Bipyridinyl sulfonamides and related compounds and their use in treating medical conditions

Abstract

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

Description

Attorney Docket No. 255944.001402BIPYRIDINYL SULFONAMIDES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 776,512, filed on March 24, 2025, and U.S. Provisional Application Serial No. 63 / 845,660, filed on July 17, 2025, each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The invention provides bipyridinyl sulfonamides and related compounds, pharmaceutical compositions, and their use in treating medical conditions.BACKGROUND

[0003] ATP-binding cassette (ABC) transporters are a large, phylogenetically conserved gene family 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 more implicated 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 ABC transporter function and therefore be used for the treatment of diseases in which suchAttorney Docket No. 255944.001402enhancement 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 treating ABC transporter dysfunction. The present invention addresses the foregoing needs and provides other related advantages.SUMMARY

[0007] The invention provides bipyridinyl sulfonamides and related compounds, pharmaceutical compositions, and their use in treating medical conditions. In particular, one aspect of the invention provides a collection of bipyridinyl sulfonamide 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 bipyridinyl sulfonamide 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 transporter dysfunction. 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.

[0009] Another aspect of the invention provides a method of modulating the function of a protein selected from ABCB11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, ABCD1, and ABCD2 in a subject. The method comprises administering to a subject in need thereof anAttorney Docket No. 255944.001402effective amount of a compound described herein, such as a compound of Formula I, to thereby modulate the function of said protein, as further described in the detailed description.DETAILED DESCRIPTION

[0010] The invention provides bipyridinyl sulfonamides and related compounds, pharmaceutical compositions, and their use in treating medical conditions. The practice of the present invention employs, 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.

[0011] Various aspects of the invention are set forth below in sections; however, aspects of the invention 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

[0012] Compounds of the present invention include those described generally herein, and are further 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.Attorney Docket No. 255944.001402

[0013] 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 groups contain 1-6 aliphatic carbon atoms. In certain 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 certain 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 atachment 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.

[0014] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring 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 certain 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 certain embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. SuchAttorney Docket No. 255944.001402bridged 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] Exemplary bridged bicyclics include:H

[0016] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.Attorney Docket No. 255944.001402

[0017] The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0018] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-277-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0019] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0020] As used herein, the term “bivalent C1-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0021] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene 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.

[0022] The term “-(Co alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1.3 alkylene)- group.

[0023] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is 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.

[0024] The terms “halo” and “halogen” mean F, Cl, Br, or I.

[0025] 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 mayAttorney Docket No. 255944.001402bear 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 open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl groupwhen it has two groups attached to it (e.g., ); “phenylene” is a trivalent phenyl groupwhen it has three groups attachedto it (e.g., ). The term “arylene” refers to a bivalent aryl group.

[0026] 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 π 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 quatemized 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.Attorney Docket No. 255944.001402

[0027] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number 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.

[0028] 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).

[0029] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that 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, 3 / f-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 atached to it.Attorney Docket No. 255944.001402

[0030] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least 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.

[0031] The term “partially aromatic bicyclic ring” refers to a bicyclic ring in which one ring is aromatic and the other ring is not aromatic.A

[0032] As used herein, the term “pyridinylene-N-oxide” refers to &

[0033] 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 feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered 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.

[0034] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0–4R°, –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°;Attorney Docket No. 255944.001402–(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.

[0035] Each R° is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered 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*, –(C1–4straight or branched alkylene)C(O)OR*, or –SSR*.

[0036] Each R* is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o~iPh, 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 =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -0(C(R‘2))2-3O-, or-S(C(R*2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ct~6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Attorney Docket No. 255944.001402

[0037] When R* is Ci-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.

[0038] An optional substituent on a substitutable nitrogen is independently -R'*', -NRf2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)Rf, -S(O)2R1', -S(O)2NRf2, -C(S)NR12, -C(NH)NRf2, or -N(Rf)S(O)2Rf; wherein each R^ is independently hydrogen, C1-6 aliphatic, 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, two independent occurrences of R1', 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 Rfis C1-6 aliphatic, Rfis 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.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, 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 acidAttorney Docket No. 255944.001402or 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.

[0040] Further, acids which are generally considered suitable for the formation of pharmaceutically 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.

[0041] 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.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (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 formsAttorney Docket No. 255944.001402of 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.

[0043] Diastereomeric mixtures can be separated into their individual diastereomers on the basis 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 an appropriate 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.

[0044] Individual stereoisomers of the compounds of the invention may, for example, be substantially 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.

[0045] Chemical names, common names, and chemical structures may be used interchangeably to 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 heteroatomAttorney Docket No. 255944.001402with 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.

[0046] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0047] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0048] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (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.

[0049] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0050] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0051] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0052] The terms “alkoxy!” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to anAttorney Docket No. 255944.001402alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0053] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0054] The symbol “ — ” indicates a point of attachment.

[0055] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0056] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended 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.

[0057] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms 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.

[0058] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0059] The term “EC50” is art recognized and refers to the concentration of a compound that is required to achieve a response that is 50% of the maximum target effect relative to the baseline.

[0060] The term “Emax” is art recognized and refers to the concentration of a compound that is required to achieve maximal target effect.Attorney Docket No. 255944.001402

[0061] As used herein, the term “effective amount” refers to the amount of a compound sufficient 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.

[0062] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0063] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard 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] .

[0064] For therapeutic use, salts of the compounds of the present invention are contemplated as being 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.

[0065] 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.

[0066] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having,Attorney Docket No. 255944.001402including, 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.

[0067] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.I. Bipyridinyl Sulfonamide Compounds1.1 Bipyridinyl Sulfonamide Compounds of Formula fl)

[0068] One aspect of the invention provides bipyridinyl sulfonamide compounds. The compounds may be used 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 I:or a pharmaceutically acceptable salt thereof, wherein:Ring A1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene;Ring B1is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl;Ring C1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclicAttorney Docket No. 255944.001402heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene;R1is -N(R6)-SO2-R4, -SO2-N(R6)-R4, -S(NR6)(O)-R4, or O ■R2Arepresents independently for each occurrence C1-3 alkyl, halo, C1-3 haloalkyl, C3-5 cycloalkyl, or -O-R7, wherein each cycloalkyl is substituted with k instances of R8;R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a saturated or partially unsaturated 6-10 membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9; or two vicinal occurrences of R2Bare taken together with the atoms to which they are attached to form a 6-membered saturated, partially unsaturated, or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3represents independently for each occurrence halo, cyano, C1-6 alkyl, C1-4 haloalkyl, or a C3-5 cycloalkyl substituted with m instances of R10;R4is C1-4 alkyl or a C3-5 cycloalkyl substituted with n instances of R5;R5represents independently for each occurrence C1-4 alkyl, halo, C1-3 haloalkyl, or hydroxyl; R6is hydrogen, C1-3 alkyl, C3-5 cycloalkyl, or -(C0-3 alkylene)-O-(Ci-3 alkyl);R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, cyclopropyl, a 3-5 membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R8represents independently for each occurrence C1-3 alkyl, C1-4 haloalkyl, or halo;Attorney Docket No. 255944.001402R9represents independently for each occurrence C1-3 alkyl, halo, C1-4 haloalkyl, cyano, -C(O)-(C1-3 alkyl), -(C0-3 alkylene)-O-(C1-3 alkyl), -(C0-3 alkylene)-O-(C1-3 haloalkyl), or -SO2-(C1-3 alkyl);R10represents independently for each occurrence halo, C1-3 alkyl, or C1-4 haloalkyl;k is 0, 1, or 2;m is 0, 1, or 2;n is 0, 1, or 2;o is 0, 1, or 2;p is 0, 1, or 2;q is 1 or 2; andr is 0, 1, 2, or 3.

[0069] 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).

[0070] In certain embodiments, the compound is a compound of Formula I.

[0071] As defined generally above, Ring A1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene. In certain embodiments, Ring A1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A1is a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A1is phenylene. In certain embodiments, Ring A1is a 6-membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A1is pyridinylene. In certain embodiments, Ring A1is selected from the groups depicted in the compounds in Table 1, below.Attomey Docket No. 255944.001402

[0072] As defined generally above, Ring B1is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl. In certain embodiments, Ring B1is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B1is a 5-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B1is phenyl. In certain embodiments, Ring B1is a 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring B1is pyridinyl. In certain embodiments, Ring B1is selected from the groups depicted in the compounds in Table 1, below.

[0073] As defined generally above, Ring C1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene. In certain embodiments, Ring C1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring C1is a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring C1is phenylene. In certain embodiments, Ring C1is a 6- membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring C1is pyridinylene. In certain embodiments, Ring C1is pyrimidinylene. In certain embodiments, Ring C1is a 5 -membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring C1is pyrazolylene. In certain embodiments, Ring C1is selected from the groups depicted in the compounds in Table 1, below.

[0074] As defined generally above, R1is -N(R6)-SO2-R4, -SO2-N(R6)-R4, -S(NR6)(O)-R4, or°. In certain embodiments, R1is -N(R6)-SO2-R4. In certain embodiments, R1is -SO2-Attorney Docket No. 255944.001402vN 1O= aS-~. N(R6)-R4. In certain embodiments, R1is -S(NR6)(O)-R4. In certain embodiments, R1is O In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1, below.

[0075] As defined generally above, R2Arepresents independently for each occurrence C1-3 alkyl, halo, C1-3 haloalkyl, C3-5 cycloalkyl, or -O-R7, wherein each cycloalkyl is substituted with k instances of R8. In certain embodiments, R2Arepresents independently for each occurrence C1-3 alkyl. In certain embodiments, R2Arepresents independently for each occurrence halo. In certain embodiments, R2Arepresents independently for each occurrence C1-3 haloalkyl. In certain embodiments, R2Arepresents independently for each occurrence C3-5 cycloalkyl, wherein the cycloalkyl represents independently for each occurrence substituted with k instances of R8. In certain embodiments, R2Arepresents independently for each occurrence O-R7.

[0076] In certain embodiments, R2Ais C1-3 alkyl. In certain embodiments, R2Ais halo. In certain embodiments, R2Ais C1-3 haloalkyl. In certain embodiments, R2Ais C3-5 cycloalkyl, wherein the cycloalkyl is substituted with k instances of R8. In certain embodiments, R2Ais O-R7.

[0077] In certain embodiments, R2Arepresents independently for each occurrence C1-3 alkyl, C1-3 haloalkyl, or C3-5 cycloalkyl. In certain embodiments, R2Arepresents independently for each occurrence methyl, cyclopropyl, -CHF2, or -CF3. In certain embodiments, R2Ais selected from the groups depicted in the compounds in Table 1, below.

[0078] As defined generally above, R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a saturated or partially unsaturated 6-10 membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9; or two vicinal occurrences of R2Bare taken together with theAttorney Docket No. 255944.001402atoms to which they are attached to form a 6-membered saturated, partially unsaturated, or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In certain embodiments, R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl represents independently for each occurrence substituted with o instances of R9. In certain embodiments, R2Brepresents independently for each occurrence a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl represents independently for each occurrence substituted with o instances of R9. In certain embodiments, R2Brepresents independently for each occurrence a 5-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl represents independently for each occurrence substituted with o instances of R9.

[0080] In certain embodiments, R2Bis a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with o instances of R9. In certain embodiments, R2Bis a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with o instances of R9. In certain embodiments, R2Bis a 5-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with o instances of R9.

