Indole amide and related compounds and their use in treating medical conditions

Abstract

The invention provides indole amide and related compounds, pharmaceutical compositions, and their use in treating medical conditions.

Description

INDOLE AMIDE AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional PatentApplication serial number 63 / 610,803 filed December 15, 2023, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION

[0002] The invention provides indole amide and related compounds, pharmaceuticalcompositions, and their use in treating medical conditions. BACKGROUND

[0003] ATP-binding cassette (ABC) transporters are a large, phylogenetically conserved genefamily with broad physiological and pathological relevance.[1,2] They are expressed throughout the body and transport a diverse range of substrates across lipid membranes. ABC transporters are transmembrane, ATP-binding proteins that use the energy released during ATP hydrolysis to move substrates from one side of a lipid membrane to the other.[2,3]

[0004] At least 21 ABC transporters underly rare monogenic disorders with even moreimplicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery. Based on a handful of characterized disorders, including cystic fibrosis (CF), progressive familial intrahepatic cholestasis 2 (PFIC2), and Stargardt disease (STGD), there is a mechanistic commonality to pathogenic ABC transporter missense mutations, principally their impact on protein folding leading to endoplasmic reticulum (ER) degradation (trafficking defects), or protein function, leading to decreased substrate transport (transport defects). Importantly, small molecule compounds may enable treatment of disease symptoms not directly caused by mutations in ABC transporter genes.

[0005] There is a need for small molecule compounds that can positively modulate ABCtransporter function and therefore be used for the treatment of diseases in which such enhancement is predicted to be of therapeutic value, either in modifying disease or in treating disease symptomology. For example, there is a need for modulators that can address mutations in ABCB11, ABCB4, ABCC6, ABCA4, ABCD1, ABCA1 and ABCA7 for the treatment of PFIC2, PFIC3, PXE / GACI, STGD, X-ALD and Alzheimer’s disease, respectively.

[0006] Accordingly, the need exists for new therapeutic methods and compounds for treatingABC transporter dysfunction. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY

[0007] The invention provides indole amide and related compounds, pharmaceuticalcompositions, and their use in treating medical conditions. In particular, one aspect of the invention provides a collection of indole amide compounds, such as a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of indole amide compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0008] Another aspect of the invention provides a method of treating ABC transporterdysfunction. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the ABC transporter dysfunction, as further described in the detailed description. DETAILED DESCRIPTION

[0009] The invention provides indole amide and related compounds, pharmaceuticalcompositions, and their use in treating medical conditions. The practice of the present inventionemploys, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0010] Various aspects of the invention are set forth below in sections; however, aspects of theinvention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions

[0011] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0012] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groupscontain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0013] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclicring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:.

[0015] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary loweralkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that issubstituted with one or more halogen atoms.

[0017] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternizedform of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0018] The term “unsaturated,” as used herein, means that a moiety has one or more units ofunsaturation.

[0019] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight orbranched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0020] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is apolymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-”encompasses a bond (i.e., C0) and a -(C1-3alkylene)- group.

[0022] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chainis a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0023] The terms “halo” and “halogen” mean F, Cl, Br, or I.

[0024] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of openvalences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached to it (e.g.,when it has three groups attached taryl group.

[0025] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0026] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriatenumber of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atomthat results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.

[0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0030] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Each optional substituent on a substitutable carbon is a monovalent substituentindependently selected from halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR^2;-C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; –S(O)(NR^)R^; – S(O)2N=C(NR^2)2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; – C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4straight or branched alkylene)O–N(R^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R^)2.

[0032] Each R^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R^ selected from =O and =S; or each R^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, – (CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^.

[0033] Each R^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or – S(C(R*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionallysubstituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selectedfrom hydrogen, C1–6aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] When R* is C1–6 aliphatic, R* is optionally substituted with halogen, –R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0035] An optional substituent on a substitutable nitrogen is independently –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, twoindependent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R†is C1–6aliphatic, R†is optionally substituted with halogen, –R^, -(haloR^), -OH, –OR^, – O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0037] Further, acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould. International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal,ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0039] Unless otherwise stated, structures depicted herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with anappropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0041] Individual stereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0042] Chemical names, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0043] The terms “a” and “an” as used herein mean “one or more” and include the plural unlessthe context is inappropriate.

[0044] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as astraight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and C1-C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0045] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridgedcyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0046] The term “haloalkyl” refers to an alkyl group that is substituted with at least onehalogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0047] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least onehydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0048] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphaticgroups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0049] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, asdefined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0050] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, acyclopentane substituted with an oxo group is cyclopentanone.

[0051] The symbol “ ” indicates a point of attachment.

[0052] When any substituent or variable occurs more than one time in any constituent or thecompound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0053] One or more compounds of the invention may exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it isintended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0054] As used herein, the terms “subject” and “patient” are used interchangeable and refer toorganisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0055] The term “IC50” is art-recognized and refers to the concentration of a compound that isrequired to achieve 50% inhibition of the target.

[0056] The term “EC50” is art recognized and refers to the concentration of a compound that isrequired to achieve a response that is 50% of the maximum target effect relative to the baseline.

[0057] The term “Emax” is art recognized and refers to the concentration of a compound that isrequired to achieve maximal target effect.

[0058] As used herein, the term “effective amount” refers to the amount of a compoundsufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0059] As used herein, the term “pharmaceutical composition” refers to the combination of anactive agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0060] As used herein, the term “pharmaceutically acceptable carrier” refers to any of thestandard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0061] For therapeutic use, salts of the compounds of the present invention are contemplated asbeing pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0062] In addition, when a compound of the invention contains both a basic moiety (such as,but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0063] Throughout the description, where compositions are described as having, including, orcomprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0064] As a general matter, compositions specifying a percentage are by weight unlessotherwise specified. I. Indole Amide Compounds

[0065] One aspect of the invention provides indole amide compounds. The compounds may beused in the pharmaceutical compositions and therapeutic methods described herein. Exemplarycompounds are described in the following sections, along with exemplary procedures for making the compounds. One aspect of the invention provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein: A1is a bicyclic group selected from ,X1is one of the following: (i) -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7);(ii) -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isochromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2- c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro- 2H-pyrano[2,3-c]pyridinyl substituted by p occurrences of R7); -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,8-dihydro-6H- pyrano[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (2,3-dihydrofuro[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(benzo[d]oxazol-2(3H)-one substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted by p occurrences of R7); (iii) -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7), or -N(R4)- [C(R5)(R6)]m-(pyrimidinyl substituted by p occurrences of R7); (iv), , , each of which is substituted by phenyl substituted with p occurrences of R7;(v) -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7); -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H- cyclopenta[c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (isoindolinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3H- imidazo[4,5-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (1H-pyrazolo[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1H-pyrazolo[3,4-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-indenyl substituted by p occurrences ofR7), -N(R4)-[C(R5)(R6)]m-(indolin-2-one substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(isoindolin-1-one substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3H-imidazo[4,5-c]pyridine substituted by p occurrences of R7), or - N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[4,3-c]pyridine substituted by p occurrences of R7); (vi) -N(R4)-[C(R5)(R6)]m-(imidazo[2,1-b]thiazolyl substituted by p occurrences of R7); (vii) -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-benzo[c][1,2]thiazinyl 2,2-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3- dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[b]thiophene 1,1-dioxide substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,3- dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted by p occurrences of R7); (viii) -N(R4)-[C(R5)(R6)]m-(quinazolin-4(3H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydroquinolin-2(1H)-onyl substituted by p occurrencesof R7), -N(R4)-[C(R5)(R6)]m-(1,4-dihydroisoquinolin-3(2H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoquinolin-1(2H)-onyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,2,3,4-tetrahydroisoquinoline substituted by p occurrences of R7); or (ix) -N(R4)-[C(R5)(R6)]m-(bicyclo[1.1.1]pentanyl substituted by p occurrences of R7); R1is C1-4 alkyl or hydrogen; R2represents independently for each occurrence hydrogen; halo; C1-4alkyl; -S(O)2R8; cyano; C1-4 alkoxyl, hydroxyl, C1-4 haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R2Brepresents independently for each occurrence C1-3 alkyl or halo; R3is hydrogen; fluoro; C1-4alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R4is hydrogen, C1-4 alkyl, -C(O)(C1-4 alkyl), or -S(O)2(C1-4 alkyl); R5and R6each represent independently for each occurrence hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, -C1-3alkylene-N(R8)2, -(C1-6aliphatic substituted by R8), or - (CH2)0-3-O-(CH2)0-3-CH3; or R5and R6are taken together to form a C3-5 saturated carbocyclic ring; R7represents independently for each occurrence C1-6alkyl, halo, cyano, hydroxyl, - C(O)N(R8)2, -N(R8)C(O)-R8, -C(O)-R8, -(C1-6 aliphatic substituted by R8), C1-6 alkoxyl, C3-6 cycloalkyl, -S(O)2N(R8)2, -S(O)2R8, -N(R8)S(O)2R8, C1-3 alkylene-C(O)N(R8)2, -S(O)(NH)R8, C3-6cycloalkyl, -C(O)N(R8)(C3-6cycloalkyl), -C(O)O-C1-3alkyl, C1-3haloalkyl, -NH(R8), - C(NH)NH(R8), -O-(C3-6 cycloalkyl), or a 5–6 membered monocyclic heteroaromatic ringcontaining 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring is substituted with s occurrences of R7B; R7Brepresents independently for each occurrence C1-3 alkyl, halo, hydroxyl, or C3-6 cycloalkyl; R8represents independently for each occurrence hydrogen, C1-6 aliphatic, hydroxyl, - NH2, -S(O)2CH3, C3-6 cycloalkyl, cyano, phenyl, C1-4 haloalkyl, C1-6 alkoxyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R9is hydrogen, chloro, fluoro or C1-3alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3; q and s are independently 0, 1, 2, or 3; t is 0, 1, 2, or 3; and u is 1 or 2.

[0066] The definitions of variables in Formula I above encompass multiple chemical groups.The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0067] In certain embodiments, the compound is a compound of Formula I.

[0068] As generally described above, A1 is a bicyclic group selected from

[0069] In certain embodiments, certa 1in embodiments, A iscertain embodiments,certain embodiments,embodiments, A1isIn certain embodiments, A1iscertain embodiments, A1is. In certain embodiments, A1is. In certain embodiments, A1is. In certain embodiments, A1is rtain embodiments,certain embodiments, A1i rtain embodiments, 1certain embodiments, Ai certain embodiments,. ertain embodiments,certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0070] As generally described above, X1 is one of the following:(i) -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7); (ii) -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isochromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2- c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro- 2H-pyrano[2,3-c]pyridinyl substituted by p occurrences of R7); -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,8-dihydro-6H- pyrano[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (2,3-dihydrofuro[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(benzo[d]oxazol-2(3H)-one substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted by p occurrences of R7);(iii) -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7), or -N(R4)- [C(R5)(R6)]m-(pyrimidinyl substituted by p occurrences of R7); (each of which is substituted by phenyl substituted with p occurrences of R7; (v) -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7); -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H- cyclopenta[c]pyridinyl substituted by p occurrences of R7, -N(R4)-[C(R5)(R6)]m- (isoindolinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3H- imidazo[4,5-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (1H-pyrazolo[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1H-pyrazolo[3,4-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-indenyl substituted by p occurrences ofR7), -N(R4)-[C(R5)(R6)]m-(indolin-2-one substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(isoindolin-1-one substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3H-imidazo[4,5-c]pyridine substituted by p occurrences of R7), or - N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[4,3-c]pyridine substituted by p occurrences of R7); (vi) -N(R4)-[C(R5)(R6)]m-(imidazo[2,1-b]thiazolyl substituted by p occurrences of R7); (vii) -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-benzo[c][1,2]thiazinyl 2,2-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3- dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(benzo[b]thiophene 1,1-dioxide substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,3- dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted by p occurrences of R7); (viii) -N(R4)-[C(R5)(R6)]m-(quinazolin-4(3H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydroquinolin-2(1H)-onyl substituted by p occurrences of R7) , -N(R4)-[C(R5)(R6)]m-(1,4-dihydroisoquinolin-3(2H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoquinolin-1(2H)-onyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,2,3,4-tetrahydroisoquinoline substituted by p occurrences of R7); or (ix) -N(R4)-[C(R5)(R6)]m-(bicyclo[1.1.1]pentanyl substituted by p occurrences of R7).

[0071] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by toccurrences of R7), -N(R4)-[C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7).

[0072] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by toccurrences of R7), -N(R4)-[C(R5)(R6)]m-(isochromanyl substituted by t occurrences of R7), - N(R4)-[C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted by p occurrences of R7); -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-c]pyridinyl substituted by poccurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[d]oxazol-2(3H)-one substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted by p occurrences of R7), or-N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted by p occurrences of R7).

[0073] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrencesof R7), -N(R4)-[C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7), or -N(R4)- [C(R5)(R6)]m-(pyrimidinyl substitu

[0074] In certain embodiments,substituted by phenyl substituted with p occurrences of R7.

[0075] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substitutedby p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H- pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro- 3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H- cyclopenta[b]pyridinyl substituted by p occurrences of R7); -N(R4)-[C(R5)(R6)]m-(6,7-dihydro- 5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7, -N(R4)-[C(R5)(R6)]m-(isoindolinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3H-imidazo[4,5-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-c]pyridinylsubstituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-indenyl substituted byp occurrences of R7), -N(R4)-[C(R5)(R6)]m-(indolin-2-one substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(isoindolin-1-one substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (3H-imidazo[4,5-c]pyridine substituted by p occurrences of R7), or-N(R4)-[C(R5)(R6)]m-(1H- pyrazolo[4,3-c]pyridine substituted by p occurrences of R7).

[0076] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(imidazo[2,1-b]thiazolyl substitutedby p occurrences of R7).

[0077] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-benzo[c][1,2]thiazinyl 2,2-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[b]thiophene 1,1-dioxide substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted by p occurrences of R7).

[0078] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(quinazolin-4(3H)-onyl substitutedby p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydroquinolin-2(1H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,4-dihydroisoquinolin-3(2H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoquinolin-1(2H)-onyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,2,3,4-tetrahydroisoquinoline substituted by p occurrences of R7).

[0079] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by toccurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m- (pyrazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(oxazolyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7).

[0080] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by toccurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(isochromanyl substituted by t occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3- dihydrobenzofuranyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3- dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4- dihydro-2H-pyrano[2,3-c]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3- dihydrofuro[2,3-c]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(benzo[d]oxazol- 2(3H)-one substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted by p occurrences of R7)

[0081] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrencesof R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(pyrimidinyl substituted by p occurrences of R7).

[0082] In certain embodiments, X1 is which is substituted by phenyl substituted withp occurrences of R7. In certain embodiments, X1iswhich is substituted by phenyl substituted with p occurrences of R7. In certain embodiments, X1is, which is substituted by phenyl substituted with p occurrences of R7.

[0083] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substitutedby p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m- (indazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7.

[0084] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(imidazo[2,1-b]thiazolyl substitutedby p occurrences of R7).

[0085] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-benzo[c][1,2]thiazinyl 2,2-dioxide substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H- benzo[e][1,2]thiazinyl 1,1-dioxide substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(benzo[b]thiophene 1,1-dioxide substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted by p occurrences of R7).

[0086] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(quinazolin-4(3H)-onyl substitutedby p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4- dihydroquinolin-2(1H)-onyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(1,4-dihydroisoquinolin-3(2H)-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(isoquinolin-1(2H)-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,2,3,4- tetrahydroisoquinoline substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(bicyclo[1.1.1]pentanyl substituted by p occurrences of R7).

[0087] In certain embodiments, X1 is selected from the groups depicted in the compounds inTable 1 below.

[0088] As generally described above, R1 is C1-4 alkyl or hydrogen. In certain embodiments, R1is C1-4alkyl. In certain embodiments, R1is hydrogen. In certain embodiments, R1is C1-2alkyl. In certain embodiments, R1is -CH3. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0089] As generally described above, R2 represents independently for each occurrencehydrogen; halo; C1-4 alkyl; -S(O)2R8; cyano; C1-4 alkoxyl, hydroxyl, C1-4 haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B. In certain embodiments, R2represents independently for each occurrence halo. In certain embodiments, R2represents independently for each occurrence C1-4 alkyl. In certain embodiments, R2represents independently for each occurrence -S(O)2R8. In certain embodiments, R2represents independently for each occurrence C1-4alkoxyl. In certain embodiments, R2represents independently for each occurrence C1-4haloalkyl. In certain embodiments, R2represents independently for each occurrence a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2represents independently for each occurrence hydrogen, halo, or C1-4 alkyl.

[0090] In certain embodiments, R2 is hydrogen; halo; C1-4 alkyl; -S(O)2R8; cyano; C1-4 alkoxyl,hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B. In certain embodiments, R2is hydrogen. In certain embodiments, R2is halo. In certain embodiments, R2is C1-4 alkyl. In certain embodiments, R2is -S(O)2R8. In certain embodiments, R2is cyano. In certain embodiments, R2is C1-4 alkoxyl. In certain embodiments, R2is hydroxyl. In certain embodiments, R2is C1-4haloalkyl. In certain embodiments, R2is a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5cycloalkyl,wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2is hydrogen, halo, or C1-4 alkyl. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0091] As generally described above, R2B represents independently for each occurrence C1-3alkyl or halo. In certain embodiments, R2Brepresents independently for each occurrence C1-3 alkyl. certain embodiments, R2Brepresents independently for each occurrence halo. In certain embodiments, R2Bis selected from the groups depicted in the compounds in Table 1 below.

[0092] As generally described above, R3 is hydrogen; fluoro; C1-4 alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4 haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B.In certain embodiments, R3is hydrogen. In certain embodiments, R3is fluoro. In certain embodiments, R3is C1-4alkyl. In certain embodiments, R3is -S(O)2R8. In certain embodiments, R3is cyano. In certain embodiments, R3is C1-4 alkoxyl. In certain embodiments, R3is hydroxyl. In certain embodiments, R3is C1-4 haloalkyl. In certain embodiments, R3is a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R3is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R3is a C3-5 cycloalkyl substituted with q occurrences of R2B. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0093] As generally described above, R4 is hydrogen, C1-4 alkyl, -C(O)(C1-4 alkyl), or -S(O)2(C1-4 alkyl). In certain embodiments, R4is hydrogen or C1-4 alkyl. In certain embodiments, R4is hydrogen. In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is -C(O)(C1-4alkyl). In certain embodiments, R4is -S(O)2(C1-4 alkyl). In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0094] As generally described above, R5 and R6 each represent independently for eachoccurrence hydrogen, C1-4 alkyl, C3-5 cycloalkyl, C1-4 hydroxyalkyl, -C1-3 alkylene-N(R8)2, -(C1-6 aliphatic substituted by R8), or -(CH2)0-3-O-(CH2)0-3-CH3; or R5and R6are taken together to form a C3-5saturated carbocyclic ring. In certain embodiments, R5and R6each represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R5and R6are each hydrogen. In certain embodiments, R5is hydrogen and R6is -CH3. In certain embodiments, R5and R6each represent independently for each occurrence C1-4alkyl. In certain embodiments, R5is hydrogen. In certain embodiments, R6represents independently for each occurrence C3-5 cycloalkyl. In certain embodiments, R6represents independently for each occurrence C1-4hydroxyalkyl. In certain embodiments, R6represents independently for each occurrence -C1-3alkylene-N(R8)2. In certain embodiments, R6represents independently for each occurrence -(C1-6 aliphatic substituted by R8). In certain embodiments, R6represents independently for each occurrence -(CH2)0-3-O-(CH2)0-3-CH3. In certain embodiments, R5and R6are together to form a C3-5saturated carbocyclic ring. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0095] As generally described above, R7 represents independently for each occurrence C1-6alkyl, halo, cyano, hydroxyl, -C(O)N(R8)2, -N(R8)C(O)-R8, -C(O)-R8, -(C1-3 aliphatic substituted by R8), C1-6 alkoxyl, C3-6 cycloalkyl, -S(O)2N(R8)2, -S(O)2R8, -N(R8)S(O)2R8, C1-3 alkylene- C(O)N(R8)2, -S(O)(NH)R8, C3-6cycloalkyl, -C(O)N(R8)(C3-6cycloalkyl), -C(O)O-C1-3alkyl, C1-3haloalkyl, -NH(R8), -C(NH)NH(R8),-O-(C3-6cycloalkyl), or a 5–6 membered monocyclic heteroaromatic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring is substituted with s occurrences of R7B. In certain embodiments, R7represents independently for each occurrence C1-6alkyl. In certain embodiments, R7represents independently for each occurrence halo. In certain embodiments, R7represents independently for each occurrence cyano. In certain embodiments, R7represents independently for each occurrence -C(O)N(R8)2. In certain embodiments, R7represents independently for each occurrence -S(O)(NH)R8. In certain embodiments, R7represents independently for each occurrence C1-3 alkylene-C(O)N(R8)2. In certain embodiments, R7represents independently for each occurrence C3-6cycloalkyl. In certain embodiments, R7represents independently for each occurrence -N(R8)C(O)-R8. In certainembodiments, R7represents independently for each occurrence -C(O)-R8. In certain embodiments, R7represents independently for each occurrence -(C1-3 aliphatic substituted by R8). In certain embodiments, R7represents independently for each occurrence C1-6 alkoxyl. In certain embodiments, R7represents independently for each occurrence C3-6cycloalkyl. In certain embodiments, R7represents independently for each occurrence -C(O)N(R8)(C3-6 cycloalkyl), wherein each cycloalkyl is substituted with s occurrences of R7B. In certain embodiments, R7represents independently for each occurrence -C(O)O-C1-3alkyl. In certain embodiments, R7represents independently for each occurrence C1-3 haloalkyl. In certain embodiments, R7represents independently for each occurrence -NH(R8). In certain embodiments, R7represents independently for each occurrence -C(NH)NH(R8). In certain embodiments, R7represents independently for each occurrence -O-(C3-6cycloalkyl), wherein each cycloalkyl is substituted with s occurrences of R7B. In certain embodiments, R7represents independently for each occurrence -S(O)2N(R8)2. In certain embodiments, R7represents independently for each occurrence -S(O)2R8. In certain embodiments, R7represents independently for each occurrence - N(R8)S(O)2R8. In certain embodiments, R7represents independently for each occurrence a 5–6 membered monocyclic heteroaromatic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaromatic ring is substituted with s occurrences of R7B. In certain embodiments, R7is -C(O)-R8or -C(O)N(R8)2. In certain embodiments, R7is -C(O)N(R8)2. In certain embodiments, R7is hydroxyl. In certain embodiments, R7is -C(O)NH2. In certain embodiments, R7represents independently for each occurrence cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0096] As generally described above, R7B represents independently for each occurrence C1-3alkyl, halo, hydroxyl, or C3-6cycloalkyl. In certain embodiments, R7Brepresents independently for each occurrence C1-3 alkyl. In certain embodiments, R7Brepresents independently for each occurrence halo. In certain embodiments, R7Brepresents independently for each occurrence hydroxyl. In certain embodiments, R7Brepresents independently for each occurrence C3-6cycloalkyl. In certain embodiments, R7Bis selected from the groups depicted in the compounds in Table 1 below.

