred at room temperature for 40 minutes. TLC indicated completion of reaction. The reaction was diluted with water (15 mL) and stirred for 10 minutes. The two phases were separated, and the organic phase was washed with 10% sodium hydroxide solution (25 mL x 2). Tire combined sodium hydroxide solution phase was washed with toluene (50 mL), acidified with dilute HC1 to / >H 4~5, and extracted with CH2CI2 (40 mL x 2). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash column chromatography on silica gel(eluting with ethyl acetate in petroleum ether from 0 to 3%) to afford 4-bromo-3 -fluorobenzene- 1 -thiol (1.8 g, 79.3% yield).

[0238] Step B (4-bromo-3-fluorophenyl)(cyclopropyl)sulfane

[0239] To a solution of 4-bromo-3-fluoro-2-methylbenzene-l-thiol (1.0 g, 4.830 mmol) in DMSO (10 mL) were added potassium 2-methylpropan-2-olate (1.62 g, 14.489 mmol) and bromocyclopropane (3.095 mL, 38.636 mmol), the reaction was stirred at 100 °C for 18 h under N2. TLC showed the reaction was completed. The mixture was added to water (100 mL), extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluting 100% PE) to afford (4-bromo-3-fluorophenyl)(cyclopropyl)sulfane (1.4 g. 52.9% yield).

[0240] Step C (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-Z6-sulfanimine

[0241] To a solution of (4-bromo-3-fluorophenyl)(cyclopropyl)sulfane (6.4 g, 25.897 mmol) in MeOH (60 mL) was added (diacetoxyiodo)benzene (25.18 g, 77.692 mmol) and ammonium carbamate (8.09 g, 103.589 mmol). The reaction was stirred at room temperature for 1 h. After the reaction was completed, water (100 mL) was added. The mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (PE / EA=4 / 1) to afford (4-bromo-3- fluorophenyl)(cyclopropyl)(oxo)-λ6-sulfanimine (3.0 g, 41.6% yield). LC-MS: m / z 280.0 (M+H)+.

[0242] Step D (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-X<’-sulfanimine (enantiomer 1) 13-5aenantiomer 1

[0371] The compound mixture (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-Xb-sulfanimine (3.0 g. 4.00 mmol) was separated by SFC (Column: DAICELCHIRALCEL®AS 250 mm*25 mm, 10 pm, Mobilephase A (Supercritical CO2), Mobile phase B (MeOH (0.1% 7.0 M Ammonia in MeOH)), Gradient: B = 20%, Flow rate: 100 mL / min, Column temp.: 25 °C.) to afford (4-bromo-3- fluorophenyl)(cyclopropyl)(oxo)-Z6-sulfanimine (enantiomer 1) (1.34 g, 44.6% yield) as the fast eluent, LC-MS: m / z 280.0 (M+H)+and (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-λ6-sulfanimine (enantiomer 2) (1.36 g, 45.3% yield) as the slow eluent, LC-MS: m / z 280.0 (M+H)+.

[0243] Step E 2-methylpropan-2-yl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-( l-{4- [azanylidene(cyclopropyl)(oxo)-λ6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4, 5,6,7- tetrahydropyrazolo [4, 3 -c] pyridine -5 -carboxylate

[0244] To a solution of 2-methylpropan-2-yl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo- lH-imidazol-3-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (67 mg. 0.152 mmol) in NMP (10 mL) was added (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-Z6-sulfanimine (50.65 mg, 0.182 mmol), (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (32.32 mg, 0.228 mmol), Cui (57.80 mg, 0.304 mmol) and K2CO3 (41.94 mg, 0.304 mmol), the mixture was stirred at 130 °C for 3 h. After the reaction was completed, water (20 mL) was added. Tire mixture was extracted with EA (20 mL X 3). Tire combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (PE / EA=1 / 1) to afford 2-methylpropan-2-yl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-( l-{4-[azanylidene(cyclopropyl)(oxo)-Xb- sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (100 mg, 0.119 mmol, 78.4%) (1.10 g, 90% yield). LC-MS: m / z 639.5 (M+H)+.