[0081] In certain embodiments, two vicinal occurrences of R2Bare taken together with the atoms to which they are attached to form a 6-membered saturated, partially unsaturated, or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9. In certain embodiments, R2Brepresents independently for eachAttorney Docket No. 255944.001402occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2Brepresents independently for each occurrence a 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2Brepresents independently for each occurrence a saturated or partially unsaturated 6-10 membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2Brepresents independently for each occurrence a 7-12 membered bridged or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In certain embodiments, R2Brepresents independently for each occurrence pyridinyl, tetrahydropyranyl, morpholinyl, pyrazolyl, imidazolyl, or piperidinyl. In certain embodiments, R2Brepresents independently for each occurrence pyridinyl or piperidinyl. In certain embodiments, R2Bis selected from the groups depicted in the compounds in Table 1, below.

[0083] As defined generally above, R3represents independently for each occurrence halo, cyano, C1-6 alkyl, C1-4 haloalkyl, or a C3-5 cycloalkyl substituted with m instances of R10. In certain embodiments, R3is halo. In certain embodiments, R3is cyano. In certain embodiments, R3is C1-6 alkyl. In certain embodiments, R3is C1-4 haloalkyl. In certain embodiments, R3is a C3-5 cycloalkyl substituted with m instances of R10. In certain embodiments, R3represents independently for each occurrence halo, cyano, C1-6 alkyl, or C 1.4 haloalkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1, below.

[0084] As defined generally above, R4is C1-4 alkyl or a C3-5 cycloalkyl substituted with n instances of R5. In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is a C3-5 cycloalkyl substituted with n instances of R5. In certain embodiments, R4is C1-4 alkyl or C3-5 cycloalkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1, below.

[0085] As defined generally above, R5represents independently for each occurrence C1-4 alkyl, halo, C1-3 haloalkyl, or hydroxyl. In certain embodiments, R5is C1-4 alkyl. In certain embodiments, R5is halo. In certain embodiments, R5is C1-3 haloalkyl. In certain embodiments, R5is hydroxyl. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1, below.Attorney Docket No. 255944.001402

[0086] As defined generally above, R6is hydrogen, C1-3 alkyl, C3-5 cycloalkyl, or -(C0-3 alkylene)-O-(Ci-3 alkyl). In certain embodiments, R6is hydrogen. In certain embodiments, R6is C1-3 alkyl. In certain embodiments, R6is C3-5 cycloalkyl. In certain embodiments, R6is -(C0-3 alkylene)-O-(Ci.3 alkyl). In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1, below.

[0087] As defined generally above, R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, cyclopropyl, a 3-5 membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R7represents independently for each occurrence C1-4 alkyl. In certain embodiments, R7represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R7represents independently for each occurrence cyclopropyl. In certain embodiments, R7represents independently for each occurrence a 3-5 membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R7represents independently for each occurrence a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In certain embodiments, R7is C1-4 haloalkyl. In certain embodiments, R7is cyclopropyl. In certain embodiments, R7is a 3-5 membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R7is a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1, below.

[0089] As defined generally above, R8represents independently for each occurrence C1-3 alkyl, C1-4 haloalkyl, or halo. In some embodiments, R8represents independently for each occurrence C1-3 alkyl. In some embodiments, R8represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R8represents independently for each occurrence halo.

[0090] In some embodiments, R8is C1-3 alkyl. In some embodiments, R8is C1-4 haloalkyl. In some embodiments, R8is halo. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1, below.Attorney Docket No.255944.001402

[0091] As defined generally above, R9represents independently for each occurrence C1-3 alkyl, halo, C1-4 haloalkyl, cyano, -C(O)-(C1-3 alkyl), -(C0-3 alkylene)-O-(C1-3 alkyl), -(C0-3 alkylene)-O-(C1-3 haloalkyl), or -SO2-(C1-3 alkyl). In certain embodiments, R9represents independently for each occurrence C1-3 alkyl. In certain embodiments, R9represents independently for each occurrence halo. In certain embodiments, R9represents independently for each occurrence CM haloalkyl. In certain embodiments, R9represents independently for each occurrence cyano. In certain embodiments, R9represents independently for each occurrence -C(O)-(C1-3 alkyl). In certain embodiments, R9represents independently for each occurrence -(C0-3 alkylene)-O-(C1-3 alkyl). In certain embodiments, R9represents independently for each occurrence -(C0-3 alkylene)-O-(C1-3 haloalkyl). In certain embodiments, R9represents independently for each occurrence -SO2-(C1-3 alkyl).

[0092] In certain embodiments, R9is C1-3 alkyl. In certain embodiments, R9is halo. In certain embodiments, R9is C1-4 haloalkyl. In certain embodiments, R9is cyano. In certain embodiments, R9is -C(O)-(C1-3 alkyl). In certain embodiments, R9is -(C0-3 alkylene)-O-(C1-3 alkyl). In certain embodiments, R9is -SO2-(C1-3 alkyl). In certain embodiments, R9is -(C0-3 alkylene)-O-(C1-3 haloalkyl). In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1, below.

[0093] As defined generally above, R10represents independently for each occurrence halo, C1-3 alkyl, or C1-4 haloalkyl. In certain embodiments, R10represents independently for each occurrence halo. In certain embodiments, R10represents independently for each occurrence C1-3 alkyl. In certain embodiments, R10represents independently for each occurrence C1-4 haloalkyl.

[0094] In certain embodiments, R10is halo. In certain embodiments, R10is C1-3 alkyl. In certain embodiments, R10is C1-4 haloalkyl. In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1, below.

[0095] As defined generally above, k is 0, 1, or 2. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is selected from the corresponding value represented in the compounds in Table 1, below.

[0096] As defined generally above, m is 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 1 or 2. InAttorney Docket No. 255944.001402certain embodiments, m is selected from the corresponding value represented in the compounds in Table 1, below.

[0097] As defined generally above, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is selected from the corresponding value represented in the compounds in Table 1, below.

[0098] As defined generally above, o is 0, 1, or 2. In certain embodiments, o is 0. In certain embodiments, o is 1. In certain embodiments, o is 2. In certain embodiments, o is 1 or 2. In certain embodiments, o is selected from the corresponding value represented in the compounds in Table 1, below.

[0099] As defined generally above, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 1 or 2. In certain embodiments, p is selected from the corresponding value represented in the compounds in Table 1, below.

[0100] As defined generally above, q is 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the corresponding value represented in the compounds in Table 1, below.

[0101] As defined generally above, r is 0, 1, or 2. In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is selected from the corresponding value represented in the compounds in Table 1, below.

[0102] In certain embodiments, the compound of Formula I is further defined by Formula I-A, or a pharmaceutically acceptable salt thereof:(R2A)PC1I-AAttorney Docket No. 255944.001402

[0103] In certain embodiments, the compound of Formula I is further defined by Formula I-B, I-C, or I-D, or a pharmaceutically acceptable salt thereof:I-B I-C I-D.

[0104] In certain embodiments, the compound of Formula I is further defined by Formula I-E, I-F, or I-G, or a pharmaceutically acceptable salt thereof:N-NH (R2V,!,>)„I-E

[0105] In certain embodiments, the compound of Formula I is further defined by Formula I-H, or a pharmaceutically acceptable salt thereof:

[0106] In certain embodiments, the compound of Formula I is further defined by Formula I- J, or a pharmaceutically acceptable salt thereof:Attorney Docket No. 255944.001402I-J.

[0107] In certain embodiments, the compound of Formula I is further defined by Formula I-K, or a pharmaceutically acceptable salt thereof:N NI-K.

[0108] In certain embodiments, the compound of Formula I is further defined by Formula II:_^(R2A)P( C1)(R2C)qA1or a pharmaceutically acceptable salt thereof, wherein:R2Crepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9.

[0109] 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 aAttorney Docket No. 255944.001402variable 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).In certain embodiments, the compound is a compound of Formula II.Exemplary Specific Compounds 1O I co t- T bz

[0110] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is one of compounds I-1 to I-156 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is one of compounds I-1 to I-156 in Table 1.TABLE 1. Exemplary CompoundsCompound No. StructureFF-- (1-1 / O FHWo-5- # 0N1-2Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Compound No. Structure / =Ny >CF31-100F3C pNAr C / — C / NHo-v / / / ON E FF\\=N, - \1-101 F3C 0 / / / ON F FF\>=N / — \1-102 VV / 02 — P^NH / / / ON>=N z=N1-103F3C O F / — *\ / rNHo-v / / / ONAttorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Compound No. Structure\=N z=N1-112l^o o / N- \{ 2 — { NH / / / 6N)=\ / =N1-113O / / / ON E FF\NCH3°1-114 p( / X — ( / ^NH\ / \ / Q _ / / / 0NF\FF\ / =N / " \1-115N- OA ° phWNHx y __ jg__ / / / oNAttorney Docket No. 255944.001402Compound No. StructureO~ \\=N z=N1-116v / 0 / / ON0— \\=N z=N1-117 F3C p / / oN E FF\)=\ z=N1-118 / oA — ^NH\ / \ / Q _ / o''" / / / ONF\FF\Nv - \ P1-119 UN-^ N-7 p<y\> — <yyNH / O''"~ / / / oNAttorney Docket No. 255944.001402Attorney Docket No. 255944.001402Compound No. Structure1-124z^^^yyz)=N1-125lr uN-nx N-V O 1C / — (z}^ ° o zN\\OOTH I71=,>=^^0^ 1- / / / 0N)=N1-126 / 0 / / / 0NN\\ / / CF31-127 / o / / / ONAttorney Docket No. 255944.001402Attorney Docket No. 255944.001402Compound No. Structure1-132FV-Oo F >=N z=N1-133 ' 0 F / / / oN Oo zr= Ki iE Fi k1F\5=N / =N1-134 ' O Fs EFF\\=N / =N1-135 '.0 CF3N-V(zX — (z)^NH / / / 0NAttorney Docket No. 255944.001402Attorney Docket No. 255944.001402Compound No. Structure0^ / =NVV^NA / / V-Nx1-140z0 / — C / NHr / / / ON0— x>=NA? V-N1-141z0N-^ N-K(zX — (zy— NH / / / oN DX=N / =N1-142Z0 / / / oNF. FF\ >=N / — \y_^Nv^°1-143 F3C 0 / / / oNAttorney Docket No. 255944.001402 Compound No. StructureE FF\ / =N / — \1-144 VV / N— / 0Cl1A f o / / / 0N D UL)>=Nry^cF31-145 F3C O / / ON FF— (\=N / =N1-146zo / / / ON1-147Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402

[0111] In certain embodiments, the present invention provides a compound of Formula I as defined 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.Attorney Docket No. 255944.001402

[0112] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.II. Therapeutic Applications

[0113] In certain embodiments, the present invention provides a method of treating a disorder in which 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 certain embodiments, correction of one or more underlying mutations associated with ABC transporter dysfunction is rationalized. In certain embodiments, methods of the present invention provide enhancement of one or more non-mutated forms of an ABC transporter.

[0114] In certain embodiments, the invention provides a method of treating a disorder in which enhanced 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.

[0115] In certain 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 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.

[0116] In certain embodiments, the present invention provides a method of modulating function of an ABC transporter in a subject, comprising administering to the subject an effective amount of a compound of Formula I to thereby modulate function 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,Attorney Docket No. 255944.001402ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0117] Another aspect of the invention provides a method of increasing the expression of a protein selected from ABCB 11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, and ABCD2 in a subject. Another aspect of the invention provides a method of increasing the expression of a protein selected from ABCB 11, ABCB 11 E297G, ABCC6, ABCB4, ABCA4 P1380L, ABCD1, and ABCD2 in a subject. The method comprises administering to a subject in need thereof an effective amount of a compound described herein, such as a compound of Formula I, to thereby increase the expression of said protein, as further described in the detailed description.

[0118] In certain 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 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.