[0097] As generally described above, R8 represents independently for each occurrencehydrogen, C1-6aliphatic, hydroxyl, -NH2, -S(O)2CH3, C3-6cycloalkyl, cyano, phenyl, C1-4haloalkyl, C1-6alkoxyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8is hydrogen. In certain embodiments, R8represents independently for each occurrence C1-6 aliphatic. In certain embodiments, R8is hydroxyl. In certain embodiments, R8is -NH2. In certain embodiments, R8is -S(O)2CH3. In certain embodiments, R8represents independently for each occurrence C3-6cycloalkyl. In certain embodiments, R8is cyano. In certain embodiments, R8represents independently for each occurrence C1-6 alkoxyl. In certain embodiments, R8is phenyl. In certain embodiments, R8represents independently for each occurrence C1-4haloalkyl. In certain embodiments, R8represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8represents independently for each occurrence a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0098] As generally described above, R9 is hydrogen, chloro, fluoro or C1-3 alkyl. In certainembodiments, R9is hydrogen. In certain embodiments, R9is fluoro. In certain embodiments, R9is C1-3 alkyl. In certain embodiments, R9is chloro. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0099] As defined generally above, m is 0, 1, or 2, or 3. In certain embodiments, m is 0. Incertain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0100] As generally described above, n is 1, 2, or 3. In certain embodiments, n is 1. In certainembodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0101] As generally described above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. Incertain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 2 or 3. In certain embodiments,p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0102] As generally described above, q and s are independently 0, 1, 2, or 3. In certainembodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0103] As generally described above, t is 0, 1, 2, or 3. In certain embodiments, t is 0. Incertain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0104] As generally described above, u is 1 or 2. In certain embodiments, u is 1. In certainembodiments, u is 2. In certain embodiments, u is 3. In certain embodiments, u is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0105] In certain embodiments, the compound of Formula I is further defined by Formula Ia orIb, or a pharmaceutically acceptable salt thereof:Ia Ib.

[0106] In certain embodiments, the compound of Formula I is further defined by Formula Ic,Id, or Ie, or a pharmaceutically acceptable salt thereof:

[0107] In certain embodiments, the compound of Formula I is further defined by Formula If orIg, or a pharmaceutically acceptable salt thereof:

[0108] In certain embodiments, the compound of Formula I is further defined by Formula Ih orIi, or a pharmaceutically acceptable salt thereof:

[0109] In certain embodiments, the compound of Formula I is further defined by Formula Ij,Ik, Il, Im, In, or Io or a pharmaceutically acceptable salt thereof:In Io.

[0110] In certain embodiments, the compound of Formula I is further defined by Formula Ip,Iq, or Ir, or a pharmaceutically acceptable salt thereof:Ir.

[0111] In certain embodiments, the compound of Formula I is further defined by Formula Is,It, Iu, or Iv, or a pharmaceutically acceptable salt thereof:

[0112] In certain embodiments, the compound of Formula I is further defined by Formula Iwor Ix, or a pharmaceutically acceptable salt thereof:

[0113] In certain embodiments, the compound of Formula I is further defined by Formula Iy,Iz, or Iaa, or a pharmaceutically acceptable salt thereof:Iy Iz Iaa.

[0114] In certain embodiments, the compound of Formula I is further defined by Formula Iab,Iac, or Iad, or a pharmaceutically acceptable salt thereof:

[0115] In certain embodiments, the compound of Formula I is further defined by Formula Iae,or a pharmaceutically acceptable salt thereof:Iae wherein Ring B1is one of the following: (i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7; (, each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolyl substituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2- b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0116] In certain embodiments, the compound of Formula I is further defined by Formula Iafor a pharmaceutically acceptable salt thereof:Iaf wherein Ring B1is one of the following: (i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by poccurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7); (, each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0117] In certain embodiments, the compound of Formula I is further defined by Formula Iafor a pharmaceutically acceptable salt thereof:Iaf wherein Ring B1is one of the following: (i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7;(ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7); (, each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7, and

[0118] t is 1, 2, or 3.As generally described above, Ring B1 is one of the following:(i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7); (, each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolyl substituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2- b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0119] In certain embodiments, Ring B1 is (i) thiazolyl substituted by t occurrences of R7;thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7);(iv), each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0120] In certain embodiments, Ring B1 is thiazolyl substituted by t occurrences of R7. Incertain embodiments, Ring B1is thiadiazolyl substituted by p occurrences of R7. In certain embodiments, ring B1is 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; or ring B1is thiazolyl substituted by t occurrences of R7. In certain embodiments, Ring B1is 1,3,4- oxadiazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is pyrazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is oxazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is or imidazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is chromanyl substituted by t occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydrobenzofuranyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydrofuro[3,2- c]pyridine substituted by p occurrences of R7. In certain embodiments, Ring B1is 5,6- dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is or 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7). In certain embodiments, Ring B1is , substituted by phenyl substituted with p occurrences of R7. In certain embodiments,Ring B1is, substituted by phenyl substituted with p occurrences of R7. In certain embodiments, Ring B1is, substituted by phenyl substituted with p occurrences of R7. In certain embodiments, Ring B1is pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is benzo[d]imidazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is indazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is isoindolin-1-onyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 6,7-dihydro-5H- cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0121] In certain embodiments, Ring B1 is chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; or thiazolyl substituted by t occurrences of R7. In certain embodiments, Ring B1is phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolyl substituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; or isoindolin-1-onyl substituted by p occurrences of R7. In certain embodiments, Ring B1is pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7or isoindolin-1-onyl substituted by p occurrences of R7.

[0122] In certain embodiments, Ring B1 is selected from the groups depicted in the compoundsin Table 1 below.

[0123] In certain embodiments, the compound of Formula I is further defined by Formula Iag,or a pharmaceutically acceptable salt thereof:

[0124] In certain embodiments, the compound of Formula I is further defined by Formula Iah,or a pharmaceutically acceptable salt thereof:

[0125] In certain embodiments, the compound of Formula I is further defined by Formula Iai,or a pharmaceutically acceptable salt thereof:Iai.

[0126] In certain embodiments, the compound ipharmaceutically acceptable salt thereof. In certain embodiments, the compound is. II. Additional Indole Amide Compounds

[0127] One aspect of the invention provides indole amide compounds. The compounds may beused in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. One aspect of the invention provides a compound represented by Formula II:or a pharmaceutically acceptable salt thereof; wherein: A1is a bicyclic heteroaryl selected fromX1is one of the following: (i) -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7); (ii) -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7); (iii) -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7) or -N(R4)- [C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7); (iv), each of which is substituted by phenyl substituted with p occurrences of R7; or (v) -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7); or 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; R1is C1-4alkyl; R2is hydrogen; halo; C1-4 alkyl; -S(O)2R8; cyano; C1-4 alkoxyl, hydroxyl, C1-4 haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R2Brepresents independently for each occurrence C1-3 alkyl or halo; R3is hydrogen; fluoro; C1-4alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R4is hydrogen, C1-4 alkyl, -C(O)(C1-4 alkyl), or -S(O)2(C1-4 alkyl); R5and R6each represent independently for each occurrence hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, -C1-3alkylene-N(R8)2, -(C1-6aliphatic substituted by R8), or - (CH2)0-3-O-(CH2)0-3-CH3; or R5and R6are taken together to form a C3-5 saturated carbocyclic ring; R7represents independently for each occurrence C1-6alkyl, halo, cyano, -C(O)N(R8)2, - N(R8)C(O)-R8, -C(O)-R8, -(C1-6 aliphatic substituted by R8), C1-6 alkoxyl, C3-6 cycloalkyl, -S(O)2N(R8)2, -S(O)2R8, -N(R8)S(O)2R8, C1-3 alkylene-C(O)N(R8)2, -S(O)(NH)R8, C3-6cycloalkyl, or a 5–6 membered monocyclic heteroaromatic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is substituted with s occurrences of R7B;R7Brepresents independently for each occurrence C1-3alkyl, halo, hydroxyl, or C3-6cycloalkyl; R8represents independently for each occurrence hydrogen, C1-6 aliphatic, hydroxyl, - NH2, -S(O)2CH3, C3-6cycloalkyl, cyano, phenyl, C1-4haloalkyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R9is hydrogen, chloro, fluoro or C1-3 alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3; q and s are independently 0, 1, 2, or 3; and t is 1, 2, or 3.

[0128] The definitions of variables in Formula II above encompass multiple chemical groups.The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0129] In certain embodiments, the compound is a compound of Formula II.

[0130] As generally described above, A1 is a bicyclic heteroaryl selected from

[0131] In certain embodiments, A1 is. In certain embodiments, A1 isertain embodiments,certain embodiments, In certain embodiments,certain embodiments,. In certain embodiments,embodiments, A1is . In certain embodiments, A1iscertain embodiments, A1is. In certain embodiments, A1iscertain embodiments, A1is. In certain embodiments,. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0132] As generally described above, X1 is one of the following:(i) -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7); (ii) -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7) (iii) -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7) or -N(R4)- [C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7);(each of which is substituted by phenyl substituted with p occurrences of R7; or (v) -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7); or 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7.

[0133] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by toccurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m- (pyrazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(oxazolyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(7,8- dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7). In certain embodiments, X1is - N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2-d]pyrimidinylsubstituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m- (pyridinyl substituted by p occurrences of R7). In certain embodiments, X1issubstituted by phenyl substituted with p occurrences of R7. In certain embodiments, X1iswhich is substituted by phenyl substituted with p occurrences of R7. In certain embodiments, X1is, which is substituted by phenyl substituted with p occurrences of R7.

[0134] In certain embodiments, X1 is -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substitutedby p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m- (indazolyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)- [C(R5)(R6)]m-(isoindolin-1-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7). In certain embodiments, X1is -N(R4)-[C(R5)(R6)]m-(6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7). In certain embodiments, X1is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7.

[0135] In certain embodiments, X1 is selected from the groups depicted in the compounds inTable 1 below.

[0136] As generally described above, R1 is C1-4 alkyl. In certain embodiments, R1 is C1-2 alkyl.In certain embodiments, R1is -CH3. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0137] As generally described above, R2 is hydrogen; halo; C1-4 alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5cycloalkyl, wherein each ring is substituted with qoccurrences of R2B. In certain embodiments, R2is hydrogen. In certain embodiments, R2is halo. In certain embodiments, R2is C1-4 alkyl. In certain embodiments, R2is -S(O)2R8. In certain embodiments, R2is cyano. In certain embodiments, R2is C1-4 alkoxyl. In certain embodiments, R2is hydroxyl. In certain embodiments, R2is C1-4haloalkyl. In certain embodiments, R2is a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R2is hydrogen, halo, or C1-4alkyl. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0138] As generally described above, R2B represents independently for each occurrence C1-3alkyl or halo. In certain embodiments, R2Brepresents independently for each occurrence C1-3 alkyl. certain embodiments, R2Brepresents independently for each occurrence halo. In certain embodiments, R2Bis selected from the groups depicted in the compounds in Table 1 below.

[0139] As generally described above, R3 is hydrogen; fluoro; C1-4 alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5cycloalkyl, wherein each ring is substituted with q occurrences of R2B.In certain embodiments, R3is hydrogen. In certain embodiments, R3is fluoro. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is -S(O)2R8. In certain embodiments, R3is cyano. In certain embodiments, R3is C1-4 alkoxyl. In certain embodiments, R3is hydroxyl. In certain embodiments, R3is C1-4haloalkyl. In certain embodiments, R3is a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R3is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q occurrences of R2B. In certain embodiments, R3is a C3-5cycloalkyl substituted with q occurrences of R2B. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0140] As generally described above, R4 is hydrogen, C1-4 alkyl, -C(O)(C1-4 alkyl), or -S(O)2(C1-4 alkyl). In certain embodiments, R4is hydrogen or C1-4 alkyl. In certain embodiments, R4is hydrogen. In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is -C(O)(C1-4alkyl). In certain embodiments, R4is -S(O)2(C1-4 alkyl). In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0141] As generally described above, R5 and R6 each represent independently for eachoccurrence hydrogen, C1-4 alkyl, C3-5 cycloalkyl, C1-4 hydroxyalkyl, -C1-3 alkylene-N(R8)2, -(C1-6 aliphatic substituted by R8), or -(CH2)0-3-O-(CH2)0-3-CH3; or R5and R6are taken together to form a C3-5saturated carbocyclic ring. In certain embodiments, R5and R6each represent independently for each occurrence hydrogen or C1-4alkyl. In certain embodiments, R5and R6are each hydrogen. In certain embodiments, R5is hydrogen and R6is -CH3. In certain embodiments, R5and R6each represent independently for each occurrence C1-4 alkyl. In certain embodiments, R5is hydrogen. In certain embodiments, R6represents independently for each occurrence C3-5 cycloalkyl. In certain embodiments, R6represents independently for each occurrence C1-4 hydroxyalkyl. In certain embodiments, R6represents independently for each occurrence -C1-3alkylene-N(R8)2. In certain embodiments, R6represents independently for each occurrence -(C1-6 aliphatic substituted by R8). In certain embodiments, R6represents independently for each occurrence -(CH2)0-3-O-(CH2)0-3-CH3. In certain embodiments, R5and R6are together to form a C3-5saturated carbocyclic ring. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0142] As generally described above, R7 represents independently for each occurrence C1-6alkyl, halo, cyano, -C(O)N(R8)2, -N(R8)C(O)-R8, -C(O)-R8, -(C1-3aliphatic substituted by R8), C1-6 alkoxyl, C3-6 cycloalkyl, -S(O)2N(R8)2, -S(O)2R8, -N(R8)S(O)2R8, C1-3 alkylene-C(O)N(R8)2, -S(O)(NH)R8, C3-6 cycloalkyl, or a 5–6 membered monocyclic heteroaromatic ring containing 1– 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with s occurrences of R7B. In certain embodiments, R7represents independently for each occurrence C1-6 alkyl. In certain embodiments, R7represents independently for each occurrence halo. In certain embodiments, R7represents independently for each occurrence cyano. In certain embodiments, R7represents independently for each occurrence -C(O)N(R8)2.In certain embodiments, R7represents independently for each occurrence -S(O)(NH)R8. In certain embodiments, R7represents independently for each occurrence C1-3 alkylene- C(O)N(R8)2. In certain embodiments, R7represents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R7represents independently for each occurrence - N(R8)C(O)-R8. In certain embodiments, R7represents independently for each occurrence -C(O)- R8. In certain embodiments, R7represents independently for each occurrence -(C1-3 aliphatic substituted by R8). In certain embodiments, R7represents independently for each occurrence C1-6 alkoxyl. In certain embodiments, R7represents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R7represents independently for each occurrence -S(O)2N(R8)2. In certain embodiments, R7represents independently for each occurrence -S(O)2R8. In certain embodiments, R7represents independently for each occurrence - N(R8)S(O)2R8. In certain embodiments, R7represents independently for each occurrence a 5–6 membered monocyclic heteroaromatic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with s occurrences of R7B. In certain embodiments, R7is -C(O)-R8or -C(O)N(R8)2. In certain embodiments, R7represents independently for each occurrence cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0143] As generally described above, R7B represents independently for each occurrence C1-3alkyl, halo, hydroxyl, or C3-6cycloalkyl. In certain embodiments, R7Brepresents independently for each occurrence C1-3alkyl. In certain embodiments, R7Brepresents independently for each occurrence halo. In certain embodiments, R7Brepresents independently for each occurrence hydroxyl. In certain embodiments, R7Brepresents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R7Bis selected from the groups depicted in the compounds in Table 1 below.

[0144] As generally described above, R8 represents independently for each occurrencehydrogen, C1-6aliphatic, hydroxyl, -NH2, -S(O)2CH3, C3-6cycloalkyl, cyano, phenyl, C1-4haloalkyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8represents independently for each occurrencehydrogen. In certain embodiments, R8represents independently for each occurrence C1-6aliphatic. In certain embodiments, R8represents independently for each occurrence hydroxyl. In certain embodiments, R8represents independently for each occurrence -NH2. In certain embodiments, R8represents independently for each occurrence -S(O)2CH3. In certain embodiments, R8represents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R8represents independently for each occurrence cyano. In certain embodiments, R8represents independently for each occurrence phenyl. In certain embodiments, R8represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R8represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8represents independently for each occurrence a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0145] As generally described above, R9 is hydrogen, chloro, fluoro or C1-3 alkyl. In certainembodiments, R9is hydrogen. In certain embodiments, R9is fluoro. In certain embodiments, R9is C1-3alkyl. In certain embodiments, R9is chloro. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0146] As defined generally above, m is 0, 1, or 2, or 3. In certain embodiments, m is 0. Incertain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0147] As generally described above, n is 1, 2, or 3. In certain embodiments, n is 1. In certainembodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0148] As generally described above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. Incertain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0149] As generally described above, q and s are independently 0, 1, 2, or 3. In certainembodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0150] As generally described above, t is 1, 2, or 3. In certain embodiments, t is 1. In certainembodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.

[0151] In certain embodiments, the compound of Formula II is further defined by Formula IIaor IIb, or a pharmaceutically acceptable salt thereof:

[0152] In certain embodiments, the compound of Formula II is further defined by Formula IIc,IId, or IIe, or a pharmaceutically acceptable salt thereof:

[0153] In certain embodiments, the compound of Formula II is further defined by Formula IIfor IIg, or a pharmaceutically acceptable salt thereof:

[0154] In certain embodiments, the compound of Formula II is further defined by Formula IIhor IIi, or a pharmaceutically acceptable salt thereof:IIh IIi.

[0155] In certain embodiments, the compound of Formula II is further defined by Formula IIj,IIk, IIl, IIm, IIn, or IIo or a pharmaceutically acceptable salt thereof:IIn IIo.

[0156] In certain embodiments, the compound of Formula II is further defined by Formula IIp,IIq, or IIr, or a pharmaceutically acceptable salt thereof:

[0157] In certain embodiments, the compound of Formula II is further defined by Formula IIs,IIt, IIu, or IIv, or a pharmaceutically acceptable salt thereof:

[0158] In certain embodiments, the compound of Formula II is further defined by Formula IIwor IIx, or a pharmaceutically acceptable salt thereof:

[0159] In certain embodiments, the compound of Formula II is further defined by Formula IIy,IIz, or IIaa, or a pharmaceutically acceptable salt thereof:

[0160] In certain embodiments, the compound of Formula II is further defined by FormulaIIab, IIac, or IIad, or a pharmaceutically acceptable salt thereof:

[0161] In certain embodiments, the compound of Formula II is further defined by FormulaIIae, or a pharmaceutically acceptable salt thereof:IIae wherein Ring B1is one of the following: (i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7;(each of which is substituted by phenyl substituted with p occurrences of R7; or (v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolyl substituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2- b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0162] As generally described above, Ring B1 is one of the following:(i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences of R7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7; (ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by p occurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7; 6,7- dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H- pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7; (iii) phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7); (, each of which is substituted by phenyl substituted with p occurrences of R7; or(v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolyl substituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2- b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7.

[0163] In certain embodiments, Ring B1 is thiazolyl substituted by t occurrences of R7. Incertain embodiments, Ring B1is thiadiazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 1,3,4-oxadiazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is pyrazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is oxazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is or imidazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is chromanyl substituted by t occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydrobenzofuranyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 3,4-dihydro-2H- pyrano[3,2-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7. In certain embodiments, Ring B1is 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is or 7,8-dihydro-6H- pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is phenyl substituted by t occurrences of R7or pyridinyl substituted by p occurrences of R7). In certain embodiments, Ring B1is , substituted by phenyl substituted with p occurrences of R7. In certain embodiments, Ring B1is , substituted by phenyl substituted with p occurrences of R7. In certain embodiments, Ring B1is, substituted by phenyl substituted with p occurrences of R7. In certain embodiments, Ring B1is pyrrolo[3,2-b]pyridinylsubstituted by p occurrences of R7. In certain embodiments, Ring B1is benzo[d]imidazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is indazolyl substituted by p occurrences of R7. In certain embodiments, Ring B1is isoindolin-1-onyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 1,2-dihydro-3H-indazol- 3-onyl substituted by p occurrences of R7. In certain embodiments, Ring B1is 6,7-dihydro-5H- cyclopenta[c]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7. In certain embodiments, Ring B1is selected from the groups depicted in the compounds in Table 1 below. Exemplary Specific Compounds

[0164] In certain embodiments, the compound is a compound in Table 1 or 2, or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 2.

[0165] In certain embodiments, the compound is a compound in Table 1 or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound selected from Compounds I-1 through I-255 in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compounds I-1 through I-255 in Table 1.

[0166] In certain embodiments, the compound is a compound in Table 2 or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the compound is a compound in Table 2. TABLE 1. Exemplary CompoundsTABLE 2. Exemplary Compounds

[0167] In some embodiments, the present invention provides a compound of formula I asdefined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0168] In some embodiments, the present invention provides a compound of formula II asdefined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula II as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.III. Therapeutic Applications

[0169] In some embodiments, the present invention provides a method of treating a disorder inwhich enhanced ABC transporter function is of clinical benefit. For instance, in certain embodiments, a disorder is one in which ABC transporter dysfunction is etiological for disease. In some embodiments, correction of one or more underlying mutations associated with ABC transporter dysfunction is rationalized. In some embodiments, methods of the present invention provide enhancement of one or more non-mutated forms of an ABC transporter.

[0170] In some embodiments, the invention provides a method of treating a disorder in whichenhanced ABC transporter function is of clinical benefit, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder in which enhanced ABC transporter function is of clinical benefit. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.

[0171] In some embodiments, the invention provides a method of treating a disorder associatedwith ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.

[0172] In some embodiments, the present invention provides a method of alleviating one ormore symptoms of a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.

[0173] In some embodiments, the invention provides a method of treating a disorder in whichenhanced ABC transporter function is of clinical benefit, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II, to treat the disorder in which enhanced ABC transporter function is of clinical benefit. In certain embodiments, the particular compoundof Formula II is a compound defined by one of the embodiments described in Section I, above. In some embodiments, the invention provides a method of treating a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II, to treat the disorder associated with ABC transporter dysfunction. In certain embodiments, the particular compound of Formula II is a compound defined by one of the embodiments described in Section I, above. In some embodiments, the present invention provides a method of alleviating one or more symptoms of a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II, to treat the disorder associated with ABC transporter dysfunction. In certain embodiments, the particular compound of Formula II is a compound defined by one of the embodiments described in Section I, above.

[0174] In some embodiments, the disorder associated with ABC transporter dysfunction ischaracterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0175] In some embodiments, the present invention provides methods of treating a disorderselected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy, Biliary atresia, Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington's disease, Multiple sclerosis, Parkinson’s disease, Hirschsprung disease, Zellweger syndrome, Type 2 diabetes, Obesity, Type 1 diabetes, Atherosclerosis, Dyslipidemia, Generalized arterial calcification of infancy, Calciphylaxis,Autosomal recessive cone-rod dystrophy, Gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, Low phospholipid associated cholelithiasis, intrahepatic microlithiasis, hepatolithiasis, Non- anastomotic biliary strictures, Benign recurrent intrahepatic cholestasis, Progeria (Hutchinson- Gilford progeria syndrome), Chronic kidney disease, Hemodialysis, vascular calcification, vascular calcification associated with CKD, vascular calcification associated with T2D, and Calcific uremic atreriolopathy. In some embodiments, the present invention provides methods of treating cystic fibrosis. In some embodiments, the present invention provides methods of treating primary sclerosing cholangitis. For instance, in certain embodiments, the present invention provides a method of treating a disorder, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., such as a compound of Formula I), wherein the disorder is selected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy, Biliary atresia, Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington's disease, Multiple sclerosis, Parkinson’s disease, Hirschsprung disease, Zellweger syndrome, Type 2 diabetes, Obesity, Type 1 diabetes, Atherosclerosis, Dyslipidemia, Generalized arterial calcification of infancy, Calciphylaxis, Autosomal recessive cone-rod dystrophy, Gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, Low phospholipid associated cholelithiasis, intrahepatic microlithiasis, hepatolithiasis, Non-anastomotic biliary strictures, Benign recurrent intrahepatic cholestasis, Progeria (Hutchinson-Gilford progeria syndrome), Chronic kidney disease, Hemodialysis, vascular calcification, vascular calcification associated with CKD, vascular calcification associated with T2D, and Calcific uremic arteriolopathy.

[0176] In some embodiments, the disorder associated with ABC transporter dysfunction iscystic fibrosis (CF). Accordingly, in some embodiments, the present invention provides amethod of treating cystic fibrosis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I. Accordingly, in some embodiments, the present invention provides a method of treating cystic fibrosis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II. In some such embodiments, the method further comprises administering one or more additional therapeutic agents, described further below and herein.