[0245] Step F 2-methylpropan-2-yl (4S)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)-Z6-sulfanyl]-2- fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-2-(4-fluoro-3,5-dimetlrylphenyl)-4-methyl-4,5,6,7- tetrahydropyrazolo [4,3 -c] pyridine -5 -carboxylate

[0246] To a solution of 2-methylpropan-2-yl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4- [azanylidene(cyclopropyl)(oxo)-λ6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.078 mmol) in DMF (6 mL) was added NaH (3.76 mg, 0.157 mmol) at 0 °C, and the reaction was stirred at 0 °C for 1 h. CH3I (0.019 mL, 0.235 mmol) was added, the reaction was stirred at rt for 18 h. After the reaction was completed, water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). Hie combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep. TLC (MeOH / DCM=l / 20) to afford 2-methylpropan-2-yl (4S)-3- (l-{4-[cyclopropyl(methylazanylidene)(oxo)-λ6-sulfanyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)- 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (35 mg, 68.5% yield). LC-MS: m / z 653.4 (M+H)+.

[0247] Step G l-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-3 -yl] -3 - ' 4-| cyclopropyl (mcthylazany lidcnc )(o.\o)-λ6-sulfanyl] -2 -fluorophenyl } -2,3 -dihydro- lH-imidazol-2-one HC1 salt

[0248] To a solution of 2-methylpropan-2-yl (4S)-3-( l-{4-[cyclopropyl(methylazanylidene)(oxo)-Z6- sulfanyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.077 mmol) in dioxane (2 mL) was added HC1 in dioxane (4 mL). The reaction was stirred at 25 °C for 18 h. LCMS showed the reaction was completed. Tire reaction was concentrated under vacuum to give l-[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-{4-[cyclopropyl (methylazanylidene)(oxo)-Xb-sulfanyl] -2 -fluorophenyl} -2,3-dihydro- lH-imidazol-2-one HC1 salt (50 mg, 88.9%) as a yellow solid. LC-MS: m / z 553.2 (M+H)+.

[0249] Step H 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)-Z6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5 ,6,7-tetrahydropyrazolo [4,3 -c]pyridin-5 -yl]carbonyl } -5 -(3 ,4,5 ,6-tetrahydro-2H-pyran-4-yl)indol- 1 -yl)- 2-methylcyclopropyl]-5H,4H-l,2,4-oxadiazol-5-one (Compound 221) (enantiomer 1).

[0250] To a solution of l-[(4S)-2-(4-fluoro-3,5-dimcthylphcnyl)-4-mcthyl-4, 5,6,7- tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-{4-[cyclopropyl(methylazanylidene)(oxo)-λ6-sulfanyl]-2- fluorophenyl}-2,3-dihydro-lH-imidazol-2-one HC1 salt (42 mg. 0.076 mmol) and HATU (57.76 mg, 0.152 mmol) in N,N -dimethylmethanamide (8 mL) was added l-[(lS,2S)-2-methyl-l-(5-oxo-4H-L2,4- oxadiazol-3-yl)cyclopropyl]-5-(3, 4, 5, 6-tetrahydro-2H-pyran-4-yl)indole-2 -carboxylic acid (29. 14 mg, 0.076 mmol) and DIEA (49.02 mg, 0.380 mmol), the reaction was stirred at rt for 2 h. After the reaction was completed, water (20 mL) was added. The mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep. HPLC(Waters 2767 / Qda, Column: SunFire Sunfire C18, 19*250mm, 10 pm; Mobile Phase A: O. P / oFA / EEO, B: CH3CN ; flow rate: 20 mL / min; gradient: 72%~77%; Retention Time: 7.1-7.9 min of 17 min) to afford 3-[(lS,2S)-l-(2-{[(4S)-2-(4- fluoro-3 ,5 -dimethylphenyl)-3 -( 1 - { 4-| cyclopropy l(m ethy lazany lidenc)(oxo)-λ6-sulfany 11 -2 -fluorophenyl } - 2-oxoimidazol-3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}-5-(3,4,5,6- tetrahydro-2H-pyran-4-yl)indol-l-yl)-2-methylcyclopropyl]-5H,4H-L2,4-oxadiazol-5-one (11.4 mg, 16.2% yield). LC-MS: m / z 918.3 (M+H)+. ‘HNMR (400 MHz, DMSO-t / 6) d 11.60 (brs, 1 H), 7.77 - 7.71 (m, 3 H), 7.53 (s, 1 H), 7.44 (d, J= 8.4 Hz, 1 H), 7.28 (d, J= 9.2 Hz, 1 H), 7.16 (d, J= 6.0 Hz, 2 H), 7.05 (s, 1 H), 6.88 (s, 2 H), 5.58 (m, 1 H), 4.46 (m, 1 H), 4.00 - 3.97 (d, J= 10.8 Hz, 2 H), 3.58 - 3.46 (m, 3 H), 2.91 - 2.87 (m, 3 H), 2.80 - 2.77 (m, 1 H), 2.59 (s, 3 H), 2.25 (s, 6 H), 1.76 - 1.62 (m, 7 H), 1.46 (m, 3 H), 1.27 - 1.12 (m, 4 H), 1.10 - 1.08 (m, 1 H), 1.01 - 0.91 (m, 2 H)..