[0119] In certain embodiments, the disorder associated with ABC transporter dysfunction 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.

[0120] In certain embodiments, the present invention provides methods of treating a disorder 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,Attorney Docket No. 255944.001402Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH, 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, vascular calcification, vascular calcification associated with CKD, vascular calcification associated with T2D, and Calcific uremic atreriolopathy.

[0121] In certain embodiments, the present invention provides methods of treating or preventing a disorder 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, 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, and Low phospholipid associated cholelithiasis.

[0122] In certain embodiments, the present invention provides methods of treating or preventing a disorder 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 homocystinuriaAttorney Docket No. 255944.001402cblJ 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, 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, chronic kidney disease, Progeria (Hutchinson-Gilford progeria syndrome), hemodialysis, end stage renal disease, aortic stenosis, peripheral arterial disease, or ischemic stroke.

[0123] In certain embodiments, the present invention provides methods of treating a disorder selected from calciphylaxis, pseudoxanthoma elasticum, generalized arterial calcification of infancy, chronic kidney disease, Progeria (Hutchinson-Gilford progeria syndrome), hemodialysis, end stage renal disease, aortic stenosis, peripheral arterial disease, or ischemic stroke.

[0124] In certain embodiments, the disorder associated with ABC transporter dysfunction is cystic fibrosis (CF). Accordingly, in certain 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 I. In some such embodiments, the method further comprises administering one or more additional therapeutic agents, described further below and herein.

[0125] In certain embodiments, the disorder associated with ABC transporter dysfunction is cholestasis. Accordingly, in certain 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. 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 certain embodiments, the cholestasis is intrahepatic. In certain embodiments, the cholestasis is extrahepatic. In certain embodiments, the cholestasis is any of those described above and herein.Attorney Docket No. 255944.001402Subjects

[0126] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human.Medical Uses

[0127] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, 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.

[0128] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.III. Combination Therapy

[0129] Another aspect of the invention provides for combination therapy. Compounds described herein (such as a compound of Formula I, 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.

[0130] In certain embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and coadministering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In certain embodiments, the method includes co-administering one additional therapeutic agent. In certain embodiments, the method includes co-administering two additional therapeutic agents. In certain embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0131] One or more other therapeutic agent may be administered separately from a compound or 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 aAttorney Docket No. 255944.001402compound 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 certain 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.

[0132] In certain embodiments, the present invention provides a method of treating cystic fibrosis (CF) comprising administering a compound of the present invention with one or more additional therapeutic agents. In certain 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.

[0133] In some embodiments, the one or more additional therapeutic agents is an antibiotic. In some 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 with trimethoprim, sulfasalazine, sulfacetamide, sulfadiazine silver, vancomycin, dalbavancin, oritavancin, telavancin, and rifaximin.

[0134] In certain embodiments, the one or more additional therapeutic agents is an S-nitrosoglutathione reductase (GSNOR) inhibitor. In certain embodiments, the GSNOR inhibitor is selected from a GSNOR inhibitor disclosed in W02010 / 019903, U. S. Pat. No. 8,470,857, U. S. Pat. No.8,642,628, W02010 / 019910, U. S. Pat. No.8,586,624, WO2011 / 100433, U. S. Pat. No. US 8,481,590, W02012 / 048181, WO2012 / 083165, W02012 / 083171, or WO 2012 / 170371.Attorney Docket No. 255944.001402

[0135] In certain embodiments, the one or more additional therapeutic agents is an ileal bile transport (IB AT) inhibitor. In certain embodiments, the IB AT inhibitor is selected from an IBAT inhibitor disclosed in AU2011326873, US2020 / 0330545, WO2012 / 064266, W02020 / 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.

[0136] In some embodiments, the one or more additional therapeutic agents is an ileal bile transport (IBAT) inhibitor. In some embodiments, the IBAT inhibitor is selected from an IBAT inhibitor disclosed in AU2011326873, US2020 / 0330545, WO2012 / 064266, W02020 / 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. In some embodiments, the one or more additional therapeutic agents is selected from odevixibat, elobixivat, maralixibat, linerixibat, GSK2330672, SHP626 (volixibat), and A4250.

[0137] In some embodiments, the one or more additional therapeutic agents is a peroxisome proliferator-activated receptors (PPAR) agonist. In some embodiments, the one or more additional therapeutic agents is a dual PPAR agonist, a PPAR-a agonist, a PPAR-y agonist, or a PPAR-3 agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR-a agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR-y agonist. In some embodiments, the one or more additional therapeutic agents is a PPAR-3 agonist. In some embodiments, the PPAR agonist is selected from elafibrinor, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, GW-9662, GW501516, GFT1007, aleglitazar, muraglitazar, tesaglitazar, saroglitazar, and seladelpar.

[0138] In some embodiments, the one or more additional therapeutic agents is an HMG-CoA reductase inhibitor. In some embodiments, the HMG-CoA reductase inhibitor is a statin. In certain embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0139] In some embodiments, the one or more additional therapeutic agents is a diseasemodifying antirheumatic drug (DMARD). In certain embodiments the DMARD is selected from azathioprine, hydroxychloroquine, leflunomide, methotrexate, and sulfasalazineAttorney Docket No. 255944.001402

[0140] In some embodiments, the one or more additional therapeutic agents is DNA methyltransferase 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.

[0141] In some embodiments, the one or more additional therapeutic agents is an antiinterleukin- 17A biological agent. In some embodiments, the anti-interleukin- 17A biological agent is selected from secukinumab, ixekizumab, bimekizumab, brodalumab, and nekalimumab.

[0142] In some embodiments, the one or more additional therapeutic agents is an antiinterleukin-23 inhibitor. In certain embodiments the anti-interleukin-23 inhibitor is selected from guselkumab, risankizumab, tildrakizumab, and ustekinumab.

[0143] In some embodiments, the one or more additional therapeutic agents is a neutrophil elastase inhibitor. In some embodiments, the neutrophil elastase inhibitor is selected from sivelestat sodium hydrate, AvKTI, and a flavonoid.

[0144] In some embodiments, the one or more additional therapeutic agents is a corticosteroid. In certain embodiments, the corticosteroid is selected from flugestone, fluoromethoIone, 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.

[0145] In some embodiments, the one or more additional therapeutic agents is a protein arginine deiminase 4 (PAD4) inhibitor. In certain embodiments, the PAD4 inhibitor is selected from JBI-589, GSK484, Cl-Amidine, Azithromycin, Clindamycin, Leflunomide, andMethotrexate.Attorney Docket No. 255944.001402

[0146] In some embodiments, the one or more additional therapeutic agents is an apical sodium-dependent BA transporter (ASBT) inhibitor. In some embodiments, the ASBT inhibitor is A3907.

[0147] In some embodiments, the one or more additional therapeutic agents is a thyroid hormone receptor beta (THR-β) agonist. In some embodiments, the THR-β) agonist is selected from resmetirom, VK2809, and cs27109.

[0148] In some embodiments, the one or more additional therapeutic agents is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, ipilimumab, atezolizumab, avelumab, and durvalumab.

[0149] In some embodiments, the one or more additional therapeutic agents is a bile acid conjugate. In certain embodiments, the bile acid conjugate is berberine ursodeoxycholate, ursodeoxycholate, and nor- ursodeoxycholate.

[0150] In some embodiments, the one or more additional therapeutic agents is an integrin inhibitor. 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.

[0151] In some embodiments, the one or more additional therapeutic agents is an endocrine fibroblast 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.

[0152] In some embodiments, the one or more additional therapeutic agents is a monoclonal antibody. 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.

[0153] In some embodiments, the one or more additional therapeutic agents is an antagonist of MAS Related GPR Family Member X4 (MRGPRX4). In some embodiments, the monoclonal antibody is EP547.Attorney Docket No. 255944.001402

[0154] In some embodiments, the one or more additional therapeutic agents is an apical sodium-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.

[0155] In some embodiments, the one or more additional therapeutic agents is a farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is selected from OCA, CS0159, tropifexor, vonafexor, and cilofexor.

[0156] In some embodiments, the one or more additional therapeutic agents is a glucagon-like peptide- 1 receptor agonists (GLP-1RA). In some embodiments, the GLP-1RA is selected from dulaglutide, exenatide, liraglutide, liraglutide / insulin degludec, lixisenatide / insulin glargine, semaglutide, and tirzepatide.

[0157] In some embodiments, the one or more additional therapeutic agents is a bile acid or analog thereof. In some embodiments, the bile acid or analog thereof is selected from ursodeoxycholic acid and 24-norursodeoxycholic acid.

[0158] In some embodiments, the one or more additional therapeutic agents is a dihydroorotate dehydrogenase inhibitor. In some embodiments, the dihydroorotate dehydrogenase inhibitor is selected from brequinar sodium, ASLAN003, ML390, BAY2402234, PTC299, leflunomide, vidofludimus calcium, teriflunomide, and IMU-838.

[0159] In some embodiments, the one or more additional therapeutic agents is sodium thiosulfate.

[0160] In some embodiments, the one or more additional therapeutic agents is a calcium reducer. In some embodiments, the one or more additional therapeutic agents is cinacalcet.

[0161] In some embodiments, the one or more additional therapeutic agents is a phosphorous reducer. In some embodiments, the one or more additional therapeutic agents is sevelamer.

[0162] In some embodiments, the one or more additional therapeutic agents is an enzyme. In some embodiments, the one or more additional therapeutic agents is a recombinanthuman ENPP 1 protein. In some embodiments, the one or more additional therapeutic agents is INZ-701.Attorney Docket No. 255944.001402

[0163] In some embodiments, the one or more additional therapeutic agents is a TNAP inhibitor. In some embodiments, the TNAP inhibitor is selected from MLS-0038949, Levamisole, and DS-1211.

[0164] In some embodiments, the one or more additional therapeutic agents is a GLP1 agonist or a GLP1 dual agonist. In some embodiments, the GLP1 agonist or GLP1 dual agonist is selected from Exenatide (Byetta, Bydureon), Liraglutide (Victoza, Saxenda), Albiglutide (Tanzeum), Dulaglutide (Trulicity), Semaglutide (Ozempic, Rybelsus), and Tirzepatide (Mounjaro).

[0165] In some embodiments, the one or more additional therapeutic agents is a SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is selected from Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Bexagliflozin, and Sotagliflozin.

[0166] In some embodiments, the one or more additional therapeutic agents is an anticoagulant. In some embodiments, the anti-coagulant is selected from apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), rivaroxaban (Xarelto), and warfarin (Coumadin).

[0167] In some embodiments, the one or more additional therapeutic agents is a statin. In some embodiments, the statin is selected from Atorvastatin (Atorvaliq, Lipitor), Fluvastatin (Lescol), Lovastatin, Pitavastatin (Livalo), Pravastatin (Pravachol), Rosuvastatin calcium (Crestor), Simvastatin (Zocor).

[0168] In some embodiments, the one or more additional therapeutic agents is an angiotensinconverting enzyme inhibitors. In some embodiments, the angiotensin-converting enzyme inhibitor is selected from Benazepril (Lotensin), Captopril (Capoten), Enalapril (Vasotec), Enalaprilat (Vasotec), Fosinopril (Monopril), Lisinopril (Zestril, Prinivil), Moexipril (Univasc), Perindopril (Coversyl), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik).

[0169] In some embodiments, the one or more additional therapeutic agents is a reninangiotensin inhibitor. In some embodiments, the renin-angiotensin inhibitor is selected from aliskiren, ciprokiren, ditekiren, enalkiren, remikiren, rasilez, terlakiren, and zankiren.