[0177] In some embodiments, the disorder associated with ABC transporter dysfunction ischolestasis. Accordingly, in some embodiments, the present invention provides a method of treating cholestasis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I. In some embodiments, the present invention provides a method of treating cholestasis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula II. One of skill in the medical arts will recognize that there are various forms of cholestasis, all of which are contemplated herein for treatment with methods and compounds of the present invention. In some embodiments, the cholestasis is intrahepatic. In some embodiments, the cholestasis is extrahepatic. In some embodiments, the cholestasis is any of those described above and herein.

[0178] Another aspect of the invention provides a method of increasing expression of an ABCtransporter in a subject, comprising administering to the subject an effective amount of a compound described herein, such as a compound of Formula I, to thereby increase expression of the ABC transporter in the subject. In certain embodiments, the ABC transporter is selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0179] Another aspect of the invention provides a method of modulating function of an ABCtransporter in a subject, comprising administering to the subject an effective amount of a compound described herein, such as a compound of Formula I, to thereby increase expression ofthe ABC transporter in the subject. In certain embodiments, the ABC transporter is selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4. Subjects

[0180] In certain embodiments, the subject is a human. In certain embodiments, the subject isan adult human. In certain embodiments, the subject is a pediatric human. Medical Uses

[0181] Another aspect of the invention provides for the use of a compound described herein(such as a compound of Formula I or Formula II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.

[0182] Another aspect of the invention provides for the use of a compound described herein(such as a compound of Formula I or Formula II, or other compounds in Section I) for treating a medical disorder, such as a disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.

[0183] Another aspect of the invention provides a compound for a use described herein (suchas a compound of Formula I or Formula II, or other compounds in Section I), such as for treating a medical disorder, such as a disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein. IV. Combination Therapy

[0184] Another aspect of the invention provides for combination therapy. Compoundsdescribed herein (such as a compound of Formula I or Formula II, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as an autoimmune disorder, cancer, etc..

[0185] In some embodiments, the present invention provides a method of treating a discloseddisease or condition comprising administering to a patient in need thereof an effective amount ofa compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0186] One or more other therapeutic agent may be administered separately from a compoundor composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.

[0187] In some embodiments, the present invention provides a method of treating cysticfibrosis (CF) comprising administering a compound of the present invention with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a cystic fibrosis transmembrane conductance (CFTR) modulator, a nutritional agent, or any agent known to treat CF.

[0188] In some embodiments, the one or more additional therapeutic agents is an antibiotic. Insome embodiments the antibiotic is selected from a penicillin, a cephalosporin, a tetracycline, a macrolide, a fluoroquinolone, a sulfonamide, a glycopeptide, or a rifamycin. In certain embodiments, the antibiotic is selected from phenoxymethyl penicillin, dicloxacillin, amoxicillin with clavulanic acid, ampicillin, nafcillin, oxacillin, penicillin V, penicillin G, cefaclor, cefazolin, cefadroxil, cephalexin, cefuroxime, cefixime, cefoxitin, ceftriaxone, doxycycline, minocycline, sarecycline, erythromycin, clarithromycin, azithromycin, fidaxomicin, roxithromycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, sulfamethoxazole withtrimethoprim, sulfasalazine, sulfacetamide, sulfadiazine silver, vancomycin, dalbavancin, oritavancin, telavancin, or rifaximin.

[0189] In some embodiments, the one or more additional therapeutic agents is an S-nitrosoglutathione reductase (GSNOR) inhibitor. In some embodiments, the GSNOR inhibitor is selected from a GSNOR inhibitor disclosed in WO2010 / 019903, U.S. Pat. No. 8,470,857, U.S. Pat. No.8,642,628, WO2010 / 019910, U.S. Pat. No.8,586,624, WO2011 / 100433, U.S. Pat. No.US 8,481,590, WO2012 / 048181, WO2012 / 083165, WO2012 / 083171, or WO 2012 / 170371.

[0190] In some embodiments, the one or more additional therapeutic agents is an ileal biletransport (IBAT) inhibitor. In some embodiments, the IBAT inhibitor is selected from an IBAT inhibitor disclosed in AU2011326873, US2020 / 0330545, WO2012 / 064266, WO2020 / 167964, or Front. Pharmacol.2018; 9: 931 (Al-Dury et al., published online August 21, 2018). Exemplary IBAT inhibitors include, but are not limited to odevixibat, elobixivat, maralixibat, linerixibat, GSK2330672, SHP626 (volixibat), A4250, etc.

[0191] In some embodiments, the one or more additional therapeutic agents is a peroxisomeproliferator-activated receptors (PPAR) agonist. In some embodiments, the one or more additional therapeutic agents is a dual PPAR agonist, a PPAR-α agonist, a PPAR-γ agonist, or a PPAR-δ agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR-α agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR-γ agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR- δ agonist. In some embodiments, the PPAR agonist is selected from elafibrinor, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, GW-9662, GW501516, GFT1007, aleglitazar, muraglitazar and tesaglitazar, saroglitazar, seladelpar.

[0192] In some embodiments, the one or more additional therapeutic agents is an HMG-CoAreductase inhibitor. In some embodiments, the HMG-CoA reductase inhibitor ks a statin. In certain embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, Pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0193] In some embodiments, the one or more additional therapeutic agents is a disease-modifying antirheumatic drug (DMARD). In certain embodiments the DMARD is selected from azathioprine, hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine

[0194] In some embodiments, the one or more additional therapeutic agents is DNAmethyltransferase inhibitor. In some embodiments, the DNA methyltransferase inhibitor is selected from azacitidine, decitabine, zebularine, hydralazine, procaine, MG98, genistein, bobcat339 hydrochloride, hinokitiol, CM-272, and larsucosterol.

[0195] In some embodiments, the one or more additional therapeutic agents is an anti-interleukin-17A biological agent. In some embodiments, the anti-interleukin-17A biological agent is selected from secukinumab, ixekizumab, bimekizumab, brodalumab, and nekalimumab.

[0196] In some embodiments, the one or more additional therapeutic agents is an anti-interleukin-23 inhibitor. In certain embodiments the anti-interleukin-23 inhibitor is selected from guselkumab, risankizumab, tildrakizumab, and ustekinumab.

[0197] In some embodiments, the one or more additional therapeutic agents is a neutrophilelastase inhibitor. In some embodiments, the neutrophil elastase inhibitor is selected fromsivelestat sodium hydrate, AvKTI, and a flavonoid.

[0198] In some embodiments, the one or more additional therapeutic agents is a corticosteroid.In certain embodiments, the corticosteroid is selected from flugestone, fluorometholone, medrysone, prebediolone acetate, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prednisone, tixocortol, triamcinolone, dexamethasone, alclometasone, beclometasone, betamethasone, clobetasol, clobetasone, clocortolone, desoximetasone, dexamethasone, diflorasone, difluocortolone, fluclorolone, flumetasone, fluocortin, fluocortolone, fluprednidene, fluticasone, fluticasone furoate, halometasone, meprednisone, mometasone, mometasone furoate, paramethasone, prednylidene, rimexolone, ulobetasol, amcinonide, budesonide, ciclesonide, deflazacort, desonide, formocortal, fluclorolone acetonide, fludroxycortide, flunisolide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, cortivazol, and RU-28362.

[0199] In some embodiments, the one or more additional therapeutic agents is a proteinarginine deiminase 4 (PAD4) inhibitor. In certain embodiments, the PAD4 inhibitor is selected from JBI-589, GSK484, Cl-Amidine, Azithromycin, Clindamycin, Leflunomide, and Methotrexate.

[0200] In some embodiments, the one or more additional therapeutic agents is an apicalsodium-dependent BA transporter (ASBT) inhibitor. In some embodiments, the ASBT inhibitor is A3907.

[0201] In some embodiments, the one or more additional therapeutic agents is a thyroidhormone receptor beta (THR-β) agonist. In some embodiments, the THR-β) agonist is selected from resmetirom, VK2809, and cs27109.

[0202] In some embodiments, the one or more additional therapeutic agents is an immunecheckpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, ipilimumab, atezolizumab, avelumab, and durvalumab.

[0203] In some embodiments, the one or more additional therapeutic agents is a bile acidconjugate. In certain embodiments, the bile acid conjugate is selected from berberine ursodeoxycholate, ursodeoxycholate, and nor- ursodeoxycholate. In certain embodiments, the bile acid conjugate is berberine ursodeoxycholate. In certain embodiments, the bile acid conjugate is ursodeoxycholate. In certain embodiments, the bile acid conjugate is nor- ursodeoxycholate.

[0204] In some embodiments, the one or more additional therapeutic agents is an integrininhibitor. In some embodiments, the integrin is a subtype selected from α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and αIIbβ3. In some embodiments, the integrin inhibitor is selected from bexotegrast, natalizumab, vedolizumab, PLN-1474, risuteganib, THR-687, OT-166, AXT107, tirofiban, eptifibatide, abciximab, MORF-057, 7HP349, efalizumab, and lifitegrast.

[0205] In some embodiments, the one or more additional therapeutic agents is an endocrinefibroblast growth factor (FGF) analog. In some embodiments, the endocrine FGF analog is selected from FGF19, FGF21 and FGF23. In some embodiments, the endocrine FGF analog is aldafermin.

[0206] In some embodiments, the one or more additional therapeutic agents is a monoclonalantibody. In some embodiments, the monoclonal antibody targets CCL24, lysyl oxidase-like 2 (LOXL2), or vascular adhesion protein (VAP). In some embodiments, the monoclonal antibody is CM-101, simtuzumab, or BTT1023.

[0207] In some embodiments, the one or more additional therapeutic agents is an antagonist ofMAS Related GPR Family Member X4 (MRGPRX4). In some embodiments, the monoclonal antibody is EP547.

[0208] In some embodiments, the one or more additional therapeutic agents is an apicalsodium-dependent bile acid transporter (ASBT) inhibitor. In some embodiments, the ASBT inhibitor is selected from resveratrol, elobixibat, A4250, 264W94, 216U90, GSK2330672, lopixibat, SC-435, S-1647, IMB17-15, baribixibat, S-8921, S-8921G, R-146224, BRL-39924A, S0960volixibat and ritivixibat.

[0209] In some embodiments, the one or more additional therapeutic agents is a farnesoid Xreceptor (FXR) agonist. In some embodiments, the FXR agonist is selected from OCA, CS0159, tropifexor, vonafexor, and cilofexor.

[0210] In some embodiments, the one or more additional therapeutic agents is a glucagon-likepeptide-1 receptor agonist (GLP-1RA). In some embodiments, the GLP-1RA is selected from dulaglutide, exenatide, liraglutide, liraglutide / insulin degludec, lixisenatide / insulin glargine, semaglutide, and tirzepatide.

[0211] In some embodiments, the one or more additional therapeutic agents is a bile acid oranalog thereof. In some embodiments, the bile acid or analog thereof is selected from ursodeoxycholic acid and 24-norursodeoxycholic acid.

[0212] In some embodiments, the one or more additional therapeutic agents is a dihydroorotatedehydrogenase inhibitor. In some embodiments, the dihydroorotate dehydrogenase inhibitor is selected from brequinar sodium, ASLAN003, ML390, BAY2402234, PTC299, leflunomide, vidofludimus calcium, teriflunomide, and IMU-838. Additional Considerations

[0213] The doses and dosage regimen of the active ingredients used in the combination therapymay be determined by an attending clinician. In certain embodiments, the compound described herein (such as a compound of Formula I or Formula II, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder. In other embodiments, the compound described herein (such as a compound of Formula I or Formula II, or other compounds inSection I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder. In certain embodiments, the compound described herein (such as a compound of Formula I or Formula II, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.

[0214] In certain embodiments, the compound described herein (such as a compound ofFormula I or Formula II, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.

[0215] Another aspect of this invention is a kit comprising a therapeutically effective amountof the compound described herein (such as a compound of Formula I or Formula II, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. IV. Pharmaceutical Compositions and Dosing Considerations

[0216] As indicated above, the invention provides pharmaceutical compositions, whichcomprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical compositioncomprising a compound described herein (such as a compound of Formula I or Formula II, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0217] The phrase “therapeutically effective amount” as used herein means that amount of acompound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0218] The phrase “pharmaceutically acceptable” is employed herein to refer to thosecompounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0219] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0220] Examples of pharmaceutically-acceptable antioxidants include: (1) water solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0221] Formulations of the present invention include those suitable for oral, nasal, topical(including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of activeingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0222] In certain embodiments, a formulation of the present invention comprises an excipientselected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0223] Methods of preparing these formulations or compositions include the step of bringinginto association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0224] Formulations of the invention suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0225] In solid dosage forms of the invention for oral administration (capsules, tablets, pills,dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0226] A tablet may be made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0227] The tablets, and other solid dosage forms of the pharmaceutical compositions of thepresent invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0228] Liquid dosage forms for oral administration of the compounds of the invention includepharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0229] Besides inert diluents, the oral compositions can also include adjuvants such as wettingagents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0230] Suspensions, in addition to the active compounds, may contain suspending agents as,for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0231] Formulations of the pharmaceutical compositions of the invention for rectal or vaginaladministration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0232] Formulations of the present invention which are suitable for vaginal administration alsoinclude pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0233] Dosage forms for the topical or transdermal administration of a compound of thisinvention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0234] The ointments, pastes, creams and gels may contain, in addition to an active compoundof this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0235] Powders and sprays can contain, in addition to a compound of this invention, excipientssuch as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0236] Transdermal patches have the added advantage of providing controlled delivery of acompound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0237] Ophthalmic formulations, eye ointments, powders, solutions and the like, are alsocontemplated as being within the scope of this invention.

[0238] Pharmaceutical compositions of this invention suitable for parenteral administrationcomprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0239] Examples of suitable aqueous and nonaqueous carriers which may be employed in thepharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0240] These compositions may also contain adjuvants such as preservatives, wetting agents,emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0241] In some cases, in order to prolong the effect of a drug, it is desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0242] Injectable depot forms are made by forming microencapsule matrices of the subjectcompounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[0243] When the compounds of the present invention are administered as pharmaceuticals, tohumans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0244] The preparations of the present invention may be given orally, parenterally, topically, orrectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0245] The phrases “parenteral administration” and “administered parenterally” as used hereinmeans modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0246] The phrases “systemic administration,” “administered systemically,” “peripheraladministration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0247] These compounds may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0248] Regardless of the route of administration selected, the compounds of the presentinvention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0249] Actual dosage levels of the active ingredients in the pharmaceutical compositions of thisinvention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0250] The selected dosage level will depend upon a variety of factors including the activity ofthe particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0251] A physician or veterinarian having ordinary skill in the art can readily determine andprescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0252] In general, a suitable daily dose of a compound of the invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0253] If desired, the effective daily dose of the active compound may be administered as two,three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. The invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. EXAMPLES

[0254] The invention now being generally described, will be more readily understood byreference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. Synthetic Methods

[0255] Methods for preparing compounds described herein are illustrated in the followingsynthetic Scheme. The Scheme is given for the purpose of illustrating the invention, and not intended to limit the scope or spirit of the invention. Starting materials shown in the Scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[0256] In the Schemes, it is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. The modular synthetic route illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional compounds by conducting functional group transformations on the intermediate and final compounds. Such functional group transformations are well known in the art, as described in, for example, “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992).

[0257] The abbreviation “TFA” refers to trifluoroacetic acid. The abbreviation “FA” refers toformic acid. Preparative HPLC Methods:

[0258] HPLC Method 1:Instrument: Shimadzu LCMS system equipped with UV and MS detector Mobile Phase: 0.225% formic acid in water (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes. Flow rate: 35 ml / min; Column: Phenomenex Gemini-NX 150*30 mm*5 mm Wavelength: UV 220 nm and 254 nm) Column temperature: 30oC; MS ionization: ESI

[0259] HPLC Method 2:Instrument: GILSON 215 and Shimadzu LCMS 2010A Column: Agela Durashell C18250*20mm *5um Mobile phase A: 0.1% ammonium bicarbonate in water (m / m)Mobile phase B: Acetonitrile Gradient: 80% A / 20% B linear to 60% A / 40% B in 10.0min, hold at 0%A / 100%B to 12.0min. Flow rate: 35mL / min or 30mL / min

[0260] HPLC Method 3:Instrument: Shimadzu LCMS system equipped with DAD detector Mobile Phase: 1.5mL / 4L TFA in water (solvent A) and 0.75mL / 4L TFA in CH3CN (solvent B), Gradient: using the elution gradient 5%-95% (solvent B) over 0.7 minutes and holding at 95% for 0.4 minutes at a flow rate of 1.5 ml / min; Column: Chromolish.Flash RP-18e 25- 2mm Wavelength: UV 220nm (or 215 nm, 254 nm) Column temperature: 50oC; MS ionization: ESI

[0261] HPLC Method 4A:Instrument: Gilson-GX281 Mobile Phase: H2O(0.1%TFA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 5%-95% (solvent B) over 25 minutes. Flow rate: 25 ml / min; Column: Nanomicro-UniSil 5-120 C18 ,5um, 30*150mm Wavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0262] HPLC Method 4B:Instrument: Gilson-GX281 Mobile Phase: H2O (0.1%FA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 5%-95% (solvent B) over 25 minutes. Flow rate: 25 ml / min; Column: YMC-Actus Triart C18250*20mm*5umWavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0263] HPLC Method 4C:Instrument: Gilson-GX281 Mobile Phase: H2O (0.1%TFA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 5%-95% (solvent B) over 25 minutes. Flow rate: 25 ml / min; Column: YMC-Actus Triart C18250*20mm*5um Wavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0264] HPLC Method 5A:Instrument: LC-8A Mobile Phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 20%-95% (solvent B) over 18 minutes. Flow rate: 18 ml / min; Column: Metasll Cloak C1821.2*250 mm, 5 mm Wavelength: UV 220 nm and 254 nm Column temperature: 25 °C; MS ionization: ESI.

[0265] HPLC Method 5B:Instrument: LC-8A Mobile Phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 30%-95% (solvent B) over 18 minutes. Flow rate: 15 ml / min; Column: Metasil Cloak C1821.2*250 mm,5 mmWavelength: UV 220nm and 254nm Column temperature: 25 °C; MS ionization: ESI.

[0266] HPLC Method 6A:Instrument: LH-40 Mobile Phase: H2O (0.1%FA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 5%-95% (solvent B) over 30 minutes Flow rate: 15 ml / min; Column: YMC-Actus TriartC18250*20mm*5um Wavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0267] HPLC Method 6B:Instrument: LH-40 Mobile Phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 40%-95% (solvent B) over 20 minutes Flow rate: 20 ml / min; Column: YMC-Actus TriartC18250*20mm*5um Wavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0268] HPLC Method 6C:Instrument: LH-40 Mobile Phase: H2O (0.1%NH4OH) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 30%-98% (solvent B) over 20 minutes Flow rate: 18 ml / min; Column: YMC-ActusTriart C18250*20mm S-5 um,12 nmWavelength: UV 220nm and 254nm) Column temperature: 25 °C; MS ionization: ESI.

[0269] HPLC Method 7A:Instrument: LC-LHS Mobile Phase: H2O (0.1%FA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 40%-95% (solvent B) over 22 minutes Flow rate: 15 ml / min; Column: YMC-Actus Triart C18 / S-5um / 12nm Lot No.18849 Wavelength: UV 220nm and 254nm) Column temperature: rt; MS ionization: ESI.

[0270] HPLC Method 7B:Instrument: LC-LHS Mobile Phase: H2O (0.1%NH4OH) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 30%-95% (solvent B) over 22 minutes Flow rate: 15 ml / min; Column: YMC-Actus Triart C18 / S-5um / 12nm Lot No.18849 Wavelength: UV 220nm and 254nm) Column temperature: rt; MS ionization: ESI.

[0271] HPLC Method 8A:Instrument: LC-LHS Mobile Phase: H2O (0.1%FA) (solvent A) and CH3CN (solvent B), Gradient: using the elution gradient 20%-95% (solvent B) over 18 minutes. Flow rate: 18 ml / min; Column: Shim-pack Scepter C1850*4.6mm, 5um,5umWavelength: UV 220nm and 254nm Column temperature: 25 °C; MS ionization: ESI. Analytical LCMS Methods:

[0272] Analytical LC / MS Analysis Method A:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO C18, 30*3.0mm, 2.6um Temperature: 30°C Gradient:

[0273] Analytical LC / MS Analysis Method B:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm, 2.0um Temperature: 40°C Gradient:

[0274] Analytical LC / MS Analysis Method C:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO, 100*4.6mm, 2.6um Temperature: 40°C Gradient:

[0275] Analytical LC / MS Analysis Method D:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO, 100*4.6mm, 2.6um Temperature: 40°C Gradient:

[0276] Analytical LC / MS Analysis Method E:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO C18, 30*3.0mm, 2.6um Temperature: 30°C Gradient:

[0277] Analytical LC / MS Analysis Method F:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO C18, 30*3.0mm, 2.6um Temperature: 30°C Gradient:

[0278] Analytical LC / MS Analysis Method G:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kinetex EVO C18, 100*4.6mm, 2.6um Temperature: 40°C Gradient:

[0279] Analytical LC / MS Analysis Method H:ESI+ / - ion mode 90-900Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0280] Analytical LC / MS Analysis Method I:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm, 2.0um Temperature: 40°C Gradient:

[0281] Analytical LC / MS Analysis Method J:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18-120, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0282] Analytical LC / MS Analysis Method K:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0283] Analytical LC / MS Analysis Method L:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm,2.2um Temperature: 40°C Gradient:

[0284] Analytical LC / MS Analysis Method M:ESI+ / - ion mode 90-900 Wavelength: UV 220 nm / ELSD Column: Shim-pack C18, 33*3.0mm,3.0um Temperature: 30°C Gradient:

[0285] Analytical LC / MS Analysis Method O:ESI+ / - ion mode 90-900 Wavelength: UV 220 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0286] Analytical LC / MS Analysis Method P:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0287] Analytical LC / MS Analysis Method Q:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°CGradient:

[0288] Analytical LC / MS Analysis Method R:ESI+ / - ion mode 90-900 Wavelength: UV 220 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0289] Analytical LC / MS Analysis Method S:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack Scepter C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0290] Analytical LC / MS Analysis Method T:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm, 2.0umTemperature: 40°C Gradient:

[0291] Analytical LC / MS Analysis Method U:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0292] Analytical LC / MS Analysis Method V:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0293] Analytical LC / MS Analysis Method W:ESI+ / - ion mode 90-900Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0294] Analytical LC / MS Analysis Method X:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0295] Analytical LC / MS Analysis Method Y:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0296] Analytical LC / MS Analysis Method Z:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0297] Analytical LC / MS Analysis Method ZA:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0298] Analytical LC / MS Analysis Method ZB:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: UniHybrid 5-120 C8, 150*4.6mm, 5um Temperature: 40°C Gradient:

[0299] Analytical LC / MS Analysis Method ZC:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0300] Analytical LC / MS Analysis Method ZD:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Kromasil-C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0301] Analytical LC / MS Analysis Method ZE:ESI+ / - ion mode 90-900 Wavelength: UV 220 nm / ELSD Column: ACQUITY UPLC BEH Shield RP181.7 um 2.1*50mm Temperature: 40°CGradient:

[0302] Analytical LC / MS Analysis Method ZF:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°C Gradient:

[0303] Analytical LC / MS Analysis Method ZG:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 33*3.0mm, 3um Temperature: 30°C Gradient:

[0304] Analytical LC / MS Analysis Method ZH:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 33*3.0mm, 3.0umTemperature: 30°C Gradient:

[0305] Analytical LC / MS Analysis Method ZI:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 33*3.0mm, 3.0um Temperature: 30°C Gradient:

[0306] Analytical LC / MS Analysis Method ZJ:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 33*3.0mm, 3.0um Temperature: 30°C Gradient:

[0307] Analytical LC / MS Analysis Method ZK:ESI+ / - ion mode 90-900 Wavelength: UV 220 nm / ELSD Column: Kinetex EVO C18, 30*3.0mm, 2.6um Temperature: 30°C Gradient:

[0308] Analytical LC / MS Analysis Method ZL:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm,2.2um Temperature: 40°C Gradient:

[0309] Analytical LC / MS Analysis Method ZM:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Halo C18, 30*3.0mm, 2.0um Temperature: 40°C Gradient:

[0310] Analytical LC / MS Analysis Method ZN:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: CORTECS T3, 30*2.1mm,2.7um Temperature: 40°C Gradient:

[0311] Analytical LC / MS Analysis Method ZO:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-Pack Scepter C18, 33*3.0mm, 3um Temperature: 40°C Gradient:

[0312] Analytical LC / MS Analysis Method ZP:ESI+ / - ion mode 90-900 Wavelength: UV 254 nm / ELSD Column: Shim-pack C18, 33*3.0mm, 3um Temperature: 30 °C Gradient:Example 1: Method A: Synthesis of Compounds I-16 and I-17

[0313] Step 1: To a stirred solution of 1-(6-bromopyridin-3-yl) ethane-1-one (R-1, 2.0 g, 1.0mmol, 1.0 eq.) and 2-methylpropane-2-sulfinamide (1.45 g, 1.2 mmol, 1.2 eq.) in THF (5 mL) was added Ti(OiPr)4 (6.84 g, 3.0 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hrs, whereupon the reaction mixture was diluted with H2O (20 mL) andextracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 25%) to afford Int-1 (2.79 g, 9.24 mmol, 92%) as a yellow solid. LCMS (ESI): m / z = 303 [M+H]+.