[0251] Step 1 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)-Z6-sulfanyl]-2-fluorophenyl}-2-oxoimidazol-3-yl)-4-methyl-4,5 ,6,7-tetrahydropyrazolo [4,3 -c]pyridin-5 -yl]carbonyl } -5 -(3 ,4,5 ,6-tetrahydro-2H-pyran-4-yl)indol- 1 -yl)-2-methylcyclopropyl]-5H,4H-l,2,4-oxadiazol-5-one (Compound 222) (enantiomer 2)

[0252] 3-[(lS,2S)-l-(2-{[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(l-{4-[cyclopropyl(methylazanylidene)(oxo)-Z6-sulfanyl]-2 -fluorophenyl }-2-oxoimidazol-3-yl)-4-methyl-4,5 ,6, 7 -tetrahydropyrazolo [4,3 -c]pyridin-5 -yl]carbonyl } -5 -(3 ,4,5 ,6-tetrahydro-2H-pyran-4-yl)indol- 1 -y 1)- 2-methylcyclopropyl]-5H.4H-1.2.4-oxadiazol-5-one (Compound 222) (enantiomer 2) were synthesized according to the procedures described for the preparation of Compound 221) (enantiomer 1) (step E to step H). LC-MS: m / z 918.3 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) 3 11.59 (brs, 1 H), 7.78 - 7.75 (m, 3 H), 7.53 (s, 1 H), 7.44 (d, J= 8.4 Hz, 1 H), 7.28 (d, J= 8.8 Hz, 1 H), 7.16 (d, J= 6.4 Hz, 2 H), 7.05 (s, 1 H), 6.88 (s, 2 H), 5.58 (m, 1 H), 4.48 (m, 1 H), 4.00 - 3.97 (m, 2 H), 3.59 - 3.46 (m, 3 H), 2.91 - 2.87 (m, 2 H), 2.80 - 2.77 (m, 1 H). 2.60 (s. 3 H). 2.25 (s. 6 H), 1.76 - 1.72 (m, 6 H), 1.64 (m, 1 H). 1.46 (m, 3 H), 1.27 - 1.08 (m, 6 H). 1.01 - 0.91 (m. 2 H).

[0253] Example compound 164 was synthesized using a similar procedure described in the Example A13 above using the appropriate materials.Example A263-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-(methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2- oxo-2, 3-dihydr o- IH-imidazol- l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-py razolo [4,3-c] pyridine-5- carbonyl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 1)8-1 8-2

[0254] To a solution of 4-bromo-2, 3 -difluoroaniline (1000 mg, 4.807 mmol) in con. HCI (25 mL) was added sodium nitrite (398. mg, 5.769 mmol) at 0 °C. The mixture was stirred at room temperature for 5 min. To the mixture was added potassium ethylxanthate (1926.47 mg, 12.019 mmol) at 0 °C. The mixture was stirred for 20 min at 0 °C. The mixture was diluted with water (30 mL), extracted with EA (3x30 mL). The combined EA layers were washed with brine (3x 10 mL), dried over NazSCL. filtered and concentrated. Tire residue was purified by flash column chromatography, eluting with PE / EA (100: 1) to afford the intermediate. The intermediate was dissolved with EtOH (10 mL). To the solution was added KOH (1348.73 mg, 24.037 mmol). The mixture was stirred for another 10 min at 75 °C. The mixture was concentrated. The residue was diluted with water (20 mL), extracted with DCM (3x 10 mL). The aqueous layer was adjusted to pH 1-2 with HCI (aq.), extracted with EA (3x20 mL). Tire combined organic layers were washed with brine (3x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with DCM / MeOH (20 / 1) to afford 4-bromo-2,3-difluorobenzenethiol (500 mg, 46.21%).1H NMR (400 MHz, CDCh) <)' 7.22-7.18 (m, 1H), 6.97-6.93 (m,lH), 3.68 (s, 1H).