[0170] In some embodiments, the one or more additional therapeutic agents is an aldosterone inhibitor. In some embodiments, the aldosterone inhibitor is selected from spironolactone systemic, eplerenone systemic, and finerenone systemic.Attorney Docket No. 255944.001402Additional Considerations

[0171] The doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician. In certain embodiments, the compound described herein (such as a compound of Formula I, 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 other compounds in Section 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 other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.

[0172] In certain embodiments, the compound described herein (such as a compound of Formula I, 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.

[0173] Another aspect of this invention is a kit comprising a therapeutically effective amount of the compound described herein (such as a compound of Formula I, 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

[0174] As indicated above, the invention provides pharmaceutical compositions, which comprise 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 forAttorney Docket No. 255944.001402application 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 composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0175] The phrase “therapeutically effective amount” as used herein means that amount of a compound, 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.

[0176] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, 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.

[0177] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium 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.

[0178] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, 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.

[0179] 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 anyAttorney Docket No. 255944.001402methods 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 active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0180] In certain embodiments, a formulation of the present invention comprises an excipient selected 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.

[0181] Methods of preparing these formulations or compositions include the step of bringing into 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.

[0182] Formulations of the invention suitable for oral administration may be in the form of capsules, 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.

[0183] 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,Attorney Docket No. 255944.001402mannitol, 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.

[0184] A tablet may be made by compression or molding, optionally with one or more accessory 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.

[0185] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present 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 thatAttorney Docket No. 255944.001402they 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.

[0186] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically 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, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0187] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0188] 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.

[0189] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration 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.

[0190] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.Attorney Docket No. 255944.001402

[0191] Dosage forms for the topical or transdermal administration of a compound of this invention 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.

[0192] The ointments, pastes, creams and gels may contain, in addition to an active compound of 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.

[0193] Powders and sprays can contain, in addition to a compound of this invention, excipients such 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.

[0194] Transdermal patches have the added advantage of providing controlled delivery of a compound 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.

[0195] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0196] Pharmaceutical compositions of this invention suitable for parenteral administration comprise 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.Attorney Docket No. 255944.001402

[0197] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical 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.

[0198] 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.

[0199] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption 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.

[0200] Injectable depot forms are made by forming microencapsule matrices of the subject compounds 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.

[0201] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, forAttorney Docket No. 255944.001402example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0202] The preparations of the present invention may be given orally, parenterally, topically, or rectally. 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.

[0203] The phrases “parenteral administration” and “administered parenterally” as used herein means 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 intrastemal injection and infusion.

[0204] The phrases “systemic administration,” “administered systemically,” “peripheral administration” 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.

[0205] These compounds may be administered to humans and other animals for therapy by any suitable 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.

[0206] Regardless of the route of administration selected, the compounds of the present invention, 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.

[0207] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effectiveAttorney Docket No. 255944.001402to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0208] The selected dosage level will depend upon a variety of factors including the activity of the 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.

[0209] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe 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.

[0210] In general, a suitable daily dose of a compound of the invention will be that amount of the 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.

[0211] 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.

[0212] 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.Attorney Docket No. 255944.001402EXAMPLES

[0213] The invention now being generally described, will be more readily understood by reference 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

[0214] Methods for preparing compounds described herein are illustrated in the following synthetic 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.

[0215] In the Schemes, it is understood by one skilled in the art of organic synthesis that the functionality 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).

[0216] The abbreviation “TFA” refers to trifluoroacetic acid. The abbreviation “FA” refers to formic acid.Analytical LCMS Methods:

[0217] Analytical LC / MS Analysis Method A:ESH7- ion mode 150-850 DaWavelength: UV 220 nmColumn: Waters, Xbridge C1850*2.1mm, 5umAttorney Docket No. 255944.001402Temperature: 40 °CGradient:0.019% TF A inTime (min) 0.038%TFA in water Flow (mL / min) acetonitrile0 99% 1% 0.83.85 0% 100% 0.8

[0218] Analytical LC / MS Analysis Method B:ESI+ / - ion mode 150-850 DaWavelength: UV 220 nmColumn: Waters, Xbridge C1850*2.1mm, 5umTemperature: 40 °CGradient:0.019% TF A inTime (min) 0.038%TFA in water Flow (mL / min) acetonitrile0 90% 10% 0.83.85 0% 100% 0.8

[0219] Analytical LC / MS Analysis Method C:(0-70% positive-negative)ESH7- ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: Shim-pack C18, 50*4.6mm, 5um or Welch Xtimate C18, 250*4.6mm, 5um or YMC- Triart Cl 8, 50*4.6mm, 5umTemperature: 40°CGradient:0.1% FA inTime (min) 0.1%FA in water Flow (mL / min) acetonitrile0.01 80% 20% 2.52.5 5% 95% 2.5

[0220] Analytical LC / MS Analysis Method D:Attorney Docket No. 255944.001402(positive-negative 3min-1)ESU7- ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: YMC-Triart Cl 8, 50*4.6mm, 5um or Shim-pack Cl 8, 50*4.6mm, 5 urn Temperature: 40°CGradient:0.1% FA inTime (min) 0.1%FA in water Flow (mL / min) acetonitrile0.01 80% 20% 2.5 or 1.22.5 5% 95% 2.5 or 1.2

[0221] Analytical LC / MS Analysis Method E:ESU7- ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: YMC-Triart Cl 8, 50*4.6mm, 5umTemperature: 40°CGradient:0.1% TFA inTime (min) 0.1%TFA in water Flow (mL / min) acetonitrile0.4 100% 0% 2.54.6 70% 30% 2.5

[0222] Analytical LC / MS Analysis Method F:ESU7- ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: YMC-Triart Cl 8, 50*4.6mm, 5umTemperature: 40°CGradient:0.1% TFA inTime (min) 0.1%TFA in water Flow (mL / min) acetonitrile0.4 80% 20% 2.52.5 5% 95% 2.5Attorney Docket No. 255944.001402

[0223] Analytical LC / MS Analysis Method G:(0-50% positive 3 min)ESI+ / - ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: YMC-Triart C18, 50*4.6mm, 5um or Shim-Pack Scepter C18, 33*3.0mm, 3um Temperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 100% 0% 2.32.5 50% 50% 2.3

[0224] Analytical LC / MS Analysis Method H:ESI+ / - ion mode 100-1000 DaWavelength: UV 220 nm / 254 nmColumn: YMC-Triart C18, 50×4.6mm, 5umTemperature: 40°CGradient:0.1% TFA inTime (min) 0.1%TFA in water Flow (mL / min) acetonitrile0.01 80% 20% 2.52.5 5% 95% 2.5

[0225] Analytical LC / MS Analysis Method J:ESI+ / - ion mode 100-1000 DaColumn: Shim-Pack Scepter C18, 33*3.0mm, 3umTemperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 95% 5% 1.22.5 70% 30% 1.2Attorney Docket No. 255944.001402

[0226] Analytical LC / MS Analysis Method K:ESI+ / - ion mode 100-1000 DaColumn: Kromasil-C18, 50*4.6mm, 5um or YMC-Triart C18, 50*4.6mm, 5um Temperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 100% 0% 2.55.0 50% 50% 2.5

[0227] Analytical LC / MS Analysis Method M:ESI+ / - ion mode 100-1000 DaColumn: Shim-Pack Scepter C18, 33*3.0mm, 3umTemperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 20% 80% 1.23.0 5% 95% 1.2

[0228] Analytical LC / MS Analysis Method N:ESI+ / - ion mode 100-1000 DaColumn: YMC-Triart Cl 8, 50*4.6mm, 5umTemperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 40% 60% 2.55.0 5% 95% 2.5

[0229] Analytical LC / MS Analysis Method O:ESI+ / - ion mode 100-1000 DaColumn: YMC-Triart Cl 8, 50*4.6mm, 5umAttorney Docket No. 255944.001402Temperature: 40°CGradient:0.1% FA inTime (min) 0.1% FA in water Flow (mL / min) acetonitrile0.01 40% 60% 1.23.0 5% 95% 1.2

[0230] Analytical LC / MS Analysis Method P:ESI+ / - ion mode 100-1000 DaColumn: Shim-Pack Scepter C18-H₂O / MeCN / FA-0-50%Temperature: 40°CGradient:Water / acetonitrile / FATime (min) acetonitrile Flow (mL / min) (90:10:0.05)0.01 100% 0% 1.21.79 50% 50% 1.20.7 50% 50% 1.2Examples:Attorney Docket No. 255944.001402Example 1: Method A: Synthesis of Compound 1-78Attorney Docket No. 255944.001402

[0231] Step 1: A mixture of 2-bromo-4,6-dimethylpyridin-3-amine (R-l, 1.0 g, 5.0 mmol, 1 eq.), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (R-2, 1.54 g, 7.5 mmol, 1.5 eq.), Pd(PPh3)4(577.8 mg, 0.5 mmol, 0.1 eq.) and Na₂CO₃ (1.6 g, 15.0 mmol, 3.0 eq.) in dioxane (50 mL) and H2O (10 mL) was stirred under N2 atmosphere at 110 °C for 6 hrs. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EA = 4: 1) to afford Int-1 (850 mg, 4.27 mmol, 85.43%) as a yellow solid. LCMS (ESI): m / z = 200 [M+H]+.

[0232] Step 2: To a stirred solution of Int-1 (300 mg, 1.51 mmol, 1.0 eq.) in water (15 mL) was added concentrated sulfuric acid (3 mL) and aqueous solution of NaNO2(1 M, 2.26 mL, 2.26 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. for 6 hrs, the mixture was poured into ice water (30 mL) and neutralized by aqueous solution of NaOH (4 M). The resulting mixture was extracted with EtOAc (30 mL x 3), the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide Int-2, which was taken directly to the next step without further purification.

[0233] Step 3: The crude residue Int-2 was dissolved in anhydrous THF (20 mL), then to the resulting mixture was added NaH (90.6 mg, 2.26 mmol, 1.5 eq.) under N2 atmosphere at 0 °C slowly. After stirred for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 347.9 mg, 1.81 mmol, 1.2 eq.) and the mixture was stirred at r.t. for another 2 hrs. After completion, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EA = 2: 1) to afford Int-3 (150 mg, 0.42 mmol, 28% for two steps) as a yellow solid. LCMS (ESI): m / z = 357 [M+H]+.

[0234] Step 4: A mixture of Int-3 (150 mg, 0.42 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 74.8 mg, 0.51 mmol, 1.2 eq.), Pd(PPh₃)₄ (48.7 mg, 0.04 mmol, 0.1 eq.) and Na₂CO₃ (134 mg, 1.26 mmol, 3.0 eq.) in dioxane (20 mL) and water (4 mL) was stirred under N2 atmosphere at 100 °C for 2 hrs. After completion, the reaction mixture was diluted with H2O (50 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 flashAttorney Docket No. 255944.001402column chromatography on silica gel (eluted with PE: EA = 2: 1) to afford Int-4 (130 mg, 0.31 mmol, 73 %) as a yellow solid. LCMS (ESI): m / z = 425 [M+H]+.

[0235] Step 5: A mixture of Int-4 (130 mg, 0.31 mmol, 1.0 eq.), Fe powder (87 mg, 1.55 mmol, 5 eq.) and NH4CI (164.3 mg, 3.1 mmol, 10 eq.) in EtOH (20 mL) and H2O (10 mL) was stirred at 80 °C for 2 hrs. After completion, the reaction mixture was concentrated and the residue was filtered through a pad of Celite®, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford Int-5 (110 mg, crude) as a brown solid, which was used directly in the next step. LCMS (ESI): m / z = 395 [M+H]+.