[0314] Step 2: To a stirred solution of Int-1 (2.75 g, 9.11 mmol, 1.0 eq.) in MeOH (15 mL) wasadded NaBH4 (692 mg, 18.21 mmol, 2.0 eq.) slowly at 0oC. The resulting mixture was stirred at room temperature for 10 min, whereupon the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude Int-2 (2.7 g, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 305 [M+H]+.

[0315] Step 3: To a stirred solution of Int-2 (2.7 g, 8.88 mmol, 1.0 eq.) in THF (5 mL) was addedHCl (2 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 20 min. The reaction mixture was then concentrated under reduced pressure to afford crude Int-3 (1.6 g, 8.0 mmol, 90%) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 201 [M+H]+.

[0316] Step 4: To a stirred solution of Int-3 (4, 1.6 g, 8.0 mmol, 1.0 eq.) and TEA (2.424 g, 24.0mmol, 3.0 eq.) in DCM (10 mL) was added Boc2O (5.23 g, 24.0 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs, whereupon the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by flash column chromatography through silica gel (eluting with EtOAc in PE 0 to 25%) to afford Int-4 (2.2 g, 7.28 mmol, 92%) as a colorless oil. LCMS (ESI): m / z = 301 [M+H]+.

[0317] Step 5: To a stirred solution of Int-4 (500 mg, 1.67 mmol, 1 eq.) in THF (15 mL) wasadded n-BuLi (1.3 mL, 3.33 mmol, 2.5 M in THF, 2 eq.) at -78oC. The resulting mixture was stirred at -78oC for 20 min under N2, and then acetone (1 mL) was added, and the reaction mixture was stirred for an additional 15 min. The reaction mixture was then quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (elutingwith EtOAc in PE 0 to 50%) to afford Int-5 (158 mg, 0.56 mmol, 34%) as a white solid. LCMS(ESI): m / z = 281 [M+H]+.

[0318] Step 6: To a stirred solution of Int-5 (158 mg, 0.56 mmol, 1.0 eq.) in DCM (12 mL) wasadded TFA (1.2 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 2 hrs, whereupon the reaction mixture was concentrated under reduced pressure to afford crude Int-6 (142 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 181 [M+H]+.

[0319] Step 7: To a stirred solution of 6-chloro-1-methyl-1H-indole-2-carboxylic acid (R-2, 333mg, 1.59 mmol, 1.2 eq.) and HATU (605 mg, 1.59 mmol, 1.2 eq.) in DMF (10 mL) were addedTEA (402 mg, 3.97 mmol, 3 eq.) and Int-6 (240 mg, 1.33 mmol, 1.0 eq.). The resulting mixturewas stirred at room temperature for 30 min. The reaction mixture was then diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with PE: EtOAc = 1: 2) to afford Int-7 (210 mg, 0.56 mmol, 42%) as a white solid. LCMS (ESI): m / z = 372 [M+H]+.

[0320] Step 8: Int-7 (210 mg, 0.56 mmol, 1.0 eq.) was purified by SFC to I-16 (57.3 mg,0.15mmol, 55%) as a white solid and I-17 (55.3 mg, 0.149 mmol, 53%) as a white solid.

[0321] Compound I-17：>99% ee. Retention time:2.416 min. LC-MS (ESI): m / z =372.1[M+H]+;1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 7.9 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.2, 2.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.5, 1.7 Hz, 1H), 5.27-5.08 (m, 2H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.42 (s, 6H).

[0322] Compound I-16: 98% ee. Retention time: 3.711 min. LC-MS (ESI): m / z =372.3[M+H]+;1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.2, 2.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.5, 1.6 Hz, 1H), 5.28-5.09 (m, 2H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.42 (s, 6H).

[0323] SFC Method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralCelOJ, 250×20mm I.D., 5µm, Mobile phase: A for CO2 and B for EtOH（0.1% 7mol / L NH3 in MeOH）, Gradient: B 30 %, Flow rate: 40mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle-time:15 min, Eluted time：2 H.

[0324] Analytical Method: Column: ChiralCel OJ, 100×4.6mm I.D., 3um, Mobile phase: Afor CO2 and B for EtOH (0.05%DEA), Gradient: 8 min @B 30%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35 °C.

[0325] The following compounds were made using Method A, from the appropriate aminesand carboxylic acids: Compounds I-105, I-106, I-109, I-110, I-111, I-114, I-116, I-117, I-118, I-126, I-132, I-135, I-137, I-138, I-140, I-141, I-145, I-146, I-147, I-148, I-149, I-151, I-152, I- 153, I-154, I-156, I-159, I-160, I-161, I-162, I-163, I-164, I-165, I-166, I-167, I-168, I-169, I- 170, I-171, I-172, I-173, I-174, I-175, I-176, I-177, I-178, I-179, I-180, I-181, I-182, I-183, I- 184, I-223, I-224, I-237, I-238, I-22, I-23, I-399, I-400, I-415, I-416, I-427, I-428, I-447, I-448, I-469, I-470, I-471, I-472, I-616, I-617, I-624, I-625, I-626, and I-627. Example 2: Method B: Synthesis of Compound I-139

[0326] A solution of R-3 (80 mg, 0.379 mmol, 1.0 eq.) and R-4 (85 mg, 0.57 mmol, 1.5 eq.) inEtOH (5 mL) was stirred at 120oC overnight. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Compound I-139 (6.8 mg, 0.021 mmol, 6%) as a white solid.

[0327] LCMS (ESI): m / z = 330 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.95 (t, J = 6.3 Hz,1H), 8.04 (d, J = 2.0 Hz, 1H), 7.97-7.87 (m, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.8, 2.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 4.54 (d, J = 6.2 Hz, 2H), 4.44 (d, J = 6.5 Hz, 1H). Example 3: Method C: Synthesis of Compound I-123

[0328] Step 1: To a stirred solution of ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate (R-5,300 mg, 1.27 mmol, 1.0 eq.) in DMF (5 mL) was added NBS (271.2 mg, 1.52 mmol, 1.2 eq.) slowly. The resulting mixture was stirred at room temperature for 2 hrs, whereupon the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with PE: EtOAc = 0 to 10: 1) to afford Int-8 (393 mg, 1.25 mmol, 82%) as a white solid. LCMS (ESI): m / z = 316 [M+H]+.

[0329] Step 2: A mixture of Int-8 (393 mg, 1.25 mmol, 1 eq.), methylboronic acid (225 mg, 3.75mmol, 3.0 eq.), Pd(dppf)Cl2 (94 mg, 0.13 mmol, 0.1 eq.) and Cs2CO3 (1.22 g, 3.75 mmol, 3.0 eq.) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 105 °C under a nitrogen atmosphere overnight. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash columnchromatography on silica gel (eluting with PE: EtOAc = 10: 1) to afford ethyl Int-9 (235 mg, 0.94mmol, 75%) as a yellow oil. LCMS (ESI): m / z = 252 [M+H]+.

[0330] Step 3: To a stirred solution of Int-9 (300 mg, 1.27 mmol, 1.0 eq.) in EtOH (5 mL) wasadded an aqueous solution of NaOH (254 mg, 6.35 mmol, 5.0 eq.) slowly. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was neutralizedwith an aqueous solution of HCl (1 N) until the pH was adjusted to pH= 5-6. The solution was then extracted with DCM (10 mL x 3). The combined organic phases were dried over anhydrousNa2SO4 and concentrated under reduced pressure to afford Int-10 (200 mg, quant.), which wasused in the next step directly without further purification. LCMS (ESI): m / z = 224 [M+H]+.

[0331] Step 4: To a stirred solution of Int-10 (335 mg, 1.5 mmol, 1.0 eq.) and HATU (580 mg,1.5 mmol, 1.0 eq.) in DMF (5 mL) were added TEA (253 mg, 2.5 mmol, 1.7 eq.) and ethyl (R)-4-(1-aminoethyl)benzoate (R-6, 290 mg, 1.5 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) toafford Int-11 (354 mg, 0.89 mmol, 60%) as a white solid. LCMS (ESI): m / z = 399 [M+H]+.

[0332] Step 5: To a stirred solution of Int-11 (354 mg, 0.89 mmol, 1.0 eq.) in EtOH (5 mL) wasslowly added an aqueous solution of NaOH (178 mg, 4.45 mmol, 5.0 eq.). The resulting mixture was stirred at room temperature for 2 hrs, whereupon the reaction mixture was neutralized with an aqueous solution of HCl (1 N) until the pH was adjusted to pH= 5-6. Then the solution was extracted with DCM (10 mL x 3), and the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-12 (200 mg, quant.) which was used in the next step directly without further purification. LCMS (ESI): m / z = 371 [M+H]+.

[0333] Step 6: To a stirred solution of Int-12 (371 mg, 1.0 mmol, 1.0 eq.) and HATU (418 mg,1.1 mmol, 1.1 eq.) in DMF (5 mL) were added TEA (180 mg, 2.5 mmol, 2.5 eq.) and NH4Cl (294mg, 5.5 mmol, 5.5 eq.). The resulting mixture was stirred at room temperature for 30 min, whereupon the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with PE: EtOAc = 0 to 2: 1) to afford Compound I-123 (35 mg, 0.095 mmol, 10%) as a white solid. LCMS (ESI): m / z = 370 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.90 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.62-7.56 (m, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.09 (dd, J = 8.6, 1.7 Hz, 1H), 5.23 (p, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.34 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H).

[0334] The following compounds were made using Method C from the appropriate amines andcarboxylic acids: I-127, I-128, I-143, I-144, I-150, I-155, I-157, I-158 I-439, I-453, I-468, I-611, I-656, I-657, I-658, I-659, I-662, I-663, I-664, I-665, I-669, I-670, I-671, I-672, I-676, I-679, I- 680, I-681, I-682, I-690, I-693, I-694, I-742, , I-769, I-771, I-775and I-743. Example 4: Method D: Synthesis of Compound I-121

[0335] To a stirred solution of R-2 (800 mg, 3.83 mmol, 1.0 eq.) and HATU (1.6 g, 4.21 mmol,1.1 eq.) in DMF (20 mL) were added TEA (1159.8 mg, 11.48 mmol, 3.0 eq.) and ethyl (R)-4-(1- aminoethyl)benzoate (R-6, 812.6 mg, 4.21 mmol, 1.1 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature for 1 hr, whereupon the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 50%) to afford Int-13 (700 mg, 1.82mmol, 48%) as a white solid. LCMS (ESI): m / z = 385 [M+H]+.

[0336] To a stirred solution of Int-13 (700 mg, 1.89 mmol, 1 eq.) in THF (15 mL) was addedDIBAL-H (5 mL, 7.547 mmol, 1.5M in THF, 4 eq.) at 0oC. The resulting mixture was stirred at 0oC for 3 hrs under N2. The reaction mixture was then quenched with 10 mL of saturated aqueous potassium sodium tartrate, then was poured into H2O (15 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash columnchromatography on silica gel (eluted with EtOAc in PE 0 to 80%) to afford Compound I-121 (516 mg, 1.51 mmol, 84%) as a white solid.

[0337] LCMS (ESI): m / z = 343 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 8.1 Hz, 1H),7.67 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.18-5.05 (m, 2H), 4.46 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H). Example 5: Method E: Synthesis of Compound I-18 and Compound I-19

[0338] Step 1: To a stirred solution of 2-bromo-5-fluoroisonicotinic acid (R-7, 2.0 g, 9.1 mmol,1.0 eq.) in DMF (20 mL) were added Cs2CO3(6.0 g, 18.2 mmol, 2.0 eq.) and MeI (1.9 g, 13.7 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 30 min, whereupon the reaction had reached completion. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (40 mL x 3). The organic layers were combined and washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 10: 1) toafford Int-14 (1.9 g, 8.1 mmol, 89%) as a white solid. LCMS (ESI): m / z = 234 [M+H]+.

[0339] Step 2: To a mixture of Int-14 (1.9 g, 8.1 mmol, 1 eq.) and tributyl(1-ethoxyvinyl)stannane (R-8, 3.2 g, 8.91 mmol, 1.1 eq.) in toluene (100 mL) was added Pd(PPh3)4 (936 mg, 0.81 mmol, 0.1 eq.). The resulting mixture was stirred at 110 °C under nitrogen atmosphere overnight. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash columnchromatography on silica gel (eluted with PE: EtOAc =0 to 10: 1) to afford Int-15 (1.45 g, 6.48mmol, 80%) as a yellow oil. LCMS (ESI): m / z = 226 [M+H]+.

[0340] Step 3: To a stirred solution of Int-15 (1.45 g, 6.48 mmol, 1.0 eq.) in EtOAc (50 mL) wasadded HCl / 1,4-dioxane (20 mL). The resulting mixture was stirred at room temperature for 30 min. After completion, the solution was concentrated under reduced pressure to afford Int-16 (1.28g, quant.) as a white solid, which was used in the next step directly without further purification.LCMS (ESI): m / z = 198 [M+H]+.

[0341] Step 4: To a stirred solution of Int-16 (1.28 g, 6.48 mmol, 1.0 eq.) and 2-methylpropane-2-sulfinamide (862 mg, 7.13 mmol, 1.1 eq.) in THF (20 mL) was added Ti(OiPr)4 (3.68 g, 12.96 mmol, 1.5 eq.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hrs. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 4: 1) to afford Int-17 (956 mg, 2.9 mmol, 45%) as a yellow solid. LCMS (ESI): m / z = 329 [M+H]+.

[0342] Step 5: To a stirred solution of Int-17 (0.9 g, 2.9 mmol, 1.0 eq.) in MeOH (10 mL) wasadded NaBH4(138 mg, 3.48 mmol, 1.2 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 2: 1 to 1: 1) to afford Int-18 (0.8 g, 3 mmol, 86%) as a white solid. LCMS (ESI): m / z = 331 [M+H]+.

[0343] Step 6: To a stirred solution of Int-18 (0.8 g, 3 mmol, 1.0 eq.) in MeOH (10 mL) wasadded HCl / 1,4-dioxane (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was concentrated under reduced pressure to afford Int-19 (389 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 227 [M+H]+.

[0344] Step 7: To a stirred solution of R-2 (376 mg, 1.8 mmol, 1.2 eq.) and HATU (684 mg, 2.7mmol, 1.2 eq.) in DMF (10 mL) were added TEA (303 mg, 3 mmol, 2 eq.) and Int-19 (389 mg,1.5 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc =0 to 4: 1) to afford Int-20 (280 mg, 0.68 mmol, 45%) as a white solid. LCMS (ESI): m / z = 418 [M+H]+.

[0345] Step 8: To a stirred solution of Int-20 (280 mg, 0.68 mmol, 1.0 eq.) in MeOH (10 mL)was added an aqueous solution of LiOH (152 mg, 6.35 mmol, 5.0 eq.) slowly. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture wasneutralized with an aqueous solution of HCl (1 N) until the pH was adjusted to pH= 5-6. The solution was then extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-21 (200 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 376 [M+H]+.

[0346] Step 9: To a stirred solution of Int-21 (253 mg, 0.68 mmol, 1.0 eq.) and HATU (307 mg,0.81 mmol, 1.2 eq.) in DMF (10 mL) were added TEA (136 mg, 1.35 mmol, 2.0 eq.) and NH4Cl(127 mg, 2.4 mmol, 2.5 eq.). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 2: 1) to afford Int-22 (101 mg, 0.27 mmol, 40%) as a white solid. LCMS (ESI): m / z = 375 [M+H]+.

[0347] Step 10: Int-22 was further separated by Chiral SFC to give Compound I-19 (15mg,30%) and Compound I-18 (16 mg, 32%).

[0348] Compound I-19：>99% ee. Retention time: 2.872 min. LC-MS (ESI): m / z = 375.1[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.72-7.65 (m, 2H), 7.63 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 0.8 Hz, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[0349] Compound I-18：>99% ee. Retention time: 3.532 min. LC-MS (ESI): m / z = 375.1[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.72-7.66 (m, 2H), 7.63 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 0.9 Hz, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[0350] SFC Method: Instrument:Waters Thar 80 preparative SFC ,Column: (R,R)-WHELK,250×30mm I.D., 5µm, Mobile phase: A for CO2and B for MeOH( 0.1% 2mol / L NH3in MeOH), Gradient: B 45%, Flow rate: 60mL / min, Back pressure: 100 bar, Column temperature: 40 °C, Wavelength:220 nm, Cycle-time:8min, Eluted time: 3H.

[0351] Analytical Method: Instrument: Waters UPCC, (R,R)-WHELK, 100×4.6mm I.D., 3μm;Mobile phase: A for CO2and B for methanol (0.05% DEA); Gradient: 8 min @ 40% B; Flow rate: 2.0 mL / min; Column temperature: 40 °C.

[0352] The following compounds were made using Method C from the appropriate amines andcarboxylic acids: I-191, I-192, I-20, I-21, I-284, I-285, I-288, I-289, I-290, I-291, I-292, I-293,I-294, I-338, I-339, I-364, I-397, I-398, I-443, I-444, I-495, and I-496.Example 6: Method F: Synthesis of Compound I-119, I-120, and I-122

[0353] Step 1: To a stirred mixture of R-2 (74 mg, 3.54 mmol, 1.5 eq.) and HATU (180 mg, 4.72mmol, 2.0 eq.) in DMF (3 mL) were added R-9 (50 mg, 2.36 mmol, 1.0 eq.) and DIEA (122 mg, 9.43 mmol, 4.0 eq.). The resulting mixture was stirred at 25oC for 2 hrs. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30%, EtOAc in PE) to afford Compound I-122 (10 mg, 1.44 mmol, 61%) as a yellow solid. LCMS (ESI): m / z = 405.0 [M+H]+.

[0354] 1H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.48 (s, 1H), 7.45(s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 7.11 (dd, J = 8.5, 1.7 Hz, 1H), 3.93 (s, 3H), 1.29 (d, J = 8.1 Hz, 4H).

[0355] Step 2: To a stirred mixture of Compound I-122 (50 mg, 0.20 mmol, 1.0 eq.) in DMF (5mL) were added palladium(0) tetrakis(triphenylphosphine) (23 mg, 0.020 mmol, 0.1 eq.) and Zn(CN)2(23 mg, 0.20 mmol, 1.0 eq.). The resulting mixture was stirred at 120 °C for 4 hrs. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (10 mL), dried overNa2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with EtOAc in PE 0-30%) to afford Compound I-119 (30 mg, 0.143 mmol, 72%) as a yellow solid.

[0356] LCMS (ESI): m / z = 350.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 7.75 (d,J = 8.6 Hz, 2H), 7.68 (dd, J = 4.9, 3.4 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.27 (s, 1H), 7.12 (dd, J = 8.5, 1.8 Hz, 1H), 3.94 (s, 3H), 1.41 (s, 4H).

[0357] Step 3: To a solution of Compound I-119 (20 mg, 0.057 mmol, 1.0 eq.) in DMSO (20mL) were added K2CO3 (16 mg, 0.114 mmol, 2.0 eq.) and H2O2 (2 mL) at 0oC , the reaction mixture was stirred at 25oC under N2 for 2 hrs. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with EtOAc in PE 0-30%) to afford Compound I-120 (10 mg, 0.027 mmol, 48%) as a yellow solid. LCMS (ESI): m / z = 368.1 [M+H]+.1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 7.89 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.70- 7.65 (m, 2H), 7.26 (s, 3H), 7.24 (s, 1H), 7.12 (dd, J = 8.6, 1.7 Hz, 1H), 3.94 (s, 3H), 1.35 (s, 4H).

[0358] The following compounds were made using Method F from the appropriate amines andcarboxylic acids: I-99, I-100, I-107, and I-108. Example 7: Method G: Synthesis of Compound I-133

[0359] Step 1: To a stirred solution of 6-bromo-1H-indole-2-carboxylic acid (R-10, 1.8 g, 7.5mmol, 1.0 eq.) in DMF (50 mL) was added NaH (1.2 g, 30.0 mmol, 4.0 eq.) at 0oC. The resulting mixture was stirred for 0.5 hrs, at which point MeI (5.33 g, 37.5 mmol, 5.0 eq.) was added slowly. The resulting mixture was warmed to room temperature and stirred overnight. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 5 to 10%) to afford Int-23 (1.9 g, 7.0 mmol, 95%) as a white solid. LCMS (ESI): m / z = 268 [M+H]+.

[0360] Step 2: To a solution of Int-23 (1.0 g, 3.73 mmol, 1.0 eq.) in MeOH (20 mL) and H2O (5mL) was added LiOH.H2O (315 mg, 7.5 mmol, 2.0 eq.). The resulting mixture was stirred at room temperature overnight. After completion, the mixture was neutralized carefully with 1 N HCl (aq.) until the pH was adjusted to pH = 5-6. The resulting mixture was extracted with DCM (20 mL x 3), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, then concentrated under reduced pressure to give crude Int-24 (942 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 254 [M+H]+.

[0361] Step 3: To a solution of Int-24 (0.942 g, 3.71 mmol, 1.0 eq.) and HATU (1.7g, 4.45 mmol,1.2 eq.) in DMF (20 mL) were added R-4 (668 mg, 4.45 mmol, 1.2 eq.) and TEA (1.13 g, 11.13 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 0 to 3%) to afford Int-25 (0.726 g, 1.88 mmol, 51%) as a white solid. LCMS (ESI): m / z = 386 [M+H]+.

[0362] Step 4: To a solution of Int-25 (50 mg, 0.13 mmol, 1.0 eq.) and R-11 (26 mg, 0.16 mmol,1.2 eq.) in dioxane / H2O (5 mL / 1 mL) were added Na2CO3 (23 mg, 0.26 mmol, 2.0 eq.) and Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 eq.). The resulting mixture was degassed under vacuum and purged with N2several times. The resulting mixture was stirred at 100 °C for 4 hrs under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified via prep-HPLC (Welch-Ultimate AQ-C18, 21.2*250mm,5μm, H2O / MeCN (10- 95%) / 0.1% formic acid) to afford Compound I-133 (1.2 mg, 3.1 µmol, 2%) as a white solid. LCMS (ESI): m / z = 388 [M+H]+.

[0363] The following compounds were made using Method G from the appropriate amines andcarboxylic acids: I-129, I-130, I-131, I-134, I-136, and I-142. Example 8: Method H: Synthesis of Compound I-97 and Compound I-98

[0364] Step 1: To a stirred solution of R-1 (2.0 g, 10.05 mmol, 1.0 eq.) in DMF (20 mL) wasadded MeSNa (773.9 mg, 11.06 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 10: 1) to afford Int-26 (1.42 g, 8.50 mmol, 85%) as a yellow solid. LCMS (ESI): m / z = 168 [M+H]+.