[0255] Step B (4-bromo-2,3-difluorophenyl)(cyclopropyl)sulfane

[0256] To a solution of 4-bromo-2, 3 -difluorobenzenethiol (500 mg, 2.222 mmol) and cyclopropylboranediol (286.27 mg, 3.333 mmol) in DCE (10 mL) were added 2-(pyridin-2-yl)pyridine (347.01 mg. 2.222 mmol), cupric bis(acetate) (403.53 mg. 2.222 mmol) and CS2CO3 (723.88 mg, 2.222 mmol). The reaction mixture was sealed up and stirred at 70 °C for 16 hrs under O2. The reaction mixture was filtered and the filtrate was concentrated. Tire residue was purified by flash column chromatography, eluting with PE / EA (100 / 1) to afford (4-bromo-2,3-difluorophenyl)(cyclopropyl)sulfane (150 mg, 25.47%).]H NMR (400 MHz, CDCh) 67.31-7.24 (m, 1H), 7.17-7.13 (m, 1H), 2.20-2.15 (m, 1H), 1.11- 1.06 (m, 2H), 0.73-0.69 (m, 2H).

[0257] Step C (4-bromo-2,3-difluorophenyl)(cyclopropyl)(imino)- λ6-sulfanonc

[0258] To a solution of (4-bromo-2,3-difluorophenyl)(cyclopropyl)sulfane (400 mg, 1.509 mmol) in methanol (500 mL) were added ammonium aminomethanoate (235.58 mg, 3.018 mmol) and 1- [(acetoxyphenyl-X3-iodanyl)oxy]ethan-l-one (1222.50 mg, 3.772 mmol). Tire reaction mixture was stirred for 1 hr at room temperature. Tire mixture was concentrated and the residue was purified by flash column chromatography, eluting with PE / EA (2 / 1) to afford (4-bromo-2,3- difluorophenyl)(cyclopropyl)(imino)- λ6-sulfanonc (300 mg, 67.15%). LC-MS: m / z 296.0 (M+H)+.

[0259] Step D (4-bromo-2,3-difluorophenyl)(cyclopropyl)(methylimino)- Z '-sulfanonc

[0260] To a solution of (4-bromo-2,3-difluorophcnyl)(cyclopropyl)(imino)- λ6-sulfanonc (280 mg, 0.946 mmol) in dry dioxane (3 mL) were added cupric bis(acetate) (515.21 mg, 2.837 mmol), pyridine(0.306 mL, 3.782 mmol) and methylboronic acid (808.56 mg, 13.508 mmol). The reaction mixture was sealed up and stirred at 100 °C for 2 hrs under O2. The mixture was filtered and the filtrate was concentrated in vacuum. The resulting residue was purified by silica gel chromatography (eluting PE / EA=1 / 1) to afford (4-bromo-2,3-difluorophenyl)(cyclopropyl)(methylimino)- / / -sulfanonc (200 mg, 68.20%). LC-MS: m / z 309.9 (M+H)+.

[0261] Step E (4-bromo-3-fluoro-2-(niethylaniino)phenyl)(cyclopropyl)(methylimino)-λ6-sulfanone

[0262] To a solution of (4-bromo-2,3-difluorophenyl)(cyclopropyl)(methylimino)- / .' -sulfanonc (200 mg, 0.645 mmol) in THF (3 mb) was added methylamine in THF (2 mol / L, 5 mL). Tire reaction mixture was sealed up and stirred at 70 °C for 16 hrs under N2. To the mixture was added water (30 mL), extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SC>4. filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography, eluting with PE / EA (3 / 1) to afford (4-bromo-3-fluoro-2- (methylamino)phenyl)(cyclopropyl)(methylimino)-λ6-sulfanone (200 mg, 96.56%). LC-MS: m / z 320.7 (M+H)+.

[0263] Step F (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)-λ6-sulfanone(enantiomer 1) and (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)-Xb-sulfanone(enantiomer 2)8-1 8-2

[0264] (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)-λ6-sulfanone (200 mg) was separated by SFC (Column: DAICELCHIRALPAK®AY; Column size: 250 mm* 40 mm, 10 pm; Mobile Phase A: Supercritical CO2; Mobile Phase B: EtOH (0. 1% 7.0 M Ammonia in MeOH); Gradient: B = 15%). Flow rate: 140 mL / min, Column temp.: 25 °C) to afford (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)- L’-sulfanonc (enantiomer 1) (100 mg. 99% ee, 50%) as a colorless oil as the fast eluent, R.T=2.19 min. LC-MS: m / z 320.7 (M+H)+. And (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)- λ6-sulfanonc (enantiomer 2) (90 mg, 45%) as the slow eluent, R.T=3.23 min. LC-MS: m / z 320.7 (M+H)+.