[0236] Step 6: To a stirred solution of Int-5 (110 mg, 0.28 mmol, 1.0 eq.) and TEA (0.3 ml) in DCM (10 mL) was added MsCl (80 mg, 0.7 mmol, 2.5 eq.) at 0 °C slowly. The resulting mixture was stirred at r.t. for 20 min. After completion, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to provide Int-6.

[0237] Step 7: The crude residue Int-6 was dissolved in THF (20 mL), then to the solution was added aqueous solution KOH (1 M, 1 mL). The resulting mixture was stirred at r.t. for 30 min. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC (Column: YMC-Actus Triart Cl 8 250*20mm*5um, gradient: 5-95% MeCN in H2O (with 0.1% TFA)) to afford Compound 1-78 (116.4 mg, 0.247 mmol, 88.1%) as a white solid (TFA salt).

[0238] Compound 1-78: Retention time: 3.728 min; LC-MS (ESI) m / z = 473.0 [M+H]+;1H NMR (400 MHz, DMSO-6) 8 10.07 (s, 1H), 9.06 (d, J= 3.1 Hz, 1H), 8.94 (dd, J= 14.4, 2.1 Hz, 2H), 8.64 - 8.55 (m, 1H), 8.53 – 8.39 (m, 2H), 7.92 (d, J= 8.1 Hz, 1H), 7.81 (d, J= 8.2 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.44 (s, 1H), 3.17 (s, 3H), 2.60 (s, 3H), 2.16 (s, 3H).

[0239] The following compounds were synthesized from the appropriate reagents using Method A: Compounds 1-35, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-70, 1-71, 1-72, and 1-74.Example 2: Method B: Synthesis of Compound 1-28Attorney Docket No. 255944.001402Attorney Docket No. 255944.001402

[0240] Step 1: A mixture of 6-bromo-4-methylpyridin-3-amine (R-5, 5.0 g, 26.9 mmol, 1.0 eq.), 2-(3, 6-dihydro-2H-pyran-4-yl)-4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolane (R-6, 6.8 g, 32.3 mmol, 1.2 eq.), Pd(PPh3)4 (3.1 g, 2.69 mmol, 0.1 eq.) and K2CO3 (11.1 g, 80.6 mmol, 3.0 eq.) in dioxane (150 mL) and H2O (30 mL) was stirred at 100 °C under N2 atmosphere for 2 hrs. After completion, the mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-7 (3.9 g, 20.5 mmol, 76%) as a white solid. LCMS (ESI): m / z = 191 [M+H]+.

[0241] Step 2: To a stirred solution of Int-7 (1.5 g, 7.9 mmol) in MeOH (150 mL) was added Pd / C (150 mg, 10 wt%). The resulting mixture was stirred under H2 atmosphere at r.t. for 2 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (50 mL x 3). The combined filtrates were concentrated under reduced pressure to give Int-8 (1.21 g, 6.3 mmol, 80%) as a brown solid. LCMS (ESI): m / z = 193 [M+H]+.

[0242] Step 3: To a stirred solution of Int-8 (1.21 g, 6.3 mmol, 1.0 eq.) in DCM (50 mL) was added NBS (1.22 g, 6.93 mmol, 1.1 eq.). After stirred at r.t. for 1 hrs, the mixture was diluted with H2O (300 mL) and extracted with EtOAc (150 mL x 3). The organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-9 (1.38 g, 5.1 mmol, 81%) as a yellow solid. LCMS (ESI): m / z = 271 [M+H]+.

[0243] Step 4: A mixture of Int-9 (250 mg, 0.93 mmol, 1.0 eq.), pyridin-3-ylboronic acid (R-7, 136.7 mg, 1.11 mmol, 1.2 eq.), Pd(PPh3)4 (107 mg, 0.09 mmol, 0.1 eq.) and Na2CO3 (296 mg, 2.8 mmol, 3.0 eq.) in dioxane (30 mL) and H2O (6 mL) was stirred at 100 °C under N2 atmosphere for 2 hrs. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-10 (186 mg, 0.69 mmol, 75%) as a white solid.LCMS (ESI): m / z = 270 [M+H]+.

[0244] Step 5: To a stirred solution of Int-10 (186 mg, 0.69 mmol, 1.0 eq.) in water (30 mL) was added concentrated sulfuric acid (6 mL) and aqueous solution of NaNO2 (71.3 mg, 1.03 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. for 1 hrs, then stirred at 70 °C for 1 hrs, the mixture wasAttorney Docket No. 255944.001402poured into ice water (40 mL) and the reaction mixture was adjusted to pH = 7-8 with sat. NaHCO3. After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 10) to afford Int-11 (143 mg, 0.53 mmol, 76%) as a white solid. LCMS (ESI): m / z = 271 [M+H]+.

[0245] Step 6: The Int-11 (143 mg, 0.53 mmol, 1.0 eq.) was dissolved in anhydrous THF (20 mL), then the resulting mixture was cooled to 0 °C and NaH (32 mg, 0.79 mmol, 1.5 eq.) was added slowly under N2 atmosphere. After stirring at 0 °C for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 122.7 mg, 0.63 mmol, 1.2 eq.). After stirring at r.t. for 1 hrs, the mixture was quenched with saturated aqueous solution of NH4CI (50 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 column chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-12 (152 mg, 0.36 mmol, 67 %) as a yellow solid. LCMS (ESI): m / z = 427 [M+H]+.

[0246] Step 7: A mixture of Int-12 (152 mg, 0.36 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 64 mg, 0.43 mmol, 1.2 eq.), Pd(PPh3)4 (42 mg, 0.036 mmol, 0.1 eq.) and K2CO3 (147.7 mg, 1.07 mmol, 3.0 eq.) in dioxane (40 mL) and water (8 mL) was stirred under N2 atmosphere at 100 °C for 1 hrs. After completion, the reaction mixture was diluted with H2O (50 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 PE: EtOAc = 1: 9) to afford Int-13 (145 mg, 0.29 mmol, 82%) as a yellow solid. LCMS (ESI): m / z = 495 [M+H]+.

[0247] Step 8: A mixture of Int-13 (145 mg, 0.29 mmol, 1.0 eq.), Fe powder (83 mg, 1.47 mmol, 5.0 eq.) and NH4CI (80 mg, 1.47 mmol, 5.0 eq.) in EtOH (40 mL) and H2O (20 mL) was stirred at 80 °C for 1.5 hrs. After completion, the mixture was filtered through a pad of Celite®, the filter cake was washed with MeOH (20 mL x 3). The combined filtrate was concentrated under reduced pressure, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-14 (132 mg, crude product) as a white solid, which was used for next step directly. LCMS (ESI): m / z = 465 [M+H]+.Attorney Docket No. 255944.001402

[0248] Step 9: To a stirred solution of Int-14 (132 mg, crude) in DCM (25 mL) was added MsCl (0.3 mL) and TEA (0.5 mL) at 0 °C slowly. After stirred at r.t. for 10 min, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure to afford Int-15 (168 mg, crude product) as a yellow oil, which was used for next step directly. LCMS (ESI): m / z = 621 [M+H]+.

[0249] Step 10: The Int-15 (168 mg, crude) was dissolved with THF (25 mL) and to the mixture was added aqueous solution of NaOH (4 M, 1 mL). After stirred at r.t. for 30 min, the mixture was neutralized by HC1 (1 M) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC(column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O(with 0.1% TFA)) to afford Compound 1-28 (71.4 mg, 0.13 mmol, 45.4 % over 3 steps) as a white solid.

[0250] Compound 1-28: Retention time: 1.012 min; LCMS (ESI): m / z = 543.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) 8 10.10 (s, 1H), 9.10 (s, 1H), 8.95 (dd, J= 6.9, 2.0 Hz, 2H), 8.57 (d, J= 4.9 Hz, 1H), 8.44 (d, J= 7.4 Hz, 1H), 8.35 (t, J= 2.0 Hz, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.82 (d, J= 8.2 Hz, 1H), 7.55 (d, J= 4.6 Hz, 1H), 7.47 (s, 1H), 4.00 (dd, J= 8.2, 2.9 Hz, 2H), 3.56 - 3.44 (m, 2H), 3.19 (s, 3H), 3.07 (dt, J= 15.3, 7.5 Hz, 1H), 2.18 (s, 3H), 1.95 - 1.84 (m, 4H).

[0251] The following compounds were synthesized from the appropriate reagents using Method B: Compounds 1-2, 1-8, 1-17, 1-18, 1-20, 1-22, 1-24, 1-26, 1-43, 1-69, 1-73, 1-75, 1-76, 1-77, 1-79, 1-80, 1-81, 1-82, 1-83, and 1-84.Attorney Docket No. 255944.001402Example 3: Method C: Synthesis of Compound 1-5Attorney Docket No. 255944.001402

[0252] Step 1: A mixture of 2-chloro-6-(trifluoromethyl)pyridin-3-amine (R-8, 2.0 g, 10.2 mmol, 1.0 eq.), pyridin-3-ylboronic acid (R-7, 1.5 g, 12.2 mmol, 1.2 eq.), Pd(PPh3)4(1.2 g, 1.02 mmol, 0.1 eq.) and K2CO3 (4.2 g, 30.6 mmol, 3.0 eq.) in dioxane (50 mL) and H2O (10 mL) was stirred at 100 °C under N2 atmosphere for 3 hrs. After completion, the mixture was diluted with H2O (80 mL) and extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 5: 1) to afford Int-16 (2.2 g, 9.2 mmol, 90.2%) as a white solid. LCMS (ESI): m / z = 240 [M+H]+.

[0253] Step 2: To a stirred solution of Int-16 (2.2 g, 9.2 mmol,, 1.0 eq.) in water (50 mL) was added concentrated sulfuric acid (10 mL) and aqueous solution of NaNO2(1 M, 13.8 mL,13.8 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. for 6 hrs, the mixture was poured into ice water (100 mL) and neutralized by aqueous solution of NaOH (4 M). After completion, the resulting mixture was extracted with EtOAc (60 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide Int-17.

[0254] Step 3: The crude Int-17 was dissolved with ACN (50 mL), then to the resulting mixture was added NBS (1.97 g, 11.1 mmol, 1.2 eq.) at 0 °C slowly. After stirred at r.t. for 2 hrs, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (60 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 through silica gel (eluted with PE: EtOAc = 2: 1) to afford Int-18 (1.1 g, 3.5 mmol, 37.6% for two steps) as a white solid. LCMS (ESI): m / z = 319 [M+H]+.

[0255] Step 4: To a stirred solution of Int-18 (5, 1.1 g, 3.5 mmol, 1.0 eq.) in DMF (30 mL) was added Cs2CO3 ( 3.4 g, 10.4 mmol, 3eq) and 2 -iodopropane (882 mg, 5.2 mmol, 1.5 eq.). After stirred at 50 °C. for 6 hrs, the mixture was diluted with H2O (50 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 through silica gel (eluted with PE: EtOAc = 5: 1) to afford Int-19 (850 mg, 2.4 mmol, 68.2%) as a white solid.LCMS (ESI): m / z = 361 [M+H]+.

[0256] Step 5: A mixture of Int-19 (850 mg, 2.4 mmol, 1.0 eq.), MeB(OH)2 (283 mg, 4.8 mmol, 2.0 eq.), cataCXium A Pd G3 (171.9 mg, 0.24 mmol, 0.1 eq.) and K2CO3 (977.5 mg, 7.1 mmol, 3.0 eq.) in dioxane (30 mL) and H2O (6 mL) was stirred at 100 °C under N2 atmosphere forAttorney Docket No. 255944.0014023 hrs. After completion, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (40 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 5: 1) to afford Int-20 (580 mg, 1.96 mmol, 93.0%) as a white solid.LCMS (ESI): m / z = 297 [M+H]+.