[0365] Step 2: To a stirred solution of Int-26 (1.42 g, 8.5 mmol, 1.0 eq.) and 2-methylpropane-2-sulfinamide (1.13 g, 9.35 mmol, 1.1 eq.) in THF (20 mL) was added Ti(OiPr)4(3.62 g, 12.75 mmol, 1.5 eq.) at room temperature. The resulting mixture was stirred at 80 °C for 2 hrs. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 4: 1) to afford Int-27 (1.5 g, 5.55 mmol, 65%) as a yellow solid. LCMS (ESI): m / z = 271 [M+H]+.

[0366] Step 3: To a stirred solution of Int-27 (1.5 g, 5.55 mmol, 1.0 eq.) in MeOH (10 mL)was added NaBH4 (253 mg, 6.7 mmol, 1.2 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 2: 1 to 1: 1) to afford Int-28 (1.3 g, 4.78 mmol, 86%) as a white solid. LCMS (ESI): m / z = 273 [M+H]+.

[0367] Step 4: To a stirred solution of Int-28 (1.3 g, 4.78 mmol, 1.0 eq.) in MeOH (5 mL) wasadded HCl / dioxane (10 mL) slowly at room temperature. The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was concentrated under reduced pressure to afford Int-29 (880 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 169 [M+H]+.

[0368] Step 5: To a stirred solution of R-2 (491.2 mg, 2.35 mmol, 1.2 eq.) in DMF (10 mL)were added HATU (893 mg, 2.35 mmol, 1.2 eq.), TEA (396 mg, 3.92 mmol, 2 eq.) and Int-29(400 mg, 1.96 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 0 to 4: 1) to afford Int-30 (450 mg, 1.26 mmol, 64%) as a white solid. LCMS (ESI): m / z = 360 [M+H]+.

[0369] Step 6: To a stirred solution of Int-30 (400 mg, 1.02 mmol, 1.0 eq.) in THF (5 mL) wasadded aqueous solution of Oxone (0.6 mL, 5 mol / mL, 3.0 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography on C18 column (eluted with aqueous solution of TFA (0.1%): MeCN = 1: 10 to1: 40) to afford Int-31 (300 mg, 0.767 mmol, 75%) as a white solid. LCMS (ESI): m / z = 392[M+H]+.

[0370] Step 7: Int-31 (300 mg) was further separated by Chiral SFC to give Compound I-98(80.0 mg, 53%) & Compound I-97 (81.9 mg, 55%).

[0371] Compound I-98: >99% ee. Retention time: 3.029 min. LC-MS (ESI): m / z =392.0[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.5 Hz, 1H), 8.84 (d, J = 1.7 Hz, 1H),8.16 (dd, J = 8.1, 2.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.28 (s, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 5.28 (p, J = 7.2 Hz, 1H), 3.92 (s, 3H), 3.28 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0372] Compound I-97: >99% ee. Retention time: 5.044 min. LC-MS (ESI): m / z =392.0[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.5 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H),8.16 (dd, J = 8.2, 2.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.28 (s, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 5.28 (p, J = 7.2 Hz, 1H), 3.92 (s, 3H), 3.27 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0373] SFC Method: Instrument: Shimadzu pre solution SFC, Column: ChiralPak AD,250×30mm I.D., 5µm, Mobile phase: A for CO2and B for MeOH (0.1% 2mol / L NH3 in MeOH), Gradient: B 45%, Flow rate: 60mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle-time: 22 min, Eluted time: 2 H.

[0374] Analytical Method: Instrument: Waters UPCC, ChiralPak AD, 100×4.6mm I.D., 3μm;Mobile phase: A for CO2and B for methanol (0.05% DEA); Gradient: 8 min @ 40% B; Flow rate: 2.0 mL / min; Column temperature: 35 °C.

[0375] The following compounds were made using Method H from the appropriate amines andcarboxylic acids: I-103, I-104, I-112, I-113, I-124, I-125, I-215, I-216, I-295, I-308, I-309, I-324, I-325, I-337, I-360, I-361, I-502, I-591, I-592, I-618, and I-619.Example 9: Method I: Synthesis of Compound I-188 and Compound I-189

[0376] Step 1: To a stirred solution of Compound I-121 (160 mg, 0.47 mmol, 1.0 eq.) in DCM(10 mL) was added MnO2 (204 mg, 2.35 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the suspension was filtered through a pad of Celite®, and the filter cake was washed with DCM (10 mL). The combined filtrates wereconcentrated to dryness to give crude Int-32 (150 mg, quant.) as a yellow solid, which was usedin the next step directly without further purification. LCMS (ESI): m / z = 341 [M+H]+.

[0377] Step 2: To a stirred solution of Int-32 (150 mg, 0.44 mmol, 1.0 eq.) in THF (5 mL) wasadded MeMgBr (3.1 mL, 3.08 mmol, 7.0 eq., 1 M in THF) dropwise at 0 °C. After addition, theresulting mixture was warmed up to room temperature and stirred for 2 hrs. After the reaction had gone to completion, the reaction mixture was quenched with saturated NH4Cl aqueous solution (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Int-33 (90 mg, 0.25 mmol, 57%) as a white solid. LCMS (ESI): m / z = 357 [M+H]+.

[0378] Step 3: Int-33 (90 mg, 0.25 mmol, 1.0 eq.) was purified by SFC to afford Compound I-189 (20 mg, 22%) as a white solid and Compound I-188 (20 mg, 22%) as a white solid.

[0379] Compound I-189：>99% ee. Retention time:2.280 min. LC-MS (ESI): m / z = 357.4[M+H]+;1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.6, 1.7 Hz, 1H), 5.17-5.06 (m, 2H), 4.72-4.64 (m, 1H), 3.93 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H).

[0380] Compound I-188：>99% ee. Retention time:3.220 min. LC-MS (ESI): m / z = 357.4[M+H]+;1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.6, 1.6 Hz, 1H), 5.19-5.05 (m, 2H), 4.72-4.64 (m, 1H), 3.93 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H).

[0381] SFC Method: Instrument: Instrument: SHIMADZU PREP SOLUTION SFC, Column:ChiralCel OJ, 250×20mm I.D., 5µm, Mobile phase: A for CO2and B for MeOH（0.1% 7mol / L NH3 in MeOH）, Gradient: B 40 %, Flow rate: 40mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm, Cycle-time:15 min, Eluted time: 2 H.

[0382] Analytical Method: Column: ChiralCel OJ, 100×4.6mm I.D., 3um, Mobile phase: A forCO2and B for MeOH (0.05%DEA), Gradient: 8 min @B 40%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35 °C.Example 10: Method K: Synthesis of amine building blocks

[0383] To a solution of propyl aldehyde (R-14, 3.7 mL, 51.6 mmol, 1.0 eq.) in DCM(100 mL) were added (R)-(2-methylprop-2-yl)(oxo)-λ4-sulfanamine (7.5 g, 61.9 mmol, 1.2 eq.) and CuSO4 (19.8 g, 103.3 mmol, 2.0 eq.), the reaction mixture was stirred at 25 °C for 16 hrs. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 25%) to afford R-15 (3 g, 18.6 mmol, 36%) as an oil.

[0384] To a solution of R-16 (0.76 g, 3.7 mmol, 1.2 eq.) in THF (10 mL) was added n-BuLi (2.5mL, 3.9 mmol, 1.6M, 2.0 eq.) at -78 °C and the resulting mixture was stirred for 0.5 hrs, at which point R-15 (0.5 g, 3.1 mmol,1.0 eq.) was added. The reaction was stirred at 25 °C for 0.5 hrs. After completion, the reaction mixture was quenched with NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 30%) to give R-17 (0.35 g, 1.2 mmol, 40%) as an oil. LCMS (ESI): m / z = 286 [M+H]+.

[0385] To a solution of R-17 (100 mg, 0.35 mmol, 1.0 eq.) in DCM (10 mL) was added HCl (0.9mL, 3.503 mmol, 4M in 1,4-dioxane, 10.0 eq.) at 0oC. The resulting mixture was stirred at 30 °C for 0.5 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give R-18 (35 mg, 0.19 mmol, 55%) as a solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 182 [M+H]+.Example 11: Method R: Synthesis of Compound I-116

[0386] Step 1: To a stirred solution of R-40 (300 mg, 1.0 mmol, 1.0 eq.) in DMF (5 mL) wereadded Cs2CO3 (487.5 mg, 1.5 mmol, 1.5 eq.) and Iodomethane (156 mg, 1.1 mmol, 1.1 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature overnight. After completion, the reaction was poured into H2O (15 mL) and stirred at room temperature for 0.5hrs. The solid was collected by filtration and then concentrated under reduced pressure to afford Int- 34 (293 mg, 0.93 mmol, 92%) as a white solid. LCMS (ESI): m / z = 317 [M+H]+.

[0387] Step 2: To a solution of Int-34 (290 mg, 0.91 mmol, 1.0 eq.) and Sodium thiomethoxide(96 mg, 1.36 mmol, 1.5 eq.) in dioxane (5 mL) were added Xant-Phos (52 mg, 0.09 mmol, 0.1eq.), Pd2(dba)3 (83 mg, 0.09 mmol, 0.1 eq.) and DIPEA (293 mg, 2.27 mmol, 2.5 eq.). The resultingmixture was degassed under vacuum and purged with N2several times. The resulting mixture was stirred at 105 °C overnight under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 30%) to afford Int-35 (120 mg, 0.42 mmol, 46%) as a yellow oil.

[0388] Step 3: To a stirred solution of Int-35 (120 mg, 0.42 mmol, 1.0 eq.) in EtOH / water (8mL / 8 mL) was added NaOH (50 mg, 1.26 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was adjusted to pH=3 with aq.1N HCl. The solid was collected by filtration and then concentrated under reduced pressure to afford Int-36 (100 mg, 0.39 mmol, 92%) as a white solid. LCMS (ESI): m / z = 256 [M+H]+.

[0389] Step 4: To a stirred solution of Int-36 (100 mg, 0.39 mmol, 1.0 eq.) in DMF (8 mL) wereadded TEA (118 mg, 1.17 mmol, 3.0 eq.), HATU (163 mg, 0.43 mmol, 1.1 eq.) and R-4 (58 mg, 0.39 mmol, 1.0 eq.) slowly at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 0 to 5%) to afford Int-37 (60 mg, 0.16 mmol, 39%) as a yellow solid. LCMS (ESI): m / z = 388 [M+H]+.

[0390] Step 5: To a stirred solution of Int-37 (40 mg, 0.1 mmol, 1.0 eq.) in MeOH / H2O (5 mL / 5mL) were added Oxone (69 mg, 0.2 mmol, 2.0 eq.) at 0oC. The resulting mixture was stirred at room temperature overnight. After completion, the reaction mixture was filtered. The filtrate was purified by Prep-HPLC (Column : Shim-pack Scepter C18, 50*4.6mm, 5um,Mobile Phase : Solvent A: H2O / MeCN / FA = 90:10:0.05 Solvent B: CH3CN.Temperature : 40°C.Flow Rate : 2.5mL / min .Method : positive-negative 3min-1.lcm.Run Time : 0.01min @ 20% B, 1.79min gradient (20-95% B), then 0.7min @ 95% B) to afford Compound I-116 (5.7 mg, 0.01 mmol, 13%) as a yellow solid. LCMS (ESI): m / z = 420.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.37-9.29 (m, 1H), 8.44 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.44-7.38 (m, 3H), 7.32 (s, 1H), 4.53 (d, J = 6.0 Hz, 2H), 4.04 (s, 3H), 3.35 (s, 3H).Example 12 - Method L: Synthesis of amine building blocks

[0391] To a solution of R-19 (6 g, 34.4 mmol,1.0 eq.) in DCM (100 mL) were added 2-methylpropane-2-sulfinamide (5.01 g, 41.3 mmol, 1.2 eq.) and CuSO4(13.22 g, 68.8 mmol, 2.0 eq.). The reaction was stirred at 25 °C for 16 hrs. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 25%) to afford R-20 (3.7 g, 13.3 mmol, 39%) as an oil.

[0392] To a solution of R-21 (1.02 g, 4.3 mmol, 1.2 eq.) in THF (15 mL) was added n-BuLi (4.5mL, 7.2 mmol, 1.6M, 2.0 eq.) at -78 °C and the resulting mixture was stirred for 0.5 hrs, then R- 20 (1 g, 3.6 mmol, 1.0 eq.) was added, the reaction was stirred at 25 °C for 0.5 hrs. The reaction mixture was then poured into NH4Cl solution (50 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 40%) to give R-22 (0.35 g, 0.81 mmol, 18%) as an oil. LCMS (ESI): m / z = 435 [M+H]+.

[0393] To a solution of R-22 (200 mg, 0.46 mmol, 1.0 eq.) in DCM (10 mL) was added HCl (1.8mL). The resulting mixture was stirred at 30 °C for 0.5 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give R-23 (80 mg, 0.193 mmol, 55.11%) as solid. LCMS (ESI): m / z = 217 [M+H]+.

[0394] Method L was used to make the key amine building blocks for the compounds listed, withthe general amide coupling procedures as shown in Method H used to complete the final compounds: I-440, I-441, I-442, I-450, I-454, I-455, and I-456. Example 13 - Method T: Synthesis of Compound I-43

[0395] Step 1: To a stirred solution of Int-39 (150 mg, 0.024 mmol, 1 equiv) andzincdicarbonitrile (60.65 mg, 0.516 mmol, 1.5 equiv) in DMF (10mL) was added BrettPhos (18.48 mg, 0.034 mmol, 0.1 equiv) and BrettPhos Pd G3 (31.21 mg, 0.034 mmol, 0.1 equiv) at rt under N2 atmosphere. Then the solution was stirred for 10h at 50°C. The reaction was quenched by the addition of brine (100mL) at RT and the resulting mixture was extracted with EA (3 x 60mL). The combined organic layers were concentrated under reduced pressure to provide crude Int-40, which was used in the next step directly without further purification. LC-MS: M+H found 382.15.

[0396] Step 2: To a stirred solution of Int-40 (100 mg, 0.262 mmol, 1 equiv) in NH3(g) inMeOH (10 mL, 70.000 mmol, 267.27 equiv) was added DBU (199.36 mg, 1.310 mmol, 5 equiv) at rt. Then the solution was stirred for 2 h at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=5 / 1). The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26% B to 51% B in 8 min;Wave Length: 220nm nm; RT1(min): 7.6) to afford Compound I-43 (17.8 mg, 18.51%) as a white solid. LC-MS: M+H found 367.15.1H NMR (400 MHz, DMSO-d6) δ 9.28 – 9.24 (t, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.71 – 7.65 (m, 4H), 7.22 (s, 1H), 7.15 – 7.12 (dd, J = 12.0, 4.0 Hz, 1H), 4.62 – 4.61 (d, J = 4.0 Hz, 2H), 3.98 (s, 3H). The following compounds were made using Method T, from the appropriate amines and carboxylicacids: I-79, I-80 I-77, I-710, I-726, and I-727.

[0397] .Example 14 - Method M: Synthesis of amine building blocks

[0398] To a solution of R-24 (500 mg, 3.35 mmol, 1.0 eq.) in THF (5 mL) wereadded bromo(cyclopropyl)magnesium (10.0 mL, 10.05 mmol, 3.0 eq., 1 M) and NaBH4 (254 mg, 6.70 mmol, 2.0 eq.) at 0 °C. The mixture was warmed up to room temperature and stirred for 1 hr. After completion, the reaction mixture was quenched with NH4Cl solution (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (eluted with DCM: MeOH = 0 to 10: 1) to afford R-25as a white solid. LCMS (ESI): m / z = 194 [M+H]+.

[0399] Method M was used to make the key amine building blocks for the compounds listed,with the general amide coupling procedures as shown in Method H used to complete the final compounds: I-419 and I-420. Example 15 - Method N: Synthesis of amine building blocks

[0400] To a stirred solution of R-26 (400 mg, 1.5 mmol, 1.0 eq.) in THF (20 mL) was addedNaH (120 mg, 60 wt% in mineral oil, 2 eq.) at 0 °C, the mixture was stirred at room temperature for 2 hrs, and then MeI (280 mg, 2 mmol, 1.3 eq.) was added dropwise. The reaction mixture wasstirred for 2hrs, then was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 10%) to afford R-27 (300 mg, 1.1 mmol, 71%) as a white solid. LCMS (ESI): m / z = 280 [M+H]+. Example 16: Method O: Synthesis of amine building blocks

[0401] To a stirred solution of R-4 (150 mg, 1.0 mmol, 1.0 eq.) in PPA (10 mL) was added 1,3-dioxol-2-one (129 mg, 1.5 mmol, 1.5 eq.) slowly at room temperature. The resulting mixture was stirred at 170oC for 3 hrs. After completion, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 5 to 8%) to afford R-28 (62 mg, 0.36 mmol, 36%) as a colorless oil. LCMS (ESI): m / z =175 [M+H]+. Example 17: Method P: Synthesis of amine building blocks

[0402] To a stirred solution of 4-cyanobenzoic acid (R-29, 500 mg, 3.4 mmol, 1.0 eq.) in THF(20 mL) were added cyclopropylmagnesium bromide (8.5 mL, 30.0 mmol, 2.5 eq.) at 0oC slowly.The resulting mixture was warmed to room temperature and stirred for 4 hrs. After completion, the reaction mixture was concentrated under reduced pressure to afford R-30 (642 mg, quant.) as a white solid, which was used directly without further purification. LCMS (ESI): m / z = 188 [M- H]-.

[0403] To a solution of R-30 (642 mg, 3.4 mmol, 1.0 eq.) in MeOH (20 mL) was added NaBH4(260 mg, 6.8 mmol, 2.0 eq.). The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford R-31 (650 mg, quant.) as a white solid which was used directly without further purification LCMS (ESI): m / z = 190 [M-H]-.

[0404] To a solution of R-31 (650 mg, 3.4 mmol, 1.0 eq.) in DCM (20 mL) were added (Boc)2O(667 mg, 5.1 mmol, 1.5 eq.) and TEA (1.06g, 10.2 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The organic layers were combined and washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 10 to 15%) to afford R-32 (300 mg, 1.03 mmol, 30%) as a white solid. LCMS (ESI): m / z = 236 [M+H-56]+.

[0405] To a solution of R-32 (300 mg, 1.03 mmol, 1.0 eq.) and CMPI (790 mg, 3.09 mmol, 3.0eq.) in DMF (10 mL) were added NH4Cl (83 mg, 1.55 mmol, 1.5 eq.), DMAP ( 13 mg, 0.31 mmol, 0.1 eq.) and TEA (313 mg, 3.09 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 1 hr. After completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 0 to 5%) to afford R-33 (114 mg, 0.39 mmol, 38%) as a colorless oil. LCMS (ESI): m / z = 291 [M+H]+.

[0406] To a solution of R-33 (114 mg, 0.39 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (2mL). The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to afford R-34 (74 mg, quant.) as a colorless oil, which was used in next step directly without further purification. LCMS (ESI): m / z = 191 [M+H]+.Example 18 - Method Q: Synthesis of carboxylic acid building blocks

[0407] To a stirred solution of 5-chloro-N-methyl-2-nitroaniline (R-35, 673 mg, 3.62 mmol, 1.0eq.) in EtOH (20 mL) and H2O (5 mL) were added Fe dust (1.01 g, 18.1 mmol, 5.0 eq.) and NH4Cl (1.94 g, 36.2 mmol, 10.0 eq.) at room temperature slowly. The resulting mixture was stirred at 70oC for 1 h. After completion, the reaction mixture was filtered and purified by flash column chromatography on silica gel (eluted with EtOAc in PE 15 to 25%) to afford R-36 (460 mg, 2.95 mmol, 82%) as a white solid. LCMS (ESI): m / z = 155 [M-H]-.

[0408] To a solution of R-36 (460 mg, 2.95 mmol, 1.0 eq.) in toluene (20 mL) and AcOH (5 mL)was added methyl 2,2,2-trichloroacetimidate (573 mg, 3.25 mmol, 1.1 eq.). The resulting mixture was stirred at 100 °C overnight under N2. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 5 to 10%) to afford R-37 (574 mg, 2.02 mmol, 68.58%) as a white solid. LCMS (ESI): m / z = 281 [M- H]-.

[0409] A solution of R-37 (520 mg, 1.83 mmol, 1.0 eq.) in MeOH (15 mL) was stirred at 70 oCfor 3 days. After completion, the reaction mixture was concentrated under reduced pressure to afford R-38 (250 mg, 1.11 mmol, 60.98%) as a white solid. LCMS (ESI): m / z = 225 [M+H]+.

[0410] To a solution of R-38 (200 mg, 0.89 mmol, 1.0 eq.) in MeOH (6 ml) and H2O (1 mL) wasadded NaOH (36 mg, 0.89 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was cooled down in an ice bath, then neutralizedcarefully with 1 N HCl (aq.) until the pH was adjusted to pH = 5-6. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried over with anhydrous Na2SO4, then concentrated under reduced pressure to give crude R-39 (187 mg, quant.) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 211 [M+H]+. Example 19 - Method S: Synthesis of Compound I-95

[0411] Step 1: To a stirred solution of R-41 (2.6 g, 10.831 mmol, 1 equiv) in THF (5 mL,61.714 mmol, 74.07 equiv) was added BH3.THF (16.25 mL, 16.246 mmol, 1.5 equiv) at rt under N2 atmosphere. Then the solution was stirred for 4h at RT. Desired product could be detected by LCMS. The reaction was quenched by the addition of brine (100mL) at rt. The resulting mixture was extracted with EtOAc (3 x 50mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5 / 1) to afford Int-38 (830 mg, 31.40%) as a yellow solid. LC-MS: M+H found 246.00.

[0412] Step 2: To a stirred solution of Int-38 (800 mg, 3.278 mmol, 1 equiv) and R-2 (1.03 g,4.917 mmol, 1.5 equiv) in DCM (25 mL) were added EDCI (0.94 g, 4.917 mmol, 1.5 equiv) and DMAP (0.60 g, 4.917 mmol, 1.5 equiv) at rt. The reaction mixture was stirred for 1h at rt, then was quenched by the addition of brine (100 mL) at RT. The resulting mixture was extracted with DCM (3 x 60 mL) and the combined organic layers were concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford Int-39 (1.22 g, 85.43%) as a white solid. LC-MS: M+H found 437.00.

[0413] Step 3: To a stirred solution of Int-39 (80 mg, 0.184 mmol, 1 equiv) in DMF (1 mL,12.922 mmol, 70.37 equiv) were added DBU (139.77 mg, 0.920 mmol, 5 equiv) and NH3(g) in MeOH (10 mL, 70.000 mmol, 381.24 equiv) at RT. The reaction mixture was stirred for 24h at 70°C, whereupon the solvent was removed under vacuum and the product was precipitated by addition of EtOAc. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to 55% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.72) to afford Compound I-95 (9.4 mg, 12.06%) as a white solid.

[0414] LC-MS: M+H found 419.85. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 6.1 Hz, 1H),7.84 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 17.5 Hz, 2H), 7.37 (d, J = 1.5 Hz, 2H), 7.18 (s, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 4.47 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H).

[0415] The following compounds were made using Method S, from the appropriate amines andcarboxylic acids: I-81, I-93, I-92, I-91, I-90, I-89, I-88, I-74, I-675, I-687, I-701, and I-725. Example 20: Method U: Synthesis of Compound I-94

[0416] Step 1: A mixture of R-42 (200 mg, 1.211 mmol, 1 equiv), NH4Cl (97.18 mg, 1.817mmol, 1.5 equiv), EDCI (348.29 mg, 1.817 mmol, 1.5 equiv) and DMAP (221.96 mg, 1.817 mmol, 1.5 equiv) in DCM (2 mL) was stirred for 4 h at rt under air atmosphere. The resultingmixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH (15 / 1)) to provide Int-41 (195 mg, 98.08%) as a white solid. LC-MS: M+H found: 163.00.

[0417] Step 2: A mixture of Int-41 (175 mg, 1.066 mmol, 1 equiv) and Pd / C (35.17 mg, 0.330mmol, 0.31 equiv) in MeOH (4 mL) was stirred for 4h at rt under H2 atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x50 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by Prep-TLC (DCM / MEOH (15 / 1)) to afford Int-42 (48 mg, 26.77%) as a white solid. LC-MS: M+H found: 169.00.