[0265] Step G tert-butyl (4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-(3-(2-fhioro-3-(methylamino)-4-(N- methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1)

[0266] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (106 mg. 0.240 mmol) in NMP (2.4 mb) were added copper(1+)iodide (54.87 mg, 0.288 mmol), potassium carbonate (66.36 mg, 0.480 mmol), (4-bromo-3-fluoro-2-(methylamino)phenyl)(cyclopropyl)(methylimino)- / .' -sulfanonc (enantiomer 1) (100 mg, 0.310 mmol) and methyl[(lR,2R)-2-(methylamino)cyclohexyl]amine (34.15 mg, 0.240 mmol), and the reaction mixture was stirred at 130 °C for 4 hrs under N2. The mixture was poured into water (15 mL), extracted with EA (20 mL x 3), washed with brine (20 mL x 3). The organic layer was dried and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1) to afford tert-butyl (4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-(3-(2-fluoro-3- (methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4- methyl-2,4,6,7-tetralrydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (enantiomer 1) (155 mg, 85.2%). LC-MS: m / z 682.4 (M+H)+.

[0267] Step H l-((S)-2-(4-fhioro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2EI-pyrazolo[4,3- c]pyridin-3-yl)-3-(2-fluoro-3-(methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-l,3- dihydro-2H-imidazol-2-one. hydrochloride salt (enantiomer 1)

[0268] A solution of tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-3-(methylamino)- 4-(N-niethylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-diliydro-lH-imidazol-l-yl)-4-metliyl-2,4,6,7- tetrahydro-5H-pyrazolo[4.3-c]pyridine-5-carboxylate (enantiomer 1) (155 mg, 0.227 mmol) in HCl / dioxane (4 mol / L, 10 mL) was stirred at rt for 2 hrs. The residue was concentrated in vacuum to afford l-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3- yl)-3-(2-fhioro-3-(methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-l,3-dihydro-2H- imidazol-2-one, hydrochloride salt (enantiomer 1) (130 mg, 88.48%) which was used in the next step without further purification. LC-MS: m / z 582.4 (M+H-HC1)+.

[0269] Step I 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-(3-(2-fluoro-3-(methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4.3-c]pyridine-5-carbonyl)-lH- indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (enantiomer 1) (Compound 238)

[0270] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2-carboxylic acid (30 mg. 0.073 mmol) in DMA (2 mL) were added DIPEA (56.54 mg, 0.437 mmol), HATU (33.27 mg, 0.087 mmol) and tire mixture was stirred at room temperature for 30 min. l-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2-fluoro-3-(methylamino)-4-(N-methylcyclopropanesulfonimidoyl)phenyl)-L3-dihydro-2H-imidazol-2-one, hydrochloride salt (enantiomer 1) (42.41 mg, 0.073 mmol) was added and the reaction mixture was further stirred at room temperature for 16 hrs. The reaction mixture was diluted with EA (50 mL) and washed with saturated NaCl solution (20 mL x 3). Tire organic layer was concentrated in vacuum and the crude was purified by prep-HPLC (FA) to afford 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-3-(methylamino)-4-(N- methylcyclopropanesulfonimidoyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l-yl)-2 -methylcyclopropyl)-!, 2, 4- oxadiazol-5(4H)-one (enantiomer 1) (40 mg, 56.26%).

[0271] LC-MS: m / z 488.4 (1 / 2M+H)+. H NMR (400 MHz, DMSO-ri.) 5 11.58 (s, 1H), 7.52 (s, 1H), 7.48-7.37 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.29-7.21 (m, 2H), 7.03-6.66 (m, 5H), 5.54 (s, 1H), 4.44 (s, 1H), 3.79-3.68 (d, J = 7.2 Hz, 2H), 3.56 (s, 1H), 3.18-3.05 (m, 5H), 2.93-2.77 (m, 2H), 2.64 (s, 3H), 2.30- 2.20 (d, J = 1.6 Hz, 6H). 1.90-1.38 (m, 10H), 1.33-1.05 (m, 11H), 0.98- 0.81 (m, 2H).19F NMR (376 MHz, DMSO-de) 5 -122.13. -136.34.