[0257] Step 6: To a stirred solution of Int-20 (580 mg, 1.96 mmol,, 1.0 eq.) in DCM (20 mL) was added BBr3 (728 mg, 2.9 mmol, 1.5eq) at -78 °C slowly. After stirred at r.t. for 2 hrs, the mixture was poured into ice water (30 mL) and neutralized by aqueous solution of NaOH (4 M). After completion, the resulting mixture was extracted with EtOAc (40 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Int-21.

[0258] Step 7: The crude Int-21 was dissolved in anhydrous DMF (30 mL), then to the resulting mixture was added NaH (117.6 mg, 60% in mineral oil, 2.9 mmol, 1.5 eq.) under N2 atmosphere at 0 °C slowly. After stirring at 0 °C for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 376.2 mg, 1.96 mmol, 1.2 eq.). After stirring at r.t. for 2 hrs, the mixture was quenched with saturated aqueous solution of NH4CI (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-22 (370 mg, 0.9 mmol, 46% for two steps) as a yellow solid. LCMS (ESI): m / z = 411 [M+H]+.

[0259] Step 8: A mixture of Int-22 (370 mg, 0.9 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 160 mg, l.l mmol, 1.2 eq.), Pd(PPh3)4 (104.3 mg, 0.09 mmol, 0.1 eq.) and K2CO3 (373.6 mg, 2.7 mmol, 3.0 eq.) in dioxane (15 mL) and water (3 mL) was stirred under N2 atmosphere at 100 °C for 4 hrs. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 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 PE: EtOAc = 1: 1) to afford Int-23 (280 mg, 0.6 mmol, 54.2%) as a yellow solid. LCMS (ESI): m / z = 479 [M+H]+.

[0260] Step 9: A mixture of Int-23 (280 mg, 0.6 mmol, 1.0 eq.), Fe powder (155 mg, 2.9 mmol, 5 eq.) and NH4CI (310 mg, 5.9 mmol, 10 eq.) in EtOH (20 mL) and H2O (10 mL) was stirred at 80 °C for 3 hrs. After completion, the mixture was filtered through a pad of Celite®, theAttorney Docket No. 255944.001402filter cake was washed with EA (30 mL x 3). The combined filtrate was concentrated under reduced pressure to afford Int-24 (220 mg, crude) as a brown solid, which was used for next step directly. LCMS (ESI): m / z = 449 [M+H]+.

[0261] Step 10: To a stirred solution of Int-24 (50 mg, 0.1 mmol, 1.0 eq.) in MeCN (20 mL) was added ‘BuNCh (15 mg, 0.15 mmol, 1.5 eq.) and CuBn (37 mg, 0.17 mmol, 1.5 eq.) at 0°C slowly. After stirred at r.t. for 2hrs, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-25 (28 mg, 0.05 mmol, 49.8%) as a white solid. LCMS (ESI): m / z = 512 [M+H]+.

[0262] Step 11: A mixture of Int-25 (28 mg, 0.05 mmol, 1.0 eq.), cyclopropylsodiumthiolate (R-9, 8 mg, 0.08 mmol, 1.5 eq.), Pd2(dba)3 (10 mg, 0.01 mmol, 0.2 eq.), XantPhos (9.5 mg, 0.016 mmol, 0.3 eq.) and DIEA (42.4 mg, 0.33 mmol, 6.0 eq.) in dioxane (5 mL) stirred at 100 °C under N2 atmosphere for 3hrs. After completion, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 1: 2) to afford Int-26 (10 mg, 0.02 mmol, 39.6%) as a white solid. LCMS (ESI): m / z = 506 [M+H]+.

[0263] Step 12: To a stirred mixture of Int-26 (10 mg, 0.02 mmol, 1.0 eq.) in MeOH (5 mL) was added (diacetoxyiodo)benzene (R-10, 19 mg, 0.06 mmol, 3.0 eq.) and ammonium carbamate (6.2 mg, 0.08 mmol, 4.0 eq.). After stirred at 100 °C for 3h, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC(column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 5%-95% MeCN in H2O [with 0.1% TFA]) to afford Compound 1-5 (4.0 mg, 0.008 mmol, 37.2%) as a white solid.

[0264] Compound 1-5: Retention time: 1.17 min; LCMS (ESI): m / z = 537 [M+H]+;1H NMR (400 MHz, CDCl3) 3 (ppm) 9.49, 9.43 (1H, two rotamers, ratio: 6 / 4), 9.14 – 8.99 (m, 2H), 8.90 (s, 1H), 8.73 (d, J = 6.6 Hz, 1H), 8.58-8.53 (m, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.94-7.84 (m, 2H), 7.72-7.68 (m, 1H), 3.55, 3.06 (1H, two rotamers, ratio: 6 / 4), 2.39, 2.31 (3H, two rotamers, ratio: 6 / 4), 1.80-1.05 (m, 4H).Attorney Docket No. 255944.001402Example 4: Method D: Synthesis of Compound 1-9 & Compound 1-67Attorney Docket No. 255944.001402Compound M7Compound 1-9

[0265] Step 1: A mixture of 6-bromo-4-methylpyridin-3-amine (R-5, 2.0 g, 10.8 mmol, 1.0 eq.), cyclopropylboronic acid (2.8 g, 32.3 mmol, 3.0 eq.), cataCXium A Pd G3 (0.78 g, 1.1 mmol, 0.2 eq.) and K2CO3 (4.5 g, 32.3 mmol, 3.0 eq.) in dioxane (100 mL) and H2O (40 mL) was stirred at 105 °C under N2 atmosphere for 16 hrs. After completion, the mixture was diluted with H2O (500 mL) and extracted with EtOAc (200 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-27 (460 mg, 3.1 mmol, 29%) as a white solid. LCMS (ESI): m / z = 149 [M+H]+.

[0266] Step 2: To a stirred solution of Int-27 (360 mg, 2.4 mmol, 1.0 eq.) in ACN (10 mL) was added NBS (473.6 mg, 2.7 mmol, 1.1 eq.). After stirred at r.t. for 4 hrs, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. TheAttorney Docket No. 255944.001402residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-28 (143 mg, 0.63 mmol, 26%) as a brown solid. LCMS (ESI): m / z = 227 [M+H]+.

[0267] Step 3: A mixture of Int-28 (143 mg, 0.6 mmol, 1.0 eq.), pyridin-3-ylboronic acid (R-7, 94 mg, 0.76 mmol, 1.2 eq.), Pd(PPh3)4(73 mg, 0.06 mmol, 0.1 eq.) and K2CO3 (262 mg, 1.9 mmol, 3.0 eq.) in dioxane (10 mL) and H2O (2 mL) was stirred at 100 °C under N2 atmosphere for 2 hrs. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-29 (102 mg, 0.45 mmol, 72%) as a white solid.LCMS (ESI): m / z = 226 [M+H]+.

[0268] Step 4: To a stirred solution of Int-29 (102 mg, 0.45 mmol, 1.0 eq.) in water (5 mL) was added concentrated sulfuric acid (1 mL) and aqueous solution of NaNO2 (46.9 mg, 0.7 mmol, 1.5 eq.) at 0 °C, slowly. After stirred at r.t. for 2 hrs, then stirred at 60 °C for 2 hrs, the mixture was poured into ice water (5 mL) and the reaction mixture was adjusted to pH = 7-8 with saturated NaHCO3. After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-30 (105 mg, crude) as a light yellow solid, which was used directly in the next step. LCMS (ESI): m / z = 227 [M+H]+.

[0269] Step 5: The Int-30 (105 mg, 0.46 mmol, 1.0 eq.) was dissolved in anhydrous DMF (5 mL), then to the resulting mixture was added NaH (27.8 mg, 0.7 mmol, 1.5 eq.) under N2 atmosphere at 0 °C slowly. After stirred at 0 °C for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 107.6 mg, 0.56 mmol, 1.2 eq.). After stirred at r.t. for 2 hrs, the mixture was quenched with saturated aqueous solution of NH4CI (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was 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) to afford Int-31 (129 mg, 0.34 mmol, 75.6% for two steps) as a yellow solid. LCMS (ESI): m / z = 383 [M+H]+.

[0270] Step 6: A mixture of Int-31 (129 mg, 0.34 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 60 mg, 0.4 mmol, 1.2 eq.), Pd(PPh3)4(39 mg, 0.033 mmol, 0.1 eq.) and K2CO3 (139.8 mg, 1.0 mmol, 3.0 eq.) in dioxane (20 mL) and water (4 mL) was stirred under N2 atmosphere at 100 °C for 16 hrs. After completion, the reaction mixture was diluted with H2O (50Attorney Docket No. 255944.001402mL) and extracted with EtOAc (25 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 PE: EtOAc = 1: 1) to afford Int-32 (112 mg, 0.25 mmol, 74%) as a yellow solid. LCMS (ESI): m / z = 451 [M+H]+.

[0271] Step 7: A mixture of Int-32 (112 mg, 0.25 mmol, 1.0 eq.), Fe powder (69.7 mg, 1.3 mmol, 5.0 eq.) and NH4CI (66 mg, 1.3 mmol, 5.0 eq.) in EtOH (30 mL) and H2O (6 mL) was stirred at 80 °C for 3 hrs. After completion, the mixture was filtered through a pad of Celite®, the filter cake was washed with MeOH (50 m). The combined filtrate was concentrated under reduced pressure, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-33 (96 mg, crude) as a light yellow solid, which was used for next step, directly. LCMS (ESI): m / z = 421 [M+H]+.

[0272] Step 8: To a stirred solution of Int-33 (40 mg, crude) in DCM (3 mL) was added MsCl (13, 0.2 mL) and TEA (0.2 mL) at 0 °C slowly. After stirred at r.t for 10 min, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure to afford Int-34 (46 mg, crude) as a white oil, which was used for next step directly. LCMS (ESI): m / z = 577 [M+H]+.

[0273] Step 9: The Int-34 (46 mg, crude) was dissolved in THF (1 mL) and to the mixture was added aqueous solution of NaOH (4 M, 1 mL). After stirred at r.t for 30 min, the mixture was neutralized by HC1 (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Compound 1-67 (32 mg, crude) as a white oil, which was used for next step directly.

[0274] Alternatively, Compound 1-67 could be further purified by pre-HPLC (column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O(with 0.1% TFA)) to afford pure Compound 1-67 as a white solid.

[0275] Compound 1-67: Retention time: 1.343 min; LCMS (ESI): m / z = 499.4 [M+H]+;NMR (400 MHz, CDCl3) 5 (ppm) 9.79 (s, 1H), 9.09 (d, J= 7.8 Hz, 1H), 8.97 (d, J= 1.9 Hz, 1H), 8.78 (d, J= 1.6 Hz, 1H), 8.63 (d, J= 6.0 Hz, 1H), 8.37 (s, 1H), 8.07-8.04 (m, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.54- 7.46 (m, 1H), 3.32 (s, 3H), 2.18-2.16 (m, 4H), 1.13-1.10 (m, 4H).Attorney Docket No. 255944.001402

[0276] Step 10: To a stirred solution of Compound 1-67 (32 mg) in DMF (1 mL) was added K2CO3 (50 mg) and Mel (0.05 mL) at 0 °C slowly. After stirred at r.t. for 30 min, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by pre-HPLC(column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O (with 0.1% TFA)) to afford Compound 1-9 (15.0 mg, 0.029 mmol) as a white powder.