[0418] Step 3: A mixture of R-2 (90 mg, 0.429 mmol, 1 equiv), Int-42 (108.30 mg, 0.643mmol, 1.5 equiv), EDCI (123.45 mg, 0.643 mmol, 1.5 equiv) and DMAP (78.68 mg, 0.643 mmol, 1.5 equiv) in DCM (1 mL) was stirred for 2h at rt under air atmosphere. The reaction mixture was then quenched by the addition of brine (10 mL) at RT. The resulting mixture was extracted with DCM (3 x 10mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MEOH (20 / 1)) to afford the crude product, which was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to 52% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.85; Number Of Runs: 2) to afford Compound I-94 (17.3 mg, 11.15%) as a white solid. LC-MS: M+H found: 360.00.

[0419] 1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 6.1 Hz, 1H), 7.72 – 7.58 (m, 5H), 7.26 –7.17 (m, 3H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H).

[0420] The following compounds were made using Method U, from the appropriate aminesand carboxylic acids: I-96, I-85, I-84, I-83, I-82, and I-71.Example 21: Method V: Synthesis of Compound I-52

[0421] Step 1: A mixture of Int-39 (100 mg, 0.230 mmol, 1 equiv)，cyclopropylboronic acid(29.57 mg, 0.345 mmol, 1.5 equiv)，2nd Generation XPhos Precatalyst / X-Phos aminobiph (36.12 mg, 0.046 mmol, 0.2 equiv)，XPhos (36.11 mg, 0.076 mmol, 0.33 equiv) and K3PO4(97.44 mg, 0.460 mmol, 2 equiv) in methylbenzene (0.5 mL) and H2O (0.1 mL) was stirred for 16 h at 60°C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MEOH (20 / 1)) to afford Int-43 (47 mg, 51.60%). LC-MS: M+H found: 397.15.

[0422] Step 2: To a stirred mixture of Int-43 (47 mg, 0.118 mmol, 1 equiv) in MeOH (0.5mL) was added NaOH (0.5 mL, 0.500 mmol, 4.22 equiv) dropwise at RT. The resulting mixture was stirred for an additional 16 h at 50°C. The mixture was acidified to pH 1 with HCl(1moL / L), then was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH (5 / 1)) to afford Int-44 (40 mg, 88.23%) as a white solid. LC-MS: M+H found: 383.15.

[0423] Step 3: A mixture of Int-44 (30 mg, 0.078 mmol, 1 equiv), NH4Cl (4.61 mg, 0.086mmol, 1.1 equiv), HATU (44.69 mg, 0.117 mmol, 1.5 equiv) and DIEA (15.19 mg, 0.117 mmol, 1.5 equiv) in THF (0.3 mL) was stirred for 2h at 50°C under air atmosphere. The crude reaction mixture was cooled to RT and was purified directly by Prep-TLC (DCM / MEOH (20 / 1)) to afford the crude product, which was further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A:Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 56% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.6) to afford Compound I-52 (3 mg, 9.52%) as a white solid. LC-MS: M+H found: 382.10.1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 6.0 Hz, 1H), 7.67 (d, J = 9.1 Hz, 3H), 7.36 (s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.16 – 7.08 (m, 3H), 6.88 (s, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.96 (d, J = 1.5 Hz, 3H), 2.31 (d, J = 6.1 Hz, 1H), 0.92 (d, J = 8.2 Hz, 2H), 0.63 (d, J = 5.3 Hz, 2H).

[0424] The following compounds were made using Method V, from the appropriate aminesand carboxylic acids: I-51, I-65, I-365, and I-366. Example 22: Method W: Synthesis of Compound I-87

[0425] Step 1: To a stirred solution of R-43 (1000 mg, 2.933 mmol, 1 equiv) and Pd(PPh3)4(169.47 mg, 0.147 mmol, 0.05 equiv) in DMF (20 mL) was added Zn(CN)2 (413.28 mg, 3.520 mmol, 1.2 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 20 h at 70°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE: EA = 3:1) to afford Int- 45 (600 mg, 85.22%) as an off-white solid.

[0426] Step 2: To a stirred solution of Int-45 (600 mg, 2.499 mmol, 1 equiv) in THF (10 mL)was added BH3-THF (7.50 mL, 7.497 mmol, 3 equiv) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under N2 atmosphere, then was concentrated under vacuum. The residue was purified by Prep-TLC (DCM: MeOH 20:1) to afford Int-46 (470 mg, 77.04%) as an off-white solid.

[0427] Step 3: To a stirred solution of Int-46 (450 mg, 1.844 mmol, 1 equiv) and EDCI (706.84mg, 3.688 mmol, 2 equiv) in DCM (10 mL) were added R-2 (579.71 mg, 2.766 mmol, 1.5 equiv) and DMAP (675.70 mg, 5.532 mmol, 3 equiv) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under N2atmosphere, then was concentrated under vacuum. The residue was purified by Prep-TLC (PE: EA 3:1) to afford Int-47 (500 mg, 62.25%) as an off-white solid.

[0428] Step 4: A solution of Int-47 (20 mg, 0.046 mmol, 1 equiv) and DBU (20.97 mg, 0.138mmol, 3 equiv) in NH3(g) in MeOH (2 mL) was stirred for 16 h at 50°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3) + 0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 58% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7.93) to afford Compound I-87 (6.4 mg, 32.84%) as an off-white solid. LC-MS:(M+H)+ found 420.00. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 5.9 Hz, 1H), 8.18 – 8.03(m, 2H), 7.86 (dd, J = 8.0, 1.8 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.58 – 7.40 (m, 2H), 7.26 (d, J = 0.8 Hz, 1H), 7.13 (dd, J = 8.4, 1.9 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.98 (s, 3H). Example 23: Method X: Synthesis of Compound I-15

[0429] Step 1: To a stirred solution of R-44 (200 mg, 0.864 mmol, 1 equiv) in DMF (4 mL)was added NaH (41.47 mg, 1.728 mmol, 2 equiv) in portions at 0°C. The resulting mixture was stirred for 0.5h at 0°C, then was treated with SEMCl (288.09 mg, 1.728 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred for an additional 2h at RT, then was extracted with EA (3 x 20 ml). The combined organic layers were washed with saturated brine (2x50 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EA 3:1) to afford Int-48 (250 mg, 79.99%) as a yellow oil. LC-MS: M+H found: 361.00.

[0430] Step 2: A mixture of Int-48 (240 mg, 0.663 mmol, 1 equiv), Zn(CN)2 (116.86 mg, 0.995mmol, 1.5 equiv) and Pd(PPh3)4 (153.34 mg, 0.133 mmol, 0.2 equiv) in DMF (3 mL) was stirred for 2h at 80°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 10 ml), and the combined organic layers were washed with saturated brine (2x20 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EA = 3:1) to afford Int-49 (180 mg, 88.13%) as a yellow solid. LC-MS: M+H found:308.10.

[0431] Step 3: A mixture of Int-49 (170 mg, 0.552 mmol, 1 equiv), HCONH2 (170 mg, 3.774mmol, 6.83 equiv) and PdCl2 (170 mg, 0.452 mmol, 0.82 equiv) in THF (2 mL) and H2O (0.7 mL) was stirred for 16 h at 50°C under N2atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 1:1) to afford Int-50 (100 mg, 55.57%) as a yellow solid. LC-MS: M+H found:326.10.

[0432] Step 4: A mixture of Int-50 (90 mg, 0.276 mmol, 1 equiv), R-45 (98.21 mg, 0.414mmol, 1.5 equiv), K3PO4(175.87 mg, 0.828 mmol, 3 equiv) and CataCxium A Pd G3 (25.85 mg, 0.028 mmol, 0.1 equiv) in dioxane (2 mL) and H2O (0.4 mL) was stirred for 2h at 100°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 10 ml), and the combined organic layers were washed with saturatedbrine (2x20 ml), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (DCM:MeOH = 10:1) to afford Int-51 (45 mg, 38.74%) as a yellow solid. LC-MS: M+H found:421.25.

[0433] Step 5: To a stirred solution of Int-51 (40 mg, 0.095 mmol, 1 equiv) in DCM (0.5 mL)was added HCl (gas)in 1,4-dioxane (0.25 mL) dropwise at 0°C. The resulting mixture was stirred for 2h at RT, then was concentrated under reduced pressure to afford Int-52 (18 mg, 99.50%) as a yellow solid. LC-MS: M+H found:191.10.

[0434] Step 6: A mixture of Int-52 (15 mg, 0.079 mmol, 1 equiv), R-2 (19.84 mg, 0.095 mmol,1.2 equiv), EDCI (22.68 mg, 0.118 mmol, 1.5 equiv) and DMAP (14.45 mg, 0.118 mmol, 1.5 equiv) in DCM (0.5 mL) was stirred for 2h at RT. The resulting mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford crude products. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3) + 0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 22% B to 49% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7.93) to afford Compound I-15 (12.6 mg, 41.64%) as a white solid. LC-MS: M+H found: 382.05.1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.24 (s, 1H), 7.13 (dd, J = 8.5, 1.9 Hz, 1H), 4.81 (d, J = 5.9 Hz, 2H), 3.98 (s, 3H).Example 24: Method Y: Synthesis of Compound I-78Compound I-78

[0435] Step 1: A solution of R-46 (250 mg, 1.041 mmol, 1 equiv) and BH3-THF (179.00 mg,2.082 mmol, 2 equiv) in THF (5 mL) was stirred for 2h at RT. The reaction was quenched with MeOH (5 ml) at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford Int-53 (150 mg, 59.01%) as a yellow solid. LC-MS: M+H found: 244.00.

[0436] Step 2: A mixture of Int-53 (140 mg, 0.574 mmol, 1 equiv), R-2 (132.26 mg, 0.631mmol, 1.1 equiv), EDCI (164.93 mg, 0.861 mmol, 1.5 equiv) and DMAP (105.11 mg, 0.861 mmol, 1.5 equiv) in DCM (3 mL) was stirred for 2h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford Int-54 (160 mg, 64.03%) as a white solid. LC-MS: M+H found:435.05.

[0437] Step 3: A mixture of Int-54 (150 mg, 0.344 mmol, 1 equiv) and DBU (262.06 mg,1.720 mmol, 5 equiv) in NH3(g) in MeOH (3 mL) was stirred for 16 h at 50°C. The mixture was allowed to cool down to RT, and the resulting mixture was concentrated under reduced pressure.The residue was purified by Prep-TLC (DCM:MeOH 15:1) to afford Int-55 (110 mg, 75.95%) as a white solid. LC-MS: M+Na found:441.95.

[0438] Step 4: A mixture of Int-55 (100 mg, 0.238 mmol, 1 equiv), Zn(CN)2 (41.87 mg, 0.357mmol, 1.5 equiv), BrettPhos Pd G3 (43.10 mg, 0.048 mmol, 0.2 equiv) and BrettPhos (25.52 mg, 0.048 mmol, 0.2 equiv) in DMF (5 mL) was stirred for 3 h at 50°C under N2 atmosphere. The mixture was allowed to cool down to RT, then was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford crude products. The crude products were purified by reverse phase flash with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to 52% B in 7 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.9; Number Of Runs: 2) to afford Compound I-78 (23.0 mg, 25.75%) as a white solid. LC-MS: M+H found:367.00.1H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J = 6.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 1.7 Hz, 2H), 7.73 – 7.65 (m, 2H), 7.60 (dd, J = 8.0, 1.7 Hz, 1H), 7.25 – 7.18 (m, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H).

[0439] The following compounds were made using Method Y, from the appropriate amines,carboxylic acids, and boronate reagents: I-76, I-75, I-66, I-695, and I-696. Example 25: Method Z: Synthesis of Compound I-72, Compound I-73, and Compound I- 86

[0440] Step 1: A mixture of R-47 (20 mg, 0.083 mmol, 1 equiv), R-2 (17.32 mg, 0.083 mmol,1 equiv), EDCI (23.75 mg, 0.124 mmol, 1.5 equiv) and DMAP (15.14 mg, 0.124 mmol, 1.5 equiv) in DCM (0.5 mL) was stirred for 2h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 3:1) to afford crude products. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 66% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.67) to afford Compound I-86 (7.9 mg, 21.94%) as a white solid. LC-MS: M+H found: 432.95.1H NMR (400 MHz, DMSO- d6) δ 7.69 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.4, 4.0 Hz, 3H), 7.41 (s, 2H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 6.73 (s, 1H), 5.52 (s, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.00 – 3.71 (m, 6H), 3.59 (td, J = 11.7, 2.8 Hz, 1H), 3.20 (s, 1H).

[0441] Step 2: A mixture of Compound I-86 (120 mg, 0.277 mmol, 1 equiv), Zn(CN)2 (48.73mg, 0.416 mmol, 1.5 equiv), BrettPhos Pd G3 (50.16 mg, 0.055 mmol, 0.2 equiv) and BrettPhos (29.70 mg, 0.055 mmol, 0.2 equiv) in DMF (5 mL) was stirred for 3 h at 50°C under N2 atmosphere. The mixture was allowed to cool down to RT, and the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EA 3:1) to afford crude product. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: I; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 66% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.67) to afford Compound I-72 (10.5 mg, 9.93%) as a white solid. LC-MS: M+H found: 380.10.

[0442] 1H NMR (400 MHz, DMSO-d6) δ 7.97 – 7.77 (m, 2H), 7.77 – 7.50 (m, 4H), 7.11 (dd, J= 8.4, 1.8 Hz, 1H), 6.77 (s, 1H), 5.64 (s, 1H), 4.49 (d, J = 12.5 Hz, 1H), 4.01 – 3.80 (m, 6H), 3.61 (td, J = 11.7, 2.8 Hz, 1H), 3.25 (s, 1H).

[0443] Step 3: A mixture of Compound I-72 (100 mg, 0.263 mmol, 1 equiv), PdCl2 (93.37mg, 0.526 mmol, 2 equiv) and HCONH2(100 mg, 2.220 mmol, 8.43 equiv) in THF (3 mL) and H2O (1 mL) was stirred for 2 h at 50°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH 15:1) to afford crude products. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26% B to 51% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.22) to afford Compound I-73 (61.1 mg, 57.52%) as a white solid. LC-MS: M+H found: 398.05.1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.95 – 7.86 (m, 2H), 7.74 – 7.65 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (s, 2H), 7.39 (s, 1H), 7.10 (dd, J = 8.5, 1.8 Hz, 1H), 6.74 (s, 1H), 5.59 (s, 1H), 4.50 (d, J = 12.3 Hz, 1H), 3.96 – 3.79 (m, 6H), 3.60 (td, J = 11.7, 2.8 Hz, 1H), 3.25 (s, 1H).

[0444] The following compounds were made using Method Z, from the appropriate aminecompounds: I-67, I-68, I-63, I-64, I-61, I-62, I-59, I-60, I-53, I-54, I-55, I-56, I-57, I-58, I-49, I-48, I-46, I-47, I-48, and I-44. Example 26: Method ZA: Synthesis of Compound I-42 and Compound I-41

[0445] Step 1: To a stirred solution of R-2 (200 mg, 0.954 mmol, 1 equiv) and R-48 (234.96mg, 1.431 mmol, 1.5 equiv) in DCM (15 mL) were added EDCI (274.34 mg, 1.431 mmol, 1.5 equiv) and DMAP (174.84 mg, 1.431 mmol, 1.5 equiv) at rt. The reaction mixture was stirred for 2h at rt, then was quenched by the addition of brine (150mL) at rt. The aqueous layer was extracted with EA (3x50mL) and the combined layers were concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford Int-56 (305 mg, 89.85%) as a white solid. LC-MS: M+H found 356.10

[0446] Step 2: To a stirred solution of Int-56 (290 mg, 0.815 mmol, 1 equiv) and formamide(293.69 mg, 6.520 mmol, 8 equiv) in THF (12 mL) and H2O (4 mL, 160.962 mmol, 197.50 equiv) was added PdCl2 (289.05 mg, 1.630 mmol, 2 equiv) at rt. The resulting reaction mixture was stirred for 2h at rt, then was quenched by the addition of brine (150mL) at rt. The aqueous layer was extracted with EA (3x60mL) and the combined layers were concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography, eluted with PE / EA(1 / 1). The crude product was further purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 33% B to 58% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.62) to afford Int-57 (195 mg, 64.00%) as a white solid. LC- MS: M+H found 374.10.

[0447] Step 3: Int-57 (20 mg, 0.054 mmol, 1 equiv) was purified by chiral HPLC to affordCompound I-42 (3.4 mg, 16.47%) as a white solid and Compound I-41 (4.8 mg, 23.86%) as a white solid. LC-MS: M+H found 374.15.

[0448] Compound I-42 : 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.6 Hz, 1H), 8.01 (s,1H), 7.74 – 7.67 (m, 2H), 7.71 – 7.61 (m, 2H), 7.57 (t, J = 7.8 Hz,1H), 7.47 (s, 1H), 7.30 (d, J = 0.8 Hz, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.43 – 5.29 (m, 1H), 3.91 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[0449] Compound I-41 : 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.6 Hz, 1H), 8.01 (s,1H), 7.73 – 7.66 (m, 2H), 7.69 – 7.60 (m, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.30 (s, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.36 (dt, J = 17.6, 8.9 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[0450] The following compounds were made using Method ZA, from the appropriate amines:I-70, I-69, I-40, I-39, I-32, I-31, I-583, I-584, I-708, and I-709.Example 27: Method ZB: Synthesis of Compound I-50

[0451] Step 1: To a stirred solution of R-49 (200 mg, 0.858 mmol, 1 equiv) and R-2 (269.85mg, 1.287 mmol, 1.5 equiv) in DCM (4 mL) were added EDCI (246.77 mg, 1.287 mmol, 1.5 equiv) and DMAP (157.27 mg, 1.287 mmol, 1.5 equiv) in portions at rt. The resulting mixture was stirred for 2h at rt, then was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA=3:1) to afford Int-58 (180 mg, 49.39%) as a yellow solid. LC-MS: M+H found: 425.0

[0452] Step 2: To a stirred solution of Int-58 (100 mg, 0.235 mmol, 1 equiv) and R-50 (74.50mg, 0.470 mmol, 2 equiv) in dioxane (2 mL) were added EPhos Pd G4 (32.45 mg, 0.035 mmol, 0.15 equiv) and Cs2CO3 (153.45 mg, 0.470 mmol, 2 equiv) in portions at rt. The resulting mixture was stirred for 16h at 100 °C under N2atmosphere, then was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O ), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23% B to 48% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7; Number Of Runs: 1) to afford Compound I-50 (32.1 mg, 29.79%) as a white solid. LC-MS: M-H found: 455.0.1H NMR (400 MHz, DMSO-d6) δ 10.67 – 8.53 (m, 4H), 7.60 (d, J = 5.0 Hz, 4H), 7.35 – 6.84 (m, 6H), 4.30 (d, J = 6.1 Hz, 2H), 4.04 – 3.85 (m, 3H). Example 28: Method ZC: Synthesis of Compound I-35 and Compound I-36

[0453] Step 1: A mixture of R-51 (500 mg, 3.122 mmol, 1 equiv) and Ti(Oi-Pr)4 (8872.08 mg,31.220 mmol, 10 equiv) in NH3(g) in MeOH (5 mL) and MeOH (2 mL) was stirred for 48 h at RT. To the above mixture was added NaBH4 (118.09 mg, 3.122 mmol, 1 equiv) at RT, and the resulting mixture was stirred for 2h at RT. The reaction mixture was then filtered, and the filter cake was washed with MeOH (3x10 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (1:1) to afford Int-59 (250 mg, 49.68%) as a white solid. LC-MS: M-NH2+H found: 145.10.

[0454] Step 2: A mixture of Int-59 (250 mg, 1.551 mmol, 1 equiv), R-2 (390.11 mg, 1.861mmol, 1.2 equiv), EDCI (445.93 mg, 2.326 mmol, 1.5 equiv) and DMAP (284.19 mg, 2.326 mmol, 1.5 equiv) in DCM (5 mL) was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to afford crude products. The crude products were purified by reverse phase flash with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=11--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 13.49; RT2(min): 20.84; SampleSolvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.5 mL; Number Of Runs: 10) to afford Int-60 (150 mg, 27.41%) as a white solid. LC-MS: M+H found:353.05.

[0455] Step 3: Int-60 was further purified by Prep Chiral HPLC (Column: CHIRALPAK IG,2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH) -HPLC, Mobile Phase B: MeOH: DCM=11--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 13.49; RT2(min): 20.84; Sample Solvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.5 mL; Number Of Runs: 10) to afford Compound I-36 (68.8 mg, 45.50%) as a white solid and Compound I-35 (70.9 mg, 46.98%) as a white solid. LC-MS: M+H found:353.05.

[0456] Compound I-36: 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.93 (d, J = 8.2 Hz,1H), 8.04 (t, J = 1.2 Hz, 1H), 7.75 (s, 1H), 7.69 – 7.64 (m, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.7, 1.6 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.27 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H).

[0457] Compound I-35: 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.93 (d, J = 8.2 Hz,1H), 8.04 (t, J = 1.2 Hz, 1H), 7.74 (s, 1H), 7.70 – 7.62 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.7, 1.6 Hz, 1H), 7.24 (d, J = 0.8 Hz, 1H), 7.11 (dd, J = 8.6, 1.8 Hz, 1H), 5.27 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H).

[0458] The following compounds were made using Method ZC, from the appropriate ketonesand amines: I-37, I-38, I-560, I-561, I-562, and I-563. Example 29: Method ZD: Synthesis of Compound I-33 and Compound I-34

[0459] Step 1: To a mixture of R-52 (900 mg, 4.568 mmol, 1 equiv) and R-8 (3315mg) in DMF (10 mL) was added Pd(PPh3)2Cl2 (644 mg) under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 12h at 80°C under nitrogen atmosphere, and the reaction mixture was then concentrated under reduced pressure. The crude residue was extracted with 3x20 mL of ethyl acetate. The combined organic phases were washed with 5 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with (DCM: MeOH=10:1) to afford Int-61 (850 mg, 98.86%) as a yellow oil. LC-MS: (ES, m / z): RT =0.736 min, LCMS: m / z =189.20 [M+H].

[0460] Step 2: A mixture of Int-61 (930 mg, 4.941 mmol, 1 equiv) in HCl (3.5 mL) and THF(7 mL) under an atmosphere of air at room temperature was stirred for 1h at room temperature. The mixture was then acidified to pH 7 with NaOH (2mol / L). The resulting mixture was concentrated under reduced pressure to provide crude Int-62, which was used in the next step directly without further purification. LC-MS: (ES, m / z): RT =0.517 min, LCMS: m / z =161.05 [M+H].

[0461] Step 3: A mixture of Int-62 (650 mg, 4.058 mmol, 1 equiv) and Ti(OiPr)4 (11537mg) in MeOH (6 mL) and NH3(g) in MeOH (6 mL) was stirred under an atmosphere of air at room temperature for 36 h. The reaction mixture was then treated with NaBH4(155 mg), and the resulting mixture was stirred for 1h at room temperature. The reaction mixture was thenconcentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography, eluted with MeOH (100%) to afford Int-63 (350 mg, 53.50%) as a yellow solid. LC-MS: (ES, m / z): RT =0.371 min, LCMS: m / z =162.00 [M+H].

[0462] Step 4: To a mixture of Int-63 (300 mg, 1.861 mmol, 1 equiv) and R-2 (351 mg, 1.674mmol, 0.90 equiv) in DCM (5 mL) were added EDCI (536 mg, 2.796 mmol, 1.50 equiv) and DMAP (341 mg, 2.791 mmol, 1.50 equiv) under an air atmosphere at room temperature. The resulting mixture was stirred for 2h at room temperature, then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (2:1) to afford crude product. The crude product was further purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to 53% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.73). This resulted in Int-64 (102 mg, 15.54%) as a white solid. LC-MS: (ES, m / z): RT =0.830 min, LCMS: m / z =353.05 [M+H].