[0272] The following molecules were synthesized using a similar procedure described in the Examples above using the appropriate starting material. SFC Separation conditions for certain intermediates is as follows. For compound 214, the sulfoximine intermediate were separated as follows: SFC separation (Column: Chiral Whelk - 01 (S,S) 250 mm*30 mm, 5 pm, Mobile phase A (Supercritical CO2), Mobile phase B (EtOH (0.1% NH3H2O in EtOH)), Gradient: B = 40%). Flow rate: 50 mL / min, Column temp.: 25 °C.Biological AssaysAnimals and diet

[0273] C57BL / 6J male mice were purchased from SMOC. Mice were group housed and fed a high-fat, high-sugar diet. Mice were maintained on this diet for 25-26 weeks prior to initializing the pharmacology studies. Mice were exposed to a controlled 12 h: 12 h light: dark cycle at ambient room temperature (22 °C) with ab libitum access to food and water. DIO mice were distributed into groups (n = 14 per group) such that statistical variations in the mean and standard deviations of fat mass and body weight were minimized between groups. The animals were grouped to receive treatment as follows: vehicle, tirzepatide. Compound B, Compound C-l, Compound B + tirzepatide, and Compound C-l + tirzepatide. Tirzepatide was administered by daily subQ dosing. Compound B and Compound C-l were administered by daily oral gavage.Body weight and food intake

[0274] Body weight (BW) and food intake were measured 3 times per week. The percent change in body was calculated individually for each mouse based on initial body weight prior to the first injection.Results

[0275] Fig. 1. Fig, 2, Fig. 3. and Fig. 4 show the efficacy of Compound B, Compound B + tirzepatide (TZP), azelaprag (AMG-986). azelaprag (AMG-986) + tirzepatide (TZP). and tirzepatide alone. Compound B + tirzepatide (TZP) led to additional weight loss and fat content decrease as compared to tirzepatide alone.

[0276] Compound B is G-protein biased APJ agonist with limited efficacy on receptor internalization. While azelaprag (AMG-986) is a non-biased APJ agonist with similar potency on both receptor internalization and cAMP pathway.

[0277] Both Compound B and Bioage molecule azelaprag (AMG-986) could amplify Tirzepatide efficacy on body weight loss in DIO model.

[0278] For in-vivo efficacy, Compound B required lower drug exposure than azelaprag (AMG-986). This is not consistent with in-vitro cAMP potency. Compound B demonstrated similar or better than bioage molecule azelaprag (AMG-986). Compound B required lower in-vivo drug exposure for efficacy, though azelaprag (AMG-986) is much more potent than Compound B in in-vitro cAMP assay.

[0279] Assay description: APJ-cAMP agonist assay, APJ-arrestin assay and APJ active internalization assay arc all performed in Eurofins Discovery X.

[0280] The ECso of Compound A and Compound B in APJ-cAMP assay was determined using DiscoverX Hunter® cAMP assays. Apelin / APJ mediates Gi signaling pathway. Therefore, for the agonism assay fonnat. ECso Forskolin is used to induce the cAMP response. The procedure was performed as follows: media was aspirated from cells and replaced with 10 uM HBSS / 10 mM HEPES. Then the compound was added to the cells, together witlr Forsolin, and incubated at 37°C for 30 minutes. cAMP signal is determined using DiscoverX Hunter® cAMP method.

[0281] The efficacy of the test compounds on arrestin recruitment was monitored by DiscoverX PathHunter® |3-Arrestin assay, and the efficacy of the test compounds on active internalization of APJ receptor with PathHunter® Activated GPCR. Internalization assays that could quantitative measurement of arrestin-mediated GPCR internalization.

[0282] Compound A has been shown to suppress cAMP production through activation of a G-protein- mediated signaling without significant activation of the B-arrestin pathway in order to avoid APJ internalization, and thereby potentially avoid any desensitization effects of an unbiased APJR agonist. As shown below, apelin peptide and clinically tested and clinically tested competitor compounds including azelaprag (AMG-986) and BMS-986224 are all non-biased APJR agonists in these invitro studies, with low B-arrestin / cAMP and intemalization / cAMP ratios. In contrast, Compound A and Compound B exhibit APJR biased agonism with much higher B-arrestin / cAMP and intemalization / cAMP ratios than apelin peptide and the test compounds shown below.Camp Assays

[0283] Activation of GLP-1 receptor is known to stimulate cyclic AMP (cAMP) production in cells which indicates primary coupling to the G as subunit of the G protein heterotrimeric complex. Evidence suggests signaling through G as induced cAMP stimulation elicits the desired pharmacological response regarding insulin release from pancreatic 0-cells.