[0277] Compound 1-9: Retention time: 1.391 min; LCMS (ESI): m / z = 513.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) > (ppm) 5 9.01 (s, 1H), 8.99 (s, 1H), 8.92 (s, 1H), 8.58 (d, J= 3.6 Hz, 1H), 8.54 (s, 1H), 8.28 (d, J= 7.6 Hz, 1H), 8.13 (d, J= 8.0 Hz, 1H), 7.90 (d, J= 7.8 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.45 (s, 1H), 3.24 (s, 3H), 3.19 (s, 3H), 2.28 - 2.18 (m, 1H), 2.15 (s, 3H), 1.05-1.01 (m, 4H).

[0278] The following compounds were synthesized from the appropriate reagents using Method D: Compounds 1-6, 1-7, 1-10, 1-25, 1-27, 1-29, 1-31, 1-32, 1-33, 1-36, 1-39, 1-40, 1-41, 1-42, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-86, 1-87 and 1-88.Example 5: Method E: Synthesis of Compound 1-38NaBH4, °2NMnO2,2DAST, DCM, MeOH OHDCM0 °C to RT lnt-36 OH 1CataCXium A Pd G3, K2CO3, dioxane / H2O, 100 °C -:Attorney Docket No. 255944.001402Compound 1-151

[0279] Step 1: A mixture of methyl 4-methyl-5-nitropicolinate (R-11, 2.0 g, 10.2 mmol, 1.0 eq.), NaBH4(1.55 g, 40.82 mmol, 4.0 eq.) in MeOH (30 mL) was stirred at r.t. for 2 hrs. After completion, the mixture was diluted with H2O (500 mL) and extracted with EtOAc (200 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-35 (1.64 g, 9.76 mmol, 96%) as a light yellow solid. LCMS (ESI): m / z = 169 [M+H]+.Attorney Docket No. 255944.001402

[0280] Step 2: To a stirred solution of Int-35 (1.6 g, 9.52 mmol, 1.0 eq.) in DCM (150 mL) was added MnO2(4.14 g, 47.62 mmol, 5.0 eq.). The resulting mixture was stirred under H2 atmosphere at r.t. for 6 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with DCM (150 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-36 (1.1 g, 6.63 mmol, 69%) as a light yellow solid.LCMS (ESI): m / z= 167 [M+H]+.

[0281] Step 3: To a stirred solution of Int-36 (1.1 g, 6.6 mmol, 1.0 eq.) in DCM (30 mL) was added DAST (4.3 g, 26.5 mmol, 4.0 eq.) at 0 °C slowly. After stirred at r.t. for 1 hrs, the mixture was diluted with H2O (120 mL) and extracted with DCM (60 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 5: 1) to afford Int-37 (838 mg, 4.4 mmol, 67%) as a yellow oil. LCMS (ESI): m / z = 189 [M+H]+.

[0282] Step 4: To a stirred solution of Int-37 (838 mg, 4.43 mmol) in MeOH (100 mL) was added Pd / C (84 mg, 10 wt%). The resulting mixture was stirred under H2 atmosphere at r.t. for 16 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (50 mL x 3). The combined filtrates were concentrated under reduced pressure to give Int-38 (753 mg, 4.74 mmol, crude) as a yellow oil. LCMS (ESI): m / z = 159 [M+H]+.

[0283] Step 5: To a stirred solution of Int-38 (733 mg, 4.6 mmol, 1.0 eq.) in ACN (50 mL) was added NBS (903 mg, 5.1 mmol, 1.1 eq.). After stirred at r.t. for 1 hrs, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-39 (692 mg, 5.1 mmol, 63%) as a white solid. LCMS (ESI): m / z = 237 [M+H]+.

[0284] Step 6: A mixture of Int-39 (252 mg, 1.1 mmol, 1.0 eq.), pyridin-3-ylboronic acid (R-7, 157.6 mg, 1.3 mmol, 1.2 eq.), Pd(PPh3)4(123.4 mg, 0.11 mmol, 0.1 eq.) and K2CO3 (442.1 mg, 3.2 mmol, 3.0 eq.) in dioxane (10 mL) and H2O (2 mL) was stirred at 100 °C under N2 atmosphere for 8 hrs. After completion, the mixture was diluted with H2O (120 mL) and extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography through silicaAttorney Docket No. 255944.001402gel (eluted with PE: EtOAc = 3: 1) to afford Int-40 (204 mg, 0.9 mmol, 81%) as a brown solid.LCMS (ESI): m / z = 236 [M+H]+.

[0285] Step 7: To a stirred solution of Int-40 (160 mg, 0.7 mmol, 1.0 eq.) in water (2 mL) was added concentrated HBF4 (4 mL) and aqueous solution of NaNO2(71.3 mg, 1.02 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. for 1 hr, then stirred at 60 °C for 2 hrs, the mixture was poured into ice water (15 mL) and the reaction mixture was adjusted to pH = 7-8 with saturated NaHCO3. After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc == 1: 1) to afford Int-41 (82 mg, 0.35 mmol, 51%) as a light yellow solid. LCMS (ESI): m / z = 237 [M+H]+.

[0286] Step 8: The Int-41 (82 mg, 0.35 mmol, 1.0 eq.) was dissolved with anhydrous DMF (15 mL), then to the resulting mixture was added NaH (21 mg, 0.52 mmol, 1.5 eq.) under N2 atmosphere at 0 °C slowly. After stirred at 0 °C for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 80.5 mg, 0.42 mmol, 1.2 eq.). After stirred at r.t. for 2 hrs, the mixture was quenched with saturated aqueous solution of NH4CI (40 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 column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-42 (49 mg, 0.13 mmol, 36%) as a yellow solid. LCMS (ESI): m / z = 393 [M+H]+.

[0287] Step 9: A mixture of Int-42 (49 mg, 0.13 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 22.2 mg, 0.15 mmol, 1.2 eq.), Pd(PPh3)4(14.4 mg, 0.013 mmol, 0.1 eq.) and K2CO3 (51.8 mg, 0.4 mmol, 3.0 eq.) in dioxane (5 mL) and water (1 mL) was stirred under N2 atmosphere at 100 °C for 1 hrs. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (15 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 PE: EtOAc = 1: 1) to afford Int-43 (52 mg, 0.11 mmol, 90%) as a yellow solid. LCMS (ESI): m / z = 461 [M+H]+.

[0288] Step 10: A mixture of Int-43 (52 mg, 0.11 mmol, 1.0 eq.), Fe powder (31.6 mg, 0.57 mmol, 5.0 eq.) and NH4CI (30 mg, 0.57 mmol, 5.0 eq.) in EtOH (30 mL) and H2O (5 mL) was stirred at 80 °C for 2 hrs. After completion, the mixture was filtered through a pad of Celite®, theAttorney Docket No. 255944.001402filter cake was washed with MeOH (60 mL). The combined filtrate was concentrated under reduced pressure, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-44 (43 mg, crude product) as a white solid, which was used for next step directly. LCMS (ESI): m / z = 431 [M+H]+.

[0289] Step 11: To a stirred solution of Int-44 (43 mg, crude) in DCM (3 mL) was added MsCl (0.1 mL) and TEA (0.2 mL) at 0 °C slowly. After stirred at r.t. for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure to afford Int-45 (19 mg, crude product) as a brown oil, which was used for next step directly. LCMS (ESI): m / z = 587 [M+H]+.

[0290] Step 12: The Int-45 (19 mg, crude) was dissolved with THF (3 mL) and to the mixture was added aqueous solution of NaOH (4 M, 0.5 mL). After stirred at r.t. for 30 min, the mixture was neutralized by HC1 (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Compound 1-151 (17 mg, crude) as a colorless oil, which was used for next step directly. LCMS (ESI): m / z = 509 [M+H]+.

[0291] Step 13: To a stirred solution of Compound 1-151 (17 mg, crude) in DMF(2.0 mL) was added K2CO3 (50 mg, 0.36 mmol) and Mel (0.05 mL) at 0 °C slowly. After stirred at r.t. for 30 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by pre-HPLC(column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O (with 0.1% TFA)) to afford Compound 1-38 (7.8 mg, 0.029 mmol, 26.4 % over 3 steps) as a white solid.

[0292] Compound 1-38: Retention time: 1.226 min; LCMS (ESI): m / z = 523.0 [M+H]+;1H NMR(400 MHz, DMSO) 5 9.00 (d, J= 1.6 Hz, 1H), 8.96 (d, J= 2.0 Hz, 1H), 8.93 (s, 1H), 8.61 (d, J= 4.4 Hz, 1H), 8.55 (s, 1H), 8.24 (d, J= 8.0 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.94-7.90 (m, 2H), 7.57-7.51 (m, 1H), 7.10 (t, J = 54.9 Hz, 1H), 3.25 (s, 3H), 3.20 (s, 3H), 2.29 (s, 3H);19F NMR (376 MHz, DMSO) 8 -114.68 (s).

[0293] The following compounds were synthesized from the appropriate reagents using Method E: Compounds 1-37.Attorney Docket No. 255944.001402Example 6: Method F: Synthesis of Compound 1-3lnt-50Compound M

[0294] Step 1: A mixture of Int-39 (300 mg, 1.3 mmol, 1.0 eq.), (3,6-dihydro-2H-pyran-4-yl)boronic acid (R-12, 195.3 mg, 1.6 mmol, 1.2 eq.), Pd(PPh3)4 (146.9 mg, 0.13 mmol, 0.1 eq.) and K2CO3 (526.3 mg, 3.8 mmol, 3.0 eq.) in dioxane (15 mL) and H2O (3 mL) was stirred at 100 °C under N2 atmosphere for 1 hr. After completion, the mixture was diluted with H2O (130 mL) and extracted with EtOAc (40 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash columnAttorney Docket No. 255944.001402chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-47 (276 mg, 1.2 mmol, 90%) as a white solid. LCMS (ESI): m / z = 241 [M+H]+.

[0295] Step 2: To a stirred solution of Int-47 (276 mg, 1.2 mmol) in MeOH (100 mL) was added Pd / C (84 mg, 10 wt%). The resulting mixture was stirred under H2 atmosphere at r.t. for 16 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (80 mL). The combined filtrates were concentrated under reduced pressure to give Int-48 (191 mg, 0.8 mmol, 69%) as a white solid. LCMS (ESI): m / z = 243 [M+H]+.

[0296] Step 3: To a stirred solution of Int-48 (150 mg, 0.8 mmol, 1.0 eq.) in water (1 mL)was added concentrated H2SO4 (5 mL) and aqueous solution of NaNO2(64.1 mg, 0.9 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. for 1 hrs, then warmed to 70 °C, kept stirred for 2 hrs, the mixture was poured into ice water (5 mL) and the reaction mixture was adjusted to pH = 7-8 with saturated NaHCCL. After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-49 (96 mg, 0.4 mmol, 64%) as a brown solid. LCMS (ESI): m / z = 244 [M+H]+.

[0297] Step 4: The Int-49 (30 mg, 0.12 mmol, 1.0 eq.) was dissolved with anhydrous THF (5 mL), then to the resulting mixture was added NaH (7.4 mg, 0.19 mmol, 1.5 eq.) under N2 atmosphere at 0 °C slowly. After stirred at 0 °C for 30 min, to the mixture was added 2, 6-dichloro-3 -nitropyridine (R-3, 28.6 mg, 0.15 mmol, 1.2 eq.). After stirred at r.t. for 2 hrs, the mixture was quenched with saturated aqueous solution of NH4CI (50 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 column chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-50 (21 mg, 0.05 mmol, 43%) as a yellow solid. LCMS (ESI): m / z = 400 [M+H]+.