[0463] Step 5: Int-64 (102 mg, 0.289 mmol, 1 equiv) was purified by Prep-CHIRAL-HPLCwith the following conditions (Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 8.53; RT2(min): 10.85; Sample Solvent: MEOH: DCM=1: 1; Injection Volume: 0.5 mL; Number Of Runs: 13). This resulted in Compound I-34 (36.3 mg, 35.02%) as a white solid, and Compound I-33 (35.6 mg, 34.59%) as a white solid. LC-MS: (ES, m / z): RT =0.989 min, LCMS: m / z =353.05 [M+H],

[0464] Compound I-33 : 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.99 (d, J = 8.0 Hz,1H), 8.42 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.70 – 7.65 (m, 2H), 7.62 (t, J = 3.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.4, 1.8 Hz, 1H), 6.53 (t, J = 2.5 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H). LC-MS: (ES, m / z): RT =0.983 min, LCMS: m / z =353.05 [M+H].

[0465] Compound I-34 : 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.99 (d, J = 8.0 Hz,1H), 8.41 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.61 (t, J = 3.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.6, 1.8 Hz, 1H), 6.52 (t, J = 2.6 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H). LC-MS: (ES, m / z): RT =0.989 min, LCMS: m / z =353.05 [M+H].

[0466] The following compounds were made using Method ZD, from the appropriate reagents:I-335, I-336, I-340, I-341, I-377, I-378, I-379, I-380, I-385, I-386, I-389, I-401, I-402, I-411, I- 412, I-437, I-438, I-545, I-546, I-547, I-548, I-549, I-550,I-603, I-604, I-607, I-608, I-609, I- 610, I-702, I-703, I-704, and I-705. Example 30: Method ZE: Synthesis of Compound I-30

[0467] Step 1: To a stirred solution of R-53 (150 mg, 0.776 mmol, 1 equiv) and R-2 (244.08mg, 1.164 mmol, 1.5 equiv) in DCM (2 mL) were added EDCI (223.20 mg, 1.164 mmol, 1.5 equiv) and DMAP (142.25 mg, 1.164 mmol, 1.5 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h, then was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=1 / 1) to afford Int-65 (83 mg, 10.84%) as a white solid. LC-MS: M+H found: 385.20.

[0468] Step 2: A stirred solution of Int-65 (73 mg, 0.190 mmol, 1 equiv) and DBU (144.38mg, 0.950 mmol, 5 equiv) in NH3(g) in MeOH (2 mL) at RT was heated to 70°C and stirred at that temperature for 16h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA= 1:1) to give the crude product, which was further purified by Prep-HPLC with the following conditions（Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 8.07）toafford Compound I-30 (6.6 mg, 9.27%) as a white solid. LC-MS: M+H found:370.05.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.88 (s, 1H), 7.83 – 7.76 (m, 2H), 7.70 – 7.62 (m, 2H), 7.50 – 7.43 (m, 2H), 7.29 – 7.23 (m, 2H), 7.12 (dd, J = 8.5, 1.8 Hz, 1H), 3.83 (s, 3H), 1.68 (s, 6H). Example 31: Method ZF: Synthesis of Compound I-2, Compound I-28, and Compound I- 29

[0469] Step 1: A mixture of R-54 (800 mg, 4.166 mmol, 1 equiv) and Ti(OiPr)4 (11082mg) in MeOH (4 mL) and NH3(g) in MeOH (4 mL) under atmosphere at room temperature was stirred for 36 h, and then was treated with NaBH4 (149 mg). The resulting reaction mixture was stirred for an additional 1h at room temperature, then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elutedwith MeOH (100%) to Int-66 (300 mg, 34.77%) as a yellow oil. LC-MS: (ES, m / z): RT =0.127 min, LCMS: m / z =209.00 [M+H].

[0470] Step 2: To a mixture of Int-66 (20 mg, 0.097 mmol, 1 equiv) and R-2 (18 mg) in DCM(0.5 mL) was added EDCI (28 mg) and DMAP (18 mg) under atmosphere at room temperature. The resulting mixture was stirred for 2h at room temperature, then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (2:1) to afford crude product, which was further purified by Prep-HPLC with the following conditions (Column: ER Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 39% B to 64% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.75). This resulted in Compound I-2 (7.9 mg, 20.41%) as a white solid. LC-MS: (ES, m / z): RT =1.257 min, LCMS: m / z =399.90 [M+H].1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 1.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.4, 1.9 Hz, 1H), 5.25 (p, J = 7.2 Hz, 1H), 4.10 (q, J = 5.3 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 1.51 (d, J = 7.0 Hz, 3H).

[0471] Step 3: To a stirred solution of Compound I-2 (100 mg, 0.251 mmol, 1 equiv) and R-55 (52 mg) in DMSO (1 mL) were added CuI (5 mg), L-proline (7 mg) and NaOH (1.4 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 7h at 100°C under nitrogen atmosphere. The resulting mixture was extracted with EA (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (DCM: MeOH=20:1) to afford crude product. This resulted in Int-67 (90 mg, 90.18%) as a yellow solid. LC-MS: (ES, m / z): RT =0.927 min, LCMS: m / z =398.00 [M+H].

[0472] Step 4: Int-67 (110 mg, 0.276 mmol, 1 equiv) was further purified by Prep-CHIRAL-HPLC with the following conditions (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220 / 254 nm; RT1(min): 10.835; RT2(min): 13.168; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 12). This resulted in Compound I-29 (19.5 mg, 16.93%) as a white solid.LC-MS: (ES, m / z): RT =1.594 min, LCMS: m / z =397.95 [M+H], and Compound I-28 (23.4 mg, 19.80%) as a white solid, LC-MS: (ES, m / z): RT =1.601 min, LCMS: m / z =397.95 [M+H].

[0473] Compound I-28 : 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 8.0 Hz, 1H), 8.02 (d,J = 0.8 Hz, 1H), 7.71 – 7.60 (m, 2H), 7.26 (s, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 5.36 (p, J = 7.0 Hz, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H).

[0474] Compound I-29 : 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 8.0 Hz, 1H), 8.02 (d,J = 0.9 Hz, 1H), 7.71 – 7.63 (m, 2H), 7.28 – 7.23 (m, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 5.36 (p, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H).

[0475] The following compounds were made using Method ZF, from the appropriate reagents:I-403, I-404, I-424, I-435, I-601, I-602, I-612, I-613, I-620, I-621, I-636, I-637, -646, I-647, I-667, I-668, I-677, I-678, I-691, I-692, I-706, I-707, I-241, and I-242.Example 32: Method ZG: Synthesis of Compound I-1

[0476] To a mixture of Compound I-2 (20 mg, 0.050 mmol, 1 equiv) in THF (0.3 mL) undernitrogen at -78°C was added n-BuLi (0.1 mL, 1 M in THF). The resulting mixture was stirred for 10 min at -78°C, then CO2was added in portions over 1 min at -60 °C to -78 °C. The resulting mixture was stirred for 15 min at -60 °C to -78°C, then was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 15% B to 35% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.5; Number Of Runs: 2). This resulted in Compound I-1 (5.5 mg, 29.84%) as a white solid. LC-MS: (ES, m / z): RT =0.839 min, LCMS: m / z =363.95 [M+H].1H NMR (400 MHz, DMSO-d6) δ 9.09 – 8.59 (m, 1H), 7.63 – 7.45 (m, 2H), 7.21 – 6.97 (m, 3H), 5.66 – 5.20 (m, 1H), 3.90 (d, J = 6.8 Hz, 3H), 1.41 (dd, J = 39.6, 6.9 Hz, 3H).

[0477] The following compounds were made using Method ZG, from the appropriate reagents(carbonylation, followed by amide formation where appropriate): I-333, I-334, I-390, I-426, I- 473, I-479, I-638, I-639, I-660, I-661, I-757, I-217, I-218, I-220, I-221, I-244, and I-245. Example 33 - Method ZH: Synthesis of Compound I-3, Compound I-26, and Compound I- 27

[0478] Step 1: To a stirred solution of R-2 (30 mg, 0.143 mmol, 1 equiv) and R-56 (48.96 mg,0.214 mmol, 1.5 equiv) in DCM (5 mL) were added EDCI (41.15 mg, 0.214 mmol, 1.5 equiv) and DMAP (26.23 mg, 0.214 mmol, 1.5 equiv) at rt. The reaction mixture was stirred for 2h at rt, at which point the desired product could be detected by LCMS. The reaction was quenched by the addition of brine (150mL) at rt, and the aqueous layer was extracted with DCM (3x50mL). The combined layers were concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1). The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 55% B to 80% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.88) to afford to afford Compound I-4 (24.8 mg, 40.63%) as a white solid. LC-MS: M+H found 421.05.

[0479] Compound I-4 : 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 8.4 Hz, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 6.6 Hz, 2H), 7.14 – 7.01 (m, 3H), 5.23 (q, J = 6.9 Hz, 1H), 4.31 (ddt, J = 15.2, 11.4, 5.6 Hz, 2H), 4.02 (s, 3H), 2.11 (s, 2H).

[0480] Step 2: To a stirred mixture of Compound I-4 (200 mg, 0.477 mmol, 1 equiv) andZn(CN)2 (83.93 mg, 0.716 mmol, 1.5 equiv) in DMF (12 mL) was added BrettPhos (25.58 mg, 0.048 mmol, 0.1 equiv) and BrettPhos Pd G3 (43.20 mg, 0.048 mmol, 0.1 equiv) at rt under N2 atmosphere. The resulting reaction mixture was stirred for 16h at 60°C, whereupon the reaction was quenched by the addition H2O (150mL), and then extracted with EA (3*40mL) at rt. The organic layers were combined and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=2 / 1) to afford Int-68 (100 mg, 57.36%) as a white solid. LC-MS: M+H found 366.10.

[0481] Step 3: The Int-68 (30 mg, 0.082 mmol, 1 equiv) was purified using chiral HPLC toafford Compound I-27(4.2 mg, 13.68%) as a white solid. LC-MS: M-H found 364.00, and Compound I-26 (4.3 mg, 14.33%) as a white solid. LC-MS: M+H found 366.10

[0482] Compound I-26 : 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 8.4 Hz, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.32 (dq, J = 3.1, 1.7 Hz, 2H), 7.18 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.33 (q, J = 6.8, 6.0 Hz, 1H), 4.35 (qp, J = 7.7, 3.8 Hz, 2H), 4.02 (s, 3H), 2.14 (tddt, J = 18.1, 11.5, 7.7, 3.8 Hz, 2H).

[0483] Compound I- 27: 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 8.3 Hz, 1H), 7.73 –7.68 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 0.9 Hz, 1H), 7.37 – 7.28 (m, 2H), 7.18 (d, J = 0.9 Hz, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 5.38 – 5.29 (m, 1H), 4.35 (qp, J = 7.6, 3.6 Hz, 2H), 4.02 (s, 3H), 2.23 – 2.09 (m, 2H).

[0484] The following compounds were made using Method ZH, from the appropriate amines:I-3, I-24, I-25, I-326, I-482, I-760, and I-761.Example 34 - Method ZJ: Synthesis of Compound I-9 and Compound I-10

[0485] Step 1: To a mixture of R-57 (400 mg, 2.190 mmol, 1 equiv) and R-2 (630 mg) in DCM(5 mL) was added EDCI (789 mg) and DMAP (670 mg) under atmosphere at room temperature. The resulting mixture was stirred for additional 2 h at room temperature under atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1:1) to afford Int-70 (660 mg, 89.21%) as a white solid. LC-MS: (ES, m / z): RT =0.972 min, LCMS: m / z =338.15 [M+H].

[0486] Step 2: To a solution of Int-70 (260 mg, 0.770 mmol, 1 equiv) in THF (3mL) was added B2H5-THF (2.5 mL) under atmosphere at room temperature. The resultingmixture was stirred for 2h at room temperature, and the resulting mixture was then extracted with EA and NH4Cl (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-Flash (DCM: MeOH=15:1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 18% B to 30% B in8min; Wave Length: 254nm / 220nm nm; RT1(min): 7.12). This resulted in Int-71 (11 mg, 4.18%) as a white solid. LC-MS: (ES, m / z): RT =0.563 min, LCMS: m / z =341.10 [M+H].

[0487] Step 3: The Int-71 (11 mg, 0.032 mmol, 1 equiv) was purified by Prep-CHIRAL-HPLCwith the following conditions (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.2% IPAmine), Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min;Gradient: 20% B to 20% B in 14 min; Wave Length: 220 / 254 nm; RT1(min): 10.665; RT2(min): 11.731; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 7). This resulted in Compound I-10 (3.7 mg, 32.66%) as a white solid, and also Compound I-9 (2.7 mg, 22.95%) as a white solid.

[0488] Compound I-9: LC-MS: (ES, m / z): RT =0.988 min, LCMS: m / z =340.05 [M+H]. 1HNMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.24 – 6.64 (m, 3H), 5.39 – 4.99 (m, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[0489] Compound I-10: LC-MS: (ES, m / z): RT =0.988 min, LCMS: m / z =340.05 [M+H]; 1HNMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.25 – 6.63 (m, 3H), 5.80 – 5.27 (m, 1H), 5.13 (p, J = 7.1 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 1.47 (d, J = 7.0 Hz, 3H). Example 35 - Method ZI: Synthesis of Compound I-13 and Compound I-14

[0490] Step 1: To a stirred solution of Int-68 (125 mg, 0.342 mmol, 1 equiv) and formamide(123.12 mg, 2.736 mmol, 8 equiv) in THF (6 mL) and H2O (2 mL) was added PdCl2 (121.18 mg, 0.684 mmol, 2 equiv) at rt under N2atmosphere. The resulting reaction mixture was stirred for 2 h at 50°C, then was quenched by the addition of brine (150mL) at rt. The aqueous layer was extracted with EA (3 x 50mL) and the combined organic layers were concentrated under reducedpressure. The residue was purified by Prep-TLC (EA). The crude product was purified by reverse phase flash chromatograpy with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 55% B to 80% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.88) to afford Int-69 (35 mg, 26.69%) as a white solid. LC-MS: M+H found 384.15.

[0491] Step 2: The Int-69 (17 mg, 0.044 mmol, 1 equiv) was further purified by chiral HPLCto afford Compound I-14 (5.0 mg, 28.97%) as a white solid. LC-MS: M-H found 384.20, and Compound I-13 (6.7 mg, 39.18%) as a white solid. LC-MS: M-H found 384.20.

[0492] Compound I-13 : 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.4 Hz, 1H), 7.92 (s,2H), 7.70 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.0, 1.8 Hz, 1H), 7.36 – 7.30 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J = 8.4, 1.9 Hz, 1H), 5.31 (q, J = 7.0 Hz, 1H), 4.40 – 4.24 (m, 2H), 4.03 (s, 3H), 2.12 (m, 2H).

[0493] Compound I-14 : 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 8.4 Hz, 1H), 7.91 (s,2H), 7.70 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.43 – 7.36 (m, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.31 (d, J = 7.2 Hz, 1H), 4.33 (m, 2H), 4.30 (s, 3H), ,2.12 (m, 2H).

[0494] Further analysis established that Compound I-13 has the stereochemical configurationset forth in Compound I-776.

[0495] The following compounds were made using Method ZI, from the appropriate amines:Compounds I-11, I-12, I-593, I-594, I-595, I-596, I-736, I-737, I-745, I-750, I-751, I-752, I-753, and I-754.Example 36 - Method ZK: Synthesis of Compound I-7 and Compound I-8

[0496] Step 1: A mixture of R-58 (350 mg, 1.605 mmol, 1 equiv), R-2 (336.46 mg, 1.605mmol, 1 equiv), EDCI (615.36 mg, 3.210 mmol, 2 equiv) and DMAP (392.17 mg, 3.210 mmol, 2 equiv) in DCM (5 mL) was stirred for 2h at rt. The resulting mixture was then concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography, eluted with PE: EA=3:1 to afford Int-72 (500 mg, 76.04%) as a white solid. LCMS: (ES, m / z): RT =0.929 min, LCMS: m / z =409.05 [M+H].

[0497] Step 2: A mixture of Int-72 (560 mg, 1.367 mmol, 1 equiv), (tributylstannyl)methanol(R-59, 658.36 mg, 2.050 mmol, 1.5 equiv) and Pd(PPh3)2Cl2(191.89 mg, 0.273 mmol, 0.2 equiv) in DMF (6 mL) was stirred for 16 h at 120°C under N2atmosphere. The mixture was allowed to cool down to rt, then was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2x80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography, eluted with DCM:MeOH=15:1 to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 37% B to 62% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.65; Number Of Runs: 4) to afford Int-73 (280 mg, 56.77%) as a white solid. LCMS: (ES, m / z): RT =0.917 min, LCMS: m / z =361.00 [M+H].

[0498] Step 3: The Int-73 (270 mg, 0.748 mmol, 1 equiv) underwent further purification bySFC (Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: 15% B to 15% B in 26 min; Wave Length: 220 / 254 nm; RT1(min): 16.104; RT2(min): 19.231; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.25 mL; Number Of Runs: 24) to afford Compound I-8 (88.7 mg, 32.62%) as a white solid, and Compound I-7 (107.7 mg, 39.69%) as a white solid.

[0499] Compound I-7 : LCMS: (ES, m / z): RT =1.429 min, LCMS: m / z =361.20 [M+H], 1HNMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 8.0 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (s, 1H), 7.22 (dd, J = 7.8, 1.7 Hz, 1H), 7.18 (dd, J = 11.4, 1.7 Hz, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 5.22 – 5.09 (m, 2H), 4.51 (d, J = 5.5 Hz, 2H), 3.93 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H).

[0500] Compound I-8 : LCMS: (ES, m / z): RT =0.841 min, LCMS: m / z =361.25 [M+H], 1HNMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 8.0 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.23 – 7.20 (m, 1H), 7.20 – 7.15 (m, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 5.16 (dt, J = 14.2, 6.5 Hz, 2H), 4.51 (d, J = 5.4 Hz, 2H), 3.93 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H).

[0501] The following compounds were made using Method ZK, from the appropriate amines:I-5, I-6, I-634, I-635, I-711, I-712, I-713, I-714, I-715, I-716, I-717, I-718, I-719, and I-720. Example 37: Synthesis of amine building blocks

[0502] Step1: To a stirred solution of 5-cyanopicolinic acid (R-12, 200 mg, 1.35 mmol, 1.0 eq.)in DCM (5 mL) were added NH4Cl (87 mg, 1.62 mmol, 1.2 eq.), CMPI (518 mg, 2.03 mmol, 1.5 eq.), TEA (409 mg, 4.05 mmol, 3.0 eq.) and DMAP (16 mg, 0.14 mmol, 0.1 eq) at room temperature. The resulting reaction mixture was stirred at room temperature for 0.5 h, whereupon the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with MeOH in DCM 0 to 2%) to afford R-13 (40 mg, 0.27 mmol, 20%) as a yellow solid. LCMS (ESI): m / z = 148 [M+H]+.

[0503] Step 2: To a stirred solution of R-13 (40 mg, 0.27 mmol, 1.0 eq.) in MeOH (5 mL) wasadded Pd / C (50 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (10mL). The combined filtrates were concentrated to dryness to give R-13-A (40 mg, quant.) as a white solid. LCMS (ESI): m / z = 152 [M+H]+. Example 38: Method ZL: Synthesis of Compound I-254 and Compound I-255

[0504] Step 1: To a solution of 6-chloro-N-(1-(4-(cyanomethyl)phenyl)ethyl)-1-methyl-1H-indole-2-carboxamide (Int-74, 50 mg, 0.14 mmol, 1.0 eq.) in DMSO (10 mL) were added K2CO3 (39 mg, 0.28 mmol, 2.0 eq.) and H2O2 (1 mL) at 0oC . The reaction mixture was warmed up to room temperature and stirred for 2 hrs. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with EtOAc in PE 0-30%) to afford Int- 75 (43 mg, 0.12 mmol, 83%) as a white solid. LCMS (ESI): m / z = 370 [M+H]+.

[0505] Step 2: Int-75 (43 mg, 0.12 mmol, 1.0 eq.) was purified by SFC to afford Compound I-254 (15 mg, 34%) as a white solid and Compound I-255 (13 mg, 30%) as a white solid.

[0506] Compound I-254：>99% ee. Retention time: 3.392 min. LC-MS (ESI): m / z = 370.2[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.44 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.27-7.17 (m, 3H), 7.12-7.10 (m, 1H), 6.84 (s, 1H), 5.16- 5.09 (m, 1H), 3.93 (s, 3H), 3.36 (s, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0507] Compound I-255：99% ee. Retention time: 4.488 min. LC-MS (ESI): m / z = 370.2[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 7.76-7.61 (m, 2H), 7.44 (s,1H), 7.32 (d, J = 8.0 Hz, 2H), 7.25-7.16 (m, 3H), 7.11 (dd, J = 8.6, 1.6 Hz, 1H), 6.84 (s, 1H), 5.21-5.03 (m, 1H), 3.93 (s, 3H), 3.37 (s, 2H), 1.47 (d, J = 7.0 Hz, 3H).

[0508] SFC Method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPakIH, 250×20mm I.D., 5 µm Mobile phase: A for CO2and B for MeOH (0.1% 2mol / L NH3in MeOH), Gradient: B 30%, Flow rate:40 mL / min, Back pressure: 100 bar, Column temperature: 35oC, Wavelength: 220 nm. Cycle-time:15 min, Injection volume: 3.4 mL, Number of injection needles: 5, Eluted time: 3 H. The 43 mg sample was dissolved in 10 mL MeOH. Analytical Method: ChiralPak AS, 100×4.6mm I.D., 3μm; Mobile phase: A for CO2 and B for methanol (0.05%DEA); Gradient: 8 min @ 30% B; Flow rate: 2.5 mL / min; Column temperature: 40oC. Example 39: Method ZK-1: Synthesis of Compounds I-306 and Compound I-307

[0509] Step 1: To a stirred solution of R-2 (102.4 mg, 0.49 mmol, 1.2 eq.), HATU (187 mg, 0.49mmol, 1.2 eq.) and TEA (82.82 mg, 0.82 mmol, 2 eq.) in DMF (5 mL) was added 1-(pyrimidin-5-yl)ethan-1-amine (R-60, 50 mg, 0.41 mmol, 1.2 eq.). The resulting mixture was stirred at r.t. for 30 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (25 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-76 (20 mg,0.064 mmol) as a white solid. LCMS (ESI): m / z = 315 [M+H]+.

[0510] Step 2: Int-76 was further purified by Chiral SFC to give Compound I-306 (6 mg, 30%)as a white solid and Compound I-307 (7 mg, 35%) as a white solid.

[0511] Compound I-306: >99% ee. Retention time: 3.770 min. LCMS (ESI): m / z =315[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.02 (d, J = 7.7 Hz, 1H), 8.86 (s, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.24 (s, 1H), 7.12 (dd, J = 8.5, 1.5 Hz, 1H), 5.20 (p, J = 7.1 Hz, 1H), 3.92 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0512] Compound I-307: >99% ee. Retention time: 2.774 min. LCMS (ESI): m / z =315[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.02 (d, J = 7.7 Hz, 1H), 8.86 (s, 2H), 7.68 (t, J = 4.3 Hz, 2H), 7.24 (s, 1H), 7.15 – 7.09 (m, 1H), 5.20 (t, J = 7.2 Hz, 1H), 3.92 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0513] SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: (R, R)-WHELK,250 × 20 mm I.D., 5 µm; Mobile phase: A for CO2 and B for MeOH (0.1% 7mol / L NH3 in MeOH); Gradient: B 40%; Flow rate:40mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 15 min; Eluted time: 2H.

[0514] Analytical Method: Instrument: Shimadzu E-UC; Column: (R,R)-WHELK, 250×20mm I.D., 5 µm; Mobile phase: A for CO2 and B for MeOH (0.05% DEA); Gradient: B 40%; Flow rate: 2mL / min; Back pressure: 100 bar; Column temperature: 40°C; Wavelength: 220nm; Cycle- time:8min; Eluted time: 2H.