[0284] To optimize functional activity directed toward G as coupling, a HEK293 / CRE-Luc cell line developed by HDB stably expressing the GLP-1 Receptor was used. 200* concentration of compound working solutions were prepared (Agilent Technologies Bravo) with 1 / 2 log serial dilution in 384-well Echo LDV plate (Labcyte, Cat#LP-0200). 50 nL / well 200x concentration of compound working solutions were moved to 384-well white low volume plate (Greiner, Cat#784075) using Labcyte ECHO550. 1 x 10 5 cells / mL HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspensions prepared with assay buffer (DPBS containing 0.5 mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)), 10 uL cell suspensions were added to each well of previous generated assay plate which already contains 50 nL compound at 200 x concentration using ThermoFisher Multidrop Combi (1000 cells / well). Seal the plate and incubate at 37 °C with 5% CCL for 30 min.

[0285] After incubation the cAMP assay signal was generated using cAMP dynamic 2 Kit (Cisbio). 5pL cAMP-d2 working solution was added to each well, followed with 5pL Anti -cAMP antibody - cryptate working solution added to each well using ThermoFisher Multidrop Combi. Incubate at room temperature for 1 hour protected from light. Read the fluorescence at 665 and 615 nm with Reader PerkinElmer EnVision.%Activity = 100% x (mean RLU of test sample -mean RLU of vehicle control) / (mean RLU of MAX control -mean RLU of vehicle control)

[0286] Table 3 shows tire biological activity of compounds in GLP-1R agonist cAMP stimulation assay (ECso, nM).Table 3

Claims

CLAIMS:

1. A method for inducing weight loss, maintaining body weight, maintaining muscle mass, treating obesity, inducing fat loss, and / or reducing fat mass while retaining muscle mass, comprising administering to a subject in need thereof an effective amount of Compound A or Compound B:Compound A Compound B or a pharmaceutically acceptable salt thereof; in conjunction with an effective amount of an glucagon-like peptide-1 (GLP-1) receptor modulator.

2. The method of claim 1, wherein the GLP-1 receptor modulator is a GLP-1 receptor agonist.

3. Tire method of claim 1, wherein the GLP-1 receptor modulator is a GLP-l / GIP dual receptor agonist.

4. Tire method of any preceding claim, wherein the GLP-1 receptor modulator is administered to the subject daily, every other day, every two days, even three days, once weekly, twice weeks, once every two weeks, or monthly.

5. The method of any preceding claim, w herein the Compound A or Compound B, or a pharmaceutically acceptable salt thereof, is administered to the subject daily, every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, or monthly.

6. The method of any preceding claim, wherein the Compound A or Compound B, or a pharmaceutically acceptable salt thereof, is administered to the subject for a period of time prior to administering the GLP-1 receptor modulator.

7. The method of any preceding claim, wherein the Compound A or Compound B, or a pharmaceutically acceptable salt thereof, is administered to the subject for a period time prior to administering the GLP-1 receptor modulator.

8. The method of any preceding claim, wherein the Compound A or Compound B, or a pharmaceutically acceptable salt thereof, is administered to the subject at substantially the same time as the GLP-1 receptor modulator.

9. The method of any preceding claim, wherein the Compound A or Compound B, or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with the GLP-1 receptor modulator.

10. The method of any one of claims 1-9, wherein Compound A is administered to the subject.

11. The method of any one of claims 1-9, wherein Compound B is administered to the subject.

12. The method of any one of claims 1-9. wherein the GLP-1 receptor modulator is selected from: tirzepatide (Mounjaro®, Zepbound®), exenatide (Byetta®, Bydureon®, Exendin-4), lixisenatide (Lyxumia®), liraglutide (Victoza®, NN2211), dulaglutide (LY2189265, Trulicity®), albiglutide (Tanzeum®), semaglutide (Wegovy®, Rybelsus®, Ozempic®), retatrutide (LY3437943), mazdutide (LY3305677), efpeglenatide (HM11260C), taspoglutide (R1583, BIM51077, ITM077), survodutide (BI456906). cotadutide (MEDI0382), pemvidutide (ALT-801), efmopegdutide (MK-6024), efocipegtrutide (HM15211). pegloxenatide (PEX168). pegapamodutide (LY2944876), albenatide (CJC1134PC), utreglutide (GL0034), ZP2929, NNC0113-0987, BPI-3016, TT401, SAR441255, BL 456906, ALT-801, AC-3174, SAR-425899, HM-15211, YH-25723, YH-25724, YH-22241, YH-GLP1, RPC-8844, PB-718, NN-6177, CT-388, CT-868, XW003, XW004, CJC-1134, CJC-1131, AMG133, DD- 01, DD-03, DD-14 , DD-15, ID110521156, TERN-601, MDR-0001, HPG5119, ECC5004, VK2735, orforglipron (LY3502970), danuglipron (PF06882961), lotiglipron (PF07081532), CT-996, HRS-7535, V-0219, XW014, PF-0688296L LSN3318839, and TTP273.

13. The method of any one of claims 1-9, wherein the GLP-1 modulator is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:Q2is N or CRQA;RQBis -S(O)(NRa)Rbor -P(O)Ra’Rb';Rais hydrogen, cyano, C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from the group consisting of halo, oxo, C1-6alkoxy, C3-6cycloalkyl, and heteroaryl, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl;Rbis C1-6alkyl which is optionally substituted with 1-6 substituents each independently selected from tire group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo, C3-6cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo, or C6-10aryl optionally substituted with 1-3 independently selected C1-3alkyl: or Raand Rbtaken together with the atoms to which each is attached form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-3 independently selected Ci.6alkyl;Ra’ and Rb’ are independently selected from the group consisting of C1-6alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of C1-6alkoxy, C3-6cycloalkyl, and halo; C3-6cycloalkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of C1-3alkyl and halo; and C6-10aryl optionally substituted with from 1-3 independently selected C1-3alkyl; orRa’ and Rb’ taken together with the phosphorous atom to which each is attached forms a ring including from 5-8 ring atoms, wherein from 0-2 ring atoms (in addition to the phosphorous attached to Raand Rb) are heteroatoms each independently selected from the group consisting of: O, S, and N, wherein the ring is optionally substituted with from 1-3 independently selected C1-6alkyl; each RQAis independently hydrogen, halo, cyano, hydroxy, -NRcRd, -C(O)NRcRd, -S(0)0-2Re, C1-6alkyl optionally substituted with 1-6 independently selected R1, C1-6alkoxy optionally substituted with 1-6 substituents each independently selected from the group consisting of hydroxy, halo, and C1-6alkoxy, 3-12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C« alkyl and -C(O)(C1-6alkyl), C6-10aryl optionally substituted with 1-3 independently selected -C(O)(C1-6alkyl), and 5-10 membered heteroaryl optionally substituted with 1-6 independently selected Rg: or Raor Rband an adjacent RQAare taken together with the atom to which each is attached to form a 5-8 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 independently selected Rh; q is 0, 1 , 2, 3, 4, or 5;R3is hydrogen or C1-6alkyl optionally substituted with 1-6 substituents independently selected from the group consisting of halo, hydroxy, and C1-6alkoxy;membered heteroaryl optionally substituted with 1-3 independently selected R9c, 4-6 membered heterocyclyl optionally substituted with 1-3 independently selectedX1is 0 or S;each R9cis independently hydrogen, oxo, C1-6alkyl optionally substituted with 1-6 independently selected halo and C1-6alkoxy, or -C(O)(C1-6alkyl); v is 0, 1, 2, or 3; each RCais independently halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or NRcRd; or a pair of RCaon the same or different ring atoms, taken together with the ring atom(s) to which each is attached, forms a carbocyclic ring including 3-8 ring atoms; each Rcand Rdare each independently hydrogen, C1.6 alkyl, -C(O)(Ci 6 alkyl),the group consisting of hydroxy, halo, and C1-6alkoxy; each Reis independently hydrogen, C1-6alkyl, or C1-6haloalkyl; w is 0, 1, 2, or 3; each Rlfis independently C1-6alkyl, wherein each C1-6alkyl is independently optionally substituted with 1-6 independently selected Rf; each Rfis independently halo, hydroxy, -NRcRd, C1-6alkoxy, C1-6haloalkoxy, or 3-12 membered heterocyclyl which is optionally substituted with 1-4 substituents each independently selected from the group consisting of hydroxy, C1-6alkyl, and 3-12 membered heterocyclyl;each R8is independently C1-6alkyl, Ci.s alkoxy, -NRcRd, or 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C1-6alkyl and -C(O)C1-6alkyl; and each Rhis independently halo, cyano, hydroxy, C1-6alkyl, C1-6haloalkyl, -NH2, -NH(CI-3 alkyl), -N(CI-3 alkyl)2, C1-3alkoxy, or C 1.3 haloalkoxy.

14. The method of any one of claims 1-9, wherein the GLP-1 modulator is selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.

15. A pharmaceutical composition comprising Compound A or Compound B, or a pharmaceutically acceptable salt thereof, and a GLP-1 receptor modulator.

16. A fixed dose oral formulation comprising Compound A or Compound B, or a pharmaceutically acceptable salt thereof, and a GLP-1 receptor agonist.

17. Tire pharmaceutical composition of claim 15 or the fixed dose oral formulation of claim 16, further comprising a GIP receptor agonist.

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