[0515] The crude product was purified by reverse phase flash with the following conditions(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26% B to 51% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.6) to afford Compound I-43 (17.8 mg, 18.51%) as a white solid. LC-MS: M+H found 367.15.1H NMR (400 MHz, DMSO- d6) δ 9.28 – 9.24 (t, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.71 – 7.65 (m, 4H), 7.22 (s, 1H), 7.15 – 7.12 (dd, J = 12.0, 4.0 Hz, 1H), 4.62 – 4.61 (d, J = 4.0 Hz, 2H), 3.98 (s, 3H).

[0516] The following compounds were made using Method ZK-1 from the appropriate aminesand carboxylic acids: I-312, I-313, I-355, I-356, I-357, I-432, I-433, I-483, I-484, I-493, I-494, I-666, I-732, I-734, I-735, and I-770.Example 40: Method ZL-1: Synthesis of Compounds I-300 and Compound I-301

[0517] Step 1: To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (R-61, 300 mg, 2.11mmol, 1.0 eq.), DIEA (544 mg, 4.21 mmol, 2.0 eq.) and CsF (639 mg, 4.21 mmol, 2.0 eq.) in dioxane (5 mL) was added cyclopropanol (183 mg, 3.16 mmol, 1.5 eq.). The resulting mixture was stirred at 100 ℃ for 18 h. After completion, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE, from 0 to 10%) to afford Int-77 (140 mg, 0.85 mmol, 41%) as a yellow solid. LCMS (ESI): m / z = 165 [M+H]+.

[0518] Step 2: To a solution of Int-77 (140 mg, 0.85 mmol, 1.0 eq) and (2-methylprop-2-yl)(oxo)-λ4-sulfanamine (114 mg, 0.94 mmol, 1.1 eq.) in THF (10 mL) was added Ti(iPrO)4(2 mL), the mixture was stirred at 85 ℃ for 2 h. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL x 3). The organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-78 (170 mg, 0.64 mmol, 75%) as a white solid, which was used in next step directly. LCMS (ESI): m / z = 268 [M+H]+.

[0519] Step 3: To a stirred solution of Int-78 (170 mg, 0.64 mmol, 1.0 eq.) in THF (5 mL) wasadded MeMgBr (0.32 mL, 3 M, 1.5 eq.) at 0 °C, slowly. The resulting mixture was allowed to warm to RT, and was stirred at r.t. for 2 h. After completion, the reaction was quenched by H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE, from0 to 30%) to afford Int-79 (50 mg, 0.18 mmol, 28%) as a yellow solid. LCMS (ESI): m / z = 284[M+H]+.

[0520] Step 4: To a solution of Int-79 (50 mg, 0.18 mmol, 1.0 eq.) in THF (5 mL) wasadded HCl / dioxane (0.5 mL). The mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to afford Int-80 (60 mg, crude) as a yellow oil. LCMS (ESI): m / z = 180 [M+H]+.

[0521] Step 5: To a stirred solution of R-2 (84 mg, 0.40 mmol, 1.2 eq.), DIEA (87 mg, 0.67mmol, 2.0 eq.) and HATU (159 mg, 0.40 mmol, 1.2 eq.) in DMF (2 mL) was added Int-80 (60 mg, 0.34 mmol, 1.0 eq.) the resulting mixture was stirred at r.t. for 1 h. After completion, the reaction was quenched with H2O (15 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatographyon silica gel (eluted with EtOAc in PE, from 0 to 30%) to afford Int-81 (25 mg, 0.07 mmol, 20%)as a white solid. LCMS (ESI): m / z = 371 [M+H]+.

[0522] Step 6: Int-81 (25 mg, 0.07 mmol) was further purified by SFC to afford Compound I-300 (10 mg, 0.03 mmol, 40%) as a white solid and Compound I-301 (10 mg, 0.03mmol, 40%) asa white solid.

[0523] Compound I-300：97% ee. Retention time: 3.011 min. LC-MS (ESI): m / z =371.1[M+H]+;1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 7.7 Hz, 1H), 8.66 (s, 2H), 7.74 – 7.62 (m, 2H), 7.22 (s, 1H), 7.12 (dd, J = 8.5, 1.7 Hz, 1H), 5.16 (p, J = 7.1 Hz, 1H), 4.28 (dq, J = 9.1, 3.1 Hz, 1H), 3.94 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H), 0.82 – 0.65 (m, 4H).

[0524] Compound I-301：>99% ee. Retention time: 2.087 min. LC-MS (ESI): m / z =371.1[M+H]+;1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 7.7 Hz, 1H), 8.66 (s, 2H), 7.73 – 7.64 (m,2H), 7.22 (s, 1H), 7.12 (dd, J = 8.5, 1.7 Hz, 1H), 5.16 (p, J = 7.1 Hz, 1H), 4.28 (dq, J = 9.1, 3.1 Hz, 1H), 3.94 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H), 0.81 – 0.66 (m, 4H).

[0525] SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OJ,250×20mm I.D., 5µm; Mobile phase: A for CO2and B for MeOH; Gradient: B 40 %; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 220 nm; Cycle-time: 12 min; Run time: 6 min; Injection volume: 4 mL; Eluted time: 2H.

[0526] Analytical Method: Column: ChiralCel OJ, 100×4.6mm I.D., 3um; Mobile phase: A forCO2 and B for EtOH (0.05% DEA); Gradient: 8 min @B 30%; Flow rate: 2.2 mL / min; Back pressure: 100 bar; Column temperature: 40 °C.

[0527] The following compounds were made using Method ZL-1 from the appropriate reagents:I-302, I-303, I-304, I-305, I-314, I-315, I-328, I-329, I-330, I-331, I-332, I-351, I-352, I-353, I-354, I-358, I-359, I-413, I-564, I-565., I-628, and I-629.Example 41: Method ZM: Synthesis of Compounds I-310 and Compound I-311

[0528] Step 1: To a stirred solution of 6, 7-dihydro-5H-cyclopenta[1,2-b]pyridin-5-one (R-62,150 mg, 1.13 mmol, 1.0 eq.) and NH4OAc (1.04 g, 13.52 mmol, 12.0 eq.) in EtOH (2 mL) was added NaBH3CN (71 mg, 1.13 mmol, 1.0 eq.). The resulting mixture was heated at 95 °C in a microwave reactor for 1 h. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE, from 0 to 50%)to afford Int-82 (70 mg, 0.52 mmol, 46%) as a yellow solid. LCMS (ESI): m / z = 135 [M+H]+.

[0529] Step 2: To a stirred solution of 6-chloro-1-methylindole-2-carboxylic acid (R-62, 131mg, 0.63 mmol, 1.2 eq.), DIEA (135 mg, 1.04 mmol, 2.0 eq.) and HATU (238 mg, 0.63 mmol, 1.2 eq.) in DMF (2 mL) was added Int-82 (70 mg, 0.52 mmol, 1.0 eq.). The mixture was stirred at r.t. for 1 hr. After completion, the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE 0 to 50%) to afford Int-83 (70 mg, 0.22 mmol, 41%) as a yellow solid. LCMS (ESI): m / z = 326 [M+H]+.

[0530] Step 3: Int-83 (70 mg, 0.22 mmol) was separated by SFC to afford Compound I-310(25 mg, 0.08 mmol, 36%) as a white solid and Compound I-311 (25 mg, 0.08mmol, 36%) as a white solid and.

[0531] Compound I-311：>99% ee. Retention time: 1.892 min. LCMS (ESI): m / z =326.1[M+H]+;1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J = 8.0, 4.4 Hz, 2H), 7.20 (dd, J = 7.5, 4.9 Hz, 1H), 7.16 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.57 (q, J = 7.9 Hz, 1H), 4.02 (s, 3H), 3.12 – 2.88 (m, 2H), 2.57 – 2.51 (m, 1H), 2.15 – 1.99 (m, 1H).

[0532] Compound I-310：>99% ee. Retention time: 3.107 min. LCMS (ESI): m / z =326.1[M+H]+;1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 4.7 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J = 8.0, 4.5 Hz, 2H), 7.21 (dd, J = 7.5, 4.9 Hz, 1H), 7.16 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.57 (q, J = 8.0 Hz, 1H), 4.02 (s, 3H), 3.12 – 2.87 (m, 2H), 2.55 (dd, J = 8.4, 3.9 Hz, 1H), 2.06 (dq, J = 12.7, 8.8 Hz, 1H).

[0533] SFC Method: Instrument: WATERS 150 preparative SFC (SFC-26); Column: ChiralCelOJ, 250 × 30mm I.D., 10µm; Mobile phase: A for CO2 and B for Ethanol (0.1%NH3H2O); Gradient: B 40%; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 38 °C; Wavelength: 220 nm; Cycle time: 5 min.

[0534] Analytical Method: Instrument: Waters UPC2 analytical SFC (SFC-H); Column:ChiralCel OJ, 150×4.6mm I.D., 3µm; Mobile phase: A for CO2 and B for Ethanol (0.05%DEA); Gradient: B 40%; Flow rate: 2.5 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm.

[0535] The following compounds were made using Method ZM from the appropriate reagents:I-315, I-316, I-317, I-318, I-521, and I-522. Example 42: Method ZN: Synthesis of Compounds I-405 and Compound I-406

[0536] Step 1: To a stirred mixture of methyl 5-bromo-3-chloropyridine-2-carboxylate (R-63,1.0 g, 3.992 mmol, 1eq.) and Zn(CN)2 (562.54 mg, 4.791 mmol,1.2eq) in DMF (10 mL) was added Pd(PPh3)4 (461.3 mg, 0.4 mmol, 0.1eq). The resulting mixture was stirred at 120 °C for 4h. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers was washed with brine (20 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc in PE, from 0 to 40%) to afford Int-84 (460 mg, 2.34 mmol, 58.6%) as a white solid. LCMS (ESI): m / z = 197 [M+H]+.

[0537] Step 2: To a stirred solution of Int-84 (400 mg, 2.04 mmol, 1 eq) in THF (20 mL) wasadded MeMgBr in THF (4 ml, 4 mmol, 2 eq.) at 0oC under N2, slowly. The resulting mixture was stirred at r.t. for 2 h, then to the mixture was add NaBH4(773.3 mg, 20.35 mmol, 10 eq.) and the mixture was continue stirred at r.t. for 30 minutes. After completion, the reaction mixture was quickened with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (100 mL x 3), dried over an...

Claims

Claims:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein: A1is a bicyclic group selected fromX1is one of the following:(i) -N(R4)-[C(R5)(R6)]n-(thiazolyl substituted by t occurrences of R7), -N(R4)-[C(R5)(R6)]m-(thiadiazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,3,4-oxadiazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(pyrazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(oxazolyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(imidazolyl substituted by p occurrences of R7);(ii) -N(R4)-[C(R5)(R6)]m-(chromanyl substituted by t occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isochromanyl substituted by t occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrobenzofuranyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4- dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,6-dihydrofuro[2,3-d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(7,8-dihydro-6H-pyrano[3,2- d]pyrimidinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H- pyrano[3,2-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4- dihydro-2H-pyrano[2,3-c]pyridinyl substituted by p occurrences of R7); -N(R4)- [C(R5)(R6)]m-(3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrofuro[2,3- b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[d]oxazol- 2(3H)-one substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H- pyrano[2,3-d]pyrimidine substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m- (3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted by p occurrences of R7);(iii) -N(R4)-[C(R5)(R6)]n-(phenyl substituted by t occurrences of R7), -N(R4)-[C(R5)(R6)]m-(pyridinyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(pyrimidinyl substituted by p occurrences of R7);(each of which is substituted by phenyl substituted withp occurrences of R7;(v) -N(R4)-[C(R5)(R6)]m-(pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(benzo[d]imidazolyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(indazolyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (isoindolin-1-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro- 1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7); -N(R4)-[C(R5)(R6)]m-(6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoindolinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3H-imidazo[4,5-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[4,3-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-b]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(1H-pyrazolo[3,4-c]pyridinyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydro-1H-indenyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(indolin-2-one substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(isoindolin-1-one substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m- (3H-imidazo[4,5-c]pyridine substituted by p occurrences of R7), or-N(R4)-[C(R5)(R6)]m- (1H-pyrazolo[4,3-c]pyridine substituted by p occurrences of R7);(vi) -N(R4)-[C(R5)(R6)]m-(imidazo[2,1-b]thiazolyl substituted by p occurrences of R7);(vii) -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-1H-benzo[c][1,2]thiazinyl 2,2-dioxide substituted by poccurrences of R7), -N(R4)-[C(R5)(R6)]m-(2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydro-2H- benzo[e][1,2]thiazinyl 1,1-dioxide substituted by p occurrences of R7), -N(R4)- [C(R5)(R6)]m-(benzo[b]thiophene 1,1-dioxide substituted by p occurrences of R7), or - N(R4)-[C(R5)(R6)]m-(1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted by p occurrences of R7);(viii) -N(R4)-[C(R5)(R6)]m-(quinazolin-4(3H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(3,4-dihydroquinolin-2(1H)-onyl substituted by p occurrences of R7), - N(R4)-[C(R5)(R6)]m-(1,4-dihydroisoquinolin-3(2H)-onyl substituted by p occurrences of R7), -N(R4)-[C(R5)(R6)]m-(isoquinolin-1(2H)-onyl substituted by p occurrences of R7), or -N(R4)-[C(R5)(R6)]m-(1,2,3,4-tetrahydroisoquinoline substituted by p occurrences of R7); or(ix) -N(R4)-[C(R5)(R6)]m-(bicyclo[1.1.1]pentanyl substituted by p occurrences of R7);R1is C1-4 alkyl or hydrogen; R2represents independently for each occurrence hydrogen; halo; C1-4alkyl; -S(O)2R8; cyano; C1-4alkoxyl, hydroxyl, C1-4haloalkyl; a 5–6 membered saturated monocyclic heterocyclicring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5 cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R2Brepresents independently for each occurrence C1-3 alkyl or halo; R3is hydrogen; fluoro; C1-4 alkyl; -S(O)2R8; cyano; C1-4 alkoxyl, hydroxyl, C1-4 haloalkyl; a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C3-5cycloalkyl, wherein each ring is substituted with q occurrences of R2B; R4is hydrogen, C1-4alkyl, -C(O)(C1-4alkyl), or -S(O)2(C1-4alkyl); R5and R6each represent independently for each occurrence hydrogen, C1-4 alkyl, C3-5 cycloalkyl, C1-4 hydroxyalkyl, -C1-3 alkylene-N(R8)2, -(C1-6 aliphatic substituted by R8), or - (CH2)0-3-O-(CH2)0-3-CH3; or R5and R6are taken together to form a C3-5saturated carbocyclic ring; R7represents independently for each occurrence C1-6 alkyl, halo, cyano, hydroxyl, - C(O)N(R8)2, -N(R8)C(O)-R8, -C(O)-R8, -(C1-6aliphatic substituted by R8), C1-6alkoxyl, C3-6cycloalkyl, -S(O)2N(R8)2, -S(O)2R8, -N(R8)S(O)2R8, C1-3 alkylene-C(O)N(R8)2, -S(O)(NH)R8, C3-6 cycloalkyl, -C(O)N(R8)(C3-6 cycloalkyl), -C(O)O-C1-3 alkyl, C1-3 haloalkyl, -NH(R8), - C(NH)NH(R8),-O-(C3-6cycloalkyl), or a 5–6 membered monocyclic heteroaromatic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring is substituted with s occurrences of R7B; R7Brepresents independently for each occurrence C1-3 alkyl, halo, hydroxyl, or C3-6 cycloalkyl; R8represents independently for each occurrence hydrogen, C1-6 aliphatic, hydroxyl, - NH2, -S(O)2CH3, C3-6 cycloalkyl, cyano, phenyl, C1-4 haloalkyl, C1-6 alkoxyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5–6 membered saturated monocyclic heterocyclic ring containing 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R9is hydrogen, chloro, fluoro, or C1-3alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3; q and s are independently 0, 1, 2, or 3; t is 0, 1, 2, or 3; and u is 1 or 2.

2. The compound of claim 1, wherein R1 is C1-4 alkyl.

3. The compound of claim 1 or 2, wherein the compound is a compound of Formula I.

4. The compound of claim 1 or 2, wherein the compound is a compound of Formula Ia orIb, or a pharmaceutically acceptable salt thereof:

5. The compound of claim 1 or 2, wherein the compound is a compound of Formula Ic, Id,or Ie, or a pharmaceutically acceptable salt thereof:

6. The compound of claim 1 or 2, wherein the compound is a compound of Formula If orIg, or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1 or 2, wherein the compound is a compound of Formula Ih orIi, or a pharmaceutically acceptable salt thereof:Ih Ii.

8. The compound of claim 1 or 2, wherein the compound is a compound of Formula Ij, Ik,Il, Im, In, or Io or a pharmaceutically acceptable salt thereof:In Io.

9. The compound of claim 1 or 2, wherein the compound is a compound of Formula Ip, Iq,or Ir, or a pharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000476_0002" / >10. The compound of claim 1 or 2, wherein the compound is a compound of Formula Is, It,Iu, or Iv, or a pharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000477_0001" / >11. The compound of claim 1 or 2, wherein the compound is a compound of Formula Iw orIx, or a pharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000477_0002" / >12. The compound of claim 1 or 2, wherein the compound is a compound of Formula Iy, Iz,or Iaa, or a pharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000477_0003" / >Iaa.

13. The compound of any one of claims 1-12, wherein R5 and R6 are each hydrogen.

14. The compound of any one of claims 1-12, wherein R5 is hydrogen, and R6 is -CH3.

15. The compound of any one of claims 1-12, wherein m is 0.

16. The compound of any one of claims 1-14, wherein m is 1.

17. The compound of any one of claims 1-16, wherein R4 is hydrogen.

18. The compound of claim 1 or 2, wherein the compound is a compound of Formula Iab,Iac, or Iad, or a pharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000478_0001" / >Iad.

19. The compound of any of claims 1-18, wherein Ring<img src='' class="img-anchor img-center" img-id="IMGF000478_0003" / >20.2 y of claims 1-18, wherein Ring A1 is<img src='' class="img-anchor img-center" img-id="IMGF000479_0002" / >2 The compound of any of claims 1-18, wherein Ring<img src='' class="img-anchor img-center" img-id="IMGF000479_0004" / >23. The compound of any one of claims 1-21, wherein R2 is hydrogen, halo, or C1-4 alkyl.

24. The compound of any of claims 1-18, wherein Ring A1 is.

25. The compound of any one of claims 1-20 or 22, wherein R1 is -CH3.

26. The compound of claim 1, wherein the compound is a compound of Formula Iae, or apharmaceutically acceptable salt thereof:wherein Ring B1is one of the following:(i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences ofR7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by p occurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7< / sup>;(ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by poccurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3- dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7; 6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7< / sup>;(iii) phenyl substituted by t occurrences of R7 or pyridinyl substituted by p occurrences of R7);(each of which is substituted by phenyl substituted withp occurrences of R7; or( pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; benzo[d]imidazolylsubstituted by p occurrences of R7; indazolyl substituted by p occurrences of R7; isoindolin-1-onyl substituted by p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2- b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7< / sup>.

27. The compound of claim 1, wherein the compound is a compound of Formula Iaf or apharmaceutically acceptable salt thereof:Iaf wherein Ring B1is one of the following:(i) thiazolyl substituted by t occurrences of R7; thiadiazolyl substituted by p occurrences ofR7; 1,3,4-oxadiazolyl substituted by p occurrences of R7; pyrazolyl substituted by poccurrences of R7; oxazolyl substituted by p occurrences of R7; or imidazolyl substituted by p occurrences of R7< / sup>;(ii) chromanyl substituted by t occurrences of R7; 2,3-dihydrobenzofuranyl substituted by poccurrences of R7; 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted by p occurrences of R7; 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted by p occurrences of R7; 2,3- dihydrofuro[3,2-c]pyridine substituted by p occurrences of R7; 5,6-dihydrofuro[2,3- d]pyrimidinyl substituted by p occurrences of R7; 6,7-dihydrofuro[2,3-b]pyrazinyl substituted by p occurrences of R7; 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted by p occurrences of R7; or 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted by p occurrences of R7< / sup>;(iii) phenyl substituted by t occurrences of R7 or pyridinyl substituted by p occurrences of R7;(iv), each of which is substituted by phenyl substituted withp occurrences of R7< / sup>; or(v) pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; isoindolin-1-onyl substitutedby p occurrences of R7; 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted by p occurrences of R7; 1,2-dihydro-3H-indazol-3-onyl substituted by p occurrences of R7; 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted by p occurrences of R7; or 6,7- dihydro-5H-cyclopenta[b]pyridinyl substituted by p occurrences of R7< / sup>.

28. The compound of claim 26 or 27, wherein ring B1 is chromanyl substituted by toccurrences of R7< / sup>.

29. The compound of claim 26 or 27, wherein ring B1 is 2,3-dihydrobenzofuranyl substitutedby p occurrences of R7; or ring B1is thiazolyl substituted by t occurrences of R7< / sup>.

30. The compound of claim 26 or 27, wherein ring B1 is phenyl substituted by t occurrencesof R7or pyridinyl substituted by p occurrences of R7< / sup>.

31. The compound of claim 26 or 27, wherein ring B1 is pyrrolo[3,2-b]pyridinyl substitutedby p occurrences of R7or isoindolin-1-onyl substituted by p occurrences of R7< / sup>.

32. The compound of any one of claims 1-31, wherein t is 1, 2, or 3.

33. The compound of any one of claims 1-31, wherein t is 1.

34. The compound of any one of claims 1-31, wherein p is 1, 2, or 3.

35. The compound of any one of claims 1-31, wherein p is 1.

36. The compound of claim 1, wherein the compound is a compound of Formula Iag or apharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000482_0001" / >37. The compound of claim 1, wherein the compound is a compound of Formula Iah or apharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000482_0002" / >Iah.

38. The compound of claim 1, wherein the compound is a compound of Formula Iai or apharmaceutically acceptable salt thereof:<img src='' class="img-anchor img-center" img-id="IMGF000482_0003" / >Iai.

39. The compound of any one of claims 1-38, wherein R7 is halo.

40. The compound of any one of claims 1-38, wherein R7 is -C(O)-R8 or -C(O)N(R8)2.

41. The compound of any one of claims 1-38, wherein R7 is -C(O)NH2.

42. The compound of any one of claims 1-38, wherein R7 represents independently for eachoccurrence cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo.

43. A compound in Table 1 or 2, or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound of any one of claims 1-43 and apharmaceutically acceptable carrier.

45. A method of treating a disorder associated with ABC transporter dysfunction, comprisingadministering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-43 to treat the disorder associated with ABC transporter dysfunction.

46. The method of claim 45, wherein the disorder associated with ABC transporterdysfunction is characterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

47. A method of treating a disorder, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of any one of claims 1-43 to treat the disorder, wherein the disorder is selected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy, Biliary atresia, Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington'sdisease, Multiple sclerosis, Parkinson’s disease, Hirschsprung disease, Zellweger syndrome, Type 2 diabetes, Obesity, Type 1 diabetes, Atherosclerosis, Dyslipidemia, Generalized arterial calcification of infancy, Calciphylaxis, Autosomal recessive cone- rod dystrophy, Gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, Low phospholipid associated cholelithiasis, intrahepatic microlithiasis, hepatolithiasis, Non-anastomotic biliary strictures, Benign recurrent intrahepatic cholestasis, Progeria (Hutchinson-Gilford progeria syndrome), Chronic kidney disease, Hemodialysis, vascular calcification, vascular calcification associated with CKD, vascular calcification associated with T2D, and Calcific uremic atreriolopathy.

48. The method of claim 47, wherein the disorder is cystic fibrosis.

49. The method of claim 47, wherein the disorder is primary sclerosing cholangitis.

50. The method of any of claims 45-49, wherein the subject is a human.

51. A method of modulating function of an ABC transporter in a subject, comprisingadministering to the subject an effective amount of a compound of any one of claims 1- 43 to thereby increase expression of the ABC transporter in the subject.

52. The method of claim 51, wherein the ABC transporter is selected from one or more ofABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.