[0298] Step 5: A mixture of Int-50 (21 mg, 0.05 mmol, 1.0 eq.), (5-cyanopyridin-3-yl)boronic acid (R-4, 9.3 mg, 0.06 mmol, 1.2 eq.), Pd(PPh3)4(6.1 mg, 0.005 mmol, 0.1 eq.) and K2CO3 (21.8 mg, 0.16 mmol, 3.0 eq.) in dioxane (5 mL) and water (1 mL) was stirred under N2 atmosphere at 100 °C for 8 hrs. After completion, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash columnAttorney Docket No. 255944.001402chromatography on silica gel (eluted with PE: EtOAc = 1: 10) to afford Int-51 (18 mg, 0.04 mmol, 73%) as a yellow solid. LCMS (ESI): m / z = 468 [M+H]+.

[0299] Step 6: A mixture of Int-51 (18 mg, 0.04 mmol, 1.0 eq.), Fe powder (10.8 mg, 0.2 mmol, 5.0 eq.) and NH4CI (10.2 mg, 0.2 mmol, 5.0 eq.) in EtOH (30 mL) and H2O (5 mL) was stirred at 80 °C for 1.5 hrs. After completion, the mixture was filtered through a pad of Celite®, the filter cake was washed with MeOH (20 mL x 3). The combined filtrate was concentrated under reduced pressure, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford Int-52 (14 mg, crude) as a colorless oil, which was used for next step directly. LCMS (ESI): m / z = 438 [M+H]+.

[0300] Step 7: To a stirred solution of Int-52 (14 mg, crude) in DCM (3 mL) was added MsCl (0.05 mL) and TEA (0.1 mL) at 0 °C slowly. After stirred at r.t. for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure to afford Int-53 (19 mg, crude) as a pale brown oil, which was used for next step directly. LCMS (ESI): m / z = 593 [M+H]+.

[0301] Step 8: The Int-53 (19 mg, crude) was dissolved in THF (2 mL) and to the mixture was added aqueous solution of NaOH (4 M, 0.5 mL). After stirred at r.t. for 30 min, the mixture was neutralized by HC1 (I M) 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 pre-HPLC(column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O (with 0.1% TFA)) to afford Compound 1-3 (4.4 mg, 0.008 mmol) as a white solid.

[0302] Compound 1-3: Retention time: 1.40 min; LCMS (ESI): m / z = 516.2 [M+H]+;1H NMR (400 MHz, DMSO-rf«) 5 (ppm) 10.09 (s, 1H), 8.95 (d, J= 1.6 Hz, 1H), 8.94 (d, J= 2.0 Hz, 1H), 8.55 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.64 (s, 1H), 6.98 (t, J= 55.2 Hz, 1H), 4.44-4.40 (m, 2H), 3.36-3.32 (m, 1H), 3.26 (s, 3H), 3.18-3.14 (m, 2H), 2.16 (s, 3H), 1.94 - 1.77 (m, 2H), 1.70-1.22 (m, 2H);19F NMR (376 MHz, DMSO-6) 5 (ppm) -114.20 (s).

[0303] The following compounds were synthesized from the appropriate reagents using Method F: Compounds 1-1, 1-4, 1-85.Attorney Docket No. 255944.001402Example 7: Method G: Synthesis of Compound 1-68

[0304] Step 1 and Step 2: Starting with Int-24, can use similar conditions as used in Steps 6-7 from Method A to provide Compound 1-68 as a white solid.

[0305] Compound 1-68: Retention time: 1.306 min; LCMS (ESI): m / z = 527.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.01 (s, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 3.5 Hz, 1H), 8.43 (t, J = 2.1 Hz, 1H), 8.28 - 8.21 (m, 1H), 8.13 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.53 - 7.39 (m, 1H), 3.19 (s, 3H), 2.33 (s, 3H).

[0306] The following compounds were synthesized from the appropriate reagents using Method G: Compounds 1-63, 1-64, and 1-65.Example 8: Method H: Synthesis of Compound 1-34Attorney Docket No. 255944.001402

[0307] Step 1: To a stirred solution of methyl 3 -methylpicolinate (R-13, 8.0 g, 0.053 mol, 1.0 eq.) in TCM (trichloro methane, 40 mL) was added NBS (11.3 g, 0.06 mol, 1.2 eq.) and AIBN (0.82 g, 0.005 mol, 0.1 eq.) slowly. After stirred at 60°C for 16 hrs, the reaction was diluted with H2O (150 mL) and extracted with EtOAc (70 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified byAttorney Docket No. 255944.001402flash column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-55 (4.3 g, 18.6 mmol, 35.5%) as a white solid. LCMS (ESI): m / z = 230 [M+H]+.

[0308] Step 2: A mixture of Int-55 (4.3 g, 18.6 mmol, 1.0 eq.), methyl {[(4-methylphenyl)dioxo-X6-sulfanyl]amino}acetate (R-14, 4.5 g, 18.6 mmol, 1.0 eq.), K2CO3 (3.87 g, 27.9 mmol, 1.5 eq.) and Nal (4.17 g, 27.9 mmol, 1.5 eq.) in DMF (60 mL) was stirred at 25 °C for 5 hrs. After completion, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-56 (4.7 g, 11.9 mmol, 58.7%) as a white solid. LCMS (ESI): m / z = 393 [M+H]+.

[0309] Step 3: To a stirred solution of Int-56 (4.7 g, 11.9 mmol, 1.0 eq.) in MeOH (90 mL) was added sodium methoxide (1.61 g, 29.9 mmol, 2.5 eq.) at 0 °C and stirred for 30 min. After completion, the mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated to afford Int-57 (2.3 g, 11.2 mmol, 95.6%) as a white solid. LCMS (ESI): m / z = 205 [M+H]+.

[0310] Step 4: A mixture of Int-57 (2.3 g, 11.2 mmol, 1.0 eq.), NBS (2.4 g, 13.5 mmol, 1.2 eq.) in DCM (50 mL) was stirred at 25 °C for 2 hrs. After completion, the mixture was poured into water (80 mL) and extracted with DCM (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with DCM: MeOH = 10: 1) to afford Int-58 (1.8 g, 6.3 mmol, 56.7%) as a white solid. LCMS (ESI): m / z = 283 [M+H]+.

[0311] Step 5: To a stirred solution of Int-58 (1.8 g, 6.3 mmol, 1.0 eq.), 2-iodopropane (2.2 g, 12.7 mmol, 2.0 eq.) and K2CO3 (3.5 g, 25.4 mmol, 4.0 eq.) in DMSO (40 mL) was stirred at 50 °C for 16 hrs. After completion, the mixture was poured into water (90 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 2: 1) to afford Int-59 (1.3 g, 4.0 mmol, 63.1%) as a brown solid.LCMS (ESI): m / z = 325 [M+H]+.

[0312] Step 6: To a stirred solution of Int-59 (1.3 g, 4.0 mmol, 1.0 eq.), cyclopropylboranediol (515.6 mg, 6.0 mmol, 1.5 eq.), cataCXium A Pd G3 (291.2 mg, 0.4 mmol, 0.1 eq.) and Cs2CO3 (3.9 g, 11.9 mmol, 3.0 eq.) in dioxane (20 mL) and water (4 mL) was stirredAttorney Docket No. 255944.001402at 120°C under N2 atmosphere for 4 hrs. After completion, the mixture was poured into water (130 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 2: 1) to afford Int-60 (823.6 mg, 2.87 mmol, 72.1%) as a white solid. LCMS (ESI): m / z = 287 [M+H]+.

[0313] Step 7: A mixture of Int-60 (823.6 mg, 2.9 mmol, 1.0 eq.) in MeOH (30 mL) was added aqueous NaOH (1.1 g, 28.7 mmol, 10.0 eq.) and stirred at 60 °C under N2 atmosphere for 16 hrs. After completion, the mixture was poured into ice water (50 mL) and added HC1 (2N) to PH=6. Then the solution was extracted with EtOAc (40 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to give Int-61 (672.3 mg, 2.5 mmol, 85.5%) as a brown oil. LCMS (ESI): m / z = 273 [M+H]+.

[0314] Step 8: To a stirred solution of Int-61 (672.3 mg, 2.5 mmol, 1.0 eq.), Cu (234.5 mg, 3.7 mmol, 1.5 eq.) in quinoline (5 mL) was stirred in Microwave at 155 °C for 2 hrs. After completion, the mixture was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-62 (336.2 mg, 1.46 mmol, 59.7%) as a yellow oil. LCMS (ESI): m / z = 229 [M+H]+.

[0315] Step 9: A mixture of Int-62 (336.2 mg, 1.5 mmol, 1.0 eq.), NBS (259.6 mg, 2.2 mmol, 1.5 eq.) in ACN (20 mL) was stirred at 60 °C for 2 hrs. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-63 (275.4 mg, 0.9 mmol, 61.1%) as a white oil. LCMS (ESI): m / z = 307 [M+H]+.

[0316] Step 10: To a stirred solution of Int-63 (275.4 mg, 0.9 mmol, 1.0 eq.), methylboranediol (14, 80.5 mg, 1.34 mmol, 1.5 eq.), Pd(PPh3)4(102.7 mg, 0.1 mmol, 0.1 eq.) and K2CO3 (370.0 mg, 2.7 mmol, 3.0 eq.) in dioxane (10 mL) and water (3 mL) was stirred at 100°C under N2 atmosphere for 16 hrs. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-64 (126.0 mg, 0.5 mmol, 58.1%) as a white solid. LCMS (ESI): m / z = 243 [M+H]+.Attorney Docket No. 255944.001402

[0317] Step 11: A mixture of Int-64 (126.0 mg, 0.5 mmol, 1.0 eq.) in DCM (15 mL) was added tribromoborane (0.2 mL, 2.1 mmol, 4.0 eq.) at -78 °C slowly. After addition, the mixture was warmed to r.t., then stirred at 25°C for 1 hrs. After completion, the mixture was concentrated to afford Int-65 (65.3 mg, 0.3 mmol, crude, 62.7%) as a white solid. LCMS (ESI): m / z = 201 [M+H]+.

[0318] Step 12: To a stirred solution of 2,6-dichloro-3-nitropyridine (R-3, 61.4 mg, 0.3 mmol, 1.0 eq.) in THF (5 mL) was added NaH (36 mg, 0.9 mmol, 60% in mineral oil, 3.0 eq.) at 0 °C under N2 atmosphere slowly. After stirred at 0 °C for 30 min, to the mixture was added Int-65 (65.3 mg, 0.3 mmol, crude, 1.0 eq.). The resulting mixture was stirred at r.t. for another 2 hrs. After completion, the reaction was quenched by H2O (30 mL) and extracted with EtOAc (20 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 through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-66 (32.6 mg, 0.09 mmol, 28.3%) as a yellow oil. LCMS (ESI): m / z = 357 [M+H]+.

[0319] Step 13 through 16: From Int-66, analogous conditions as used in Steps 4-7 from Method A to provide Compound 1-34 as a white solid.

[0320] Compound 1-34: Retention time: 1.437 min; LCMS (ESI): m / z = 473 [M+H]+; 1H NMR (400 MHz, CDCl3) 3 9.01 (d, J= 1.9 Hz, 1H), 8.85 (d, J = 4.1 Hz, 1H), 8.74 (s, 1H), 8.72 (d, J= 8.8 Hz, 1H), 8.37 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 8.05 (s, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.43-7.40 (m, 1H), 3.26 (s, 3H), 2.72 (s, 3H), 2.70 - 2.64 (m, 1H), 1.38 - 1.33 (m, 2H), 1.12-1.08 (m, 2H).Example 9: Method I: Synthesis of Compound 1-30TBSCI, Imidazole, DCMR-15 lnt-70 lnt-71Attorney Docket No. 255944.001402Compound 1-30

[0321] Step 1: A mixture of quinoxalin-5-ol (R-15, 3.0 g, 20.5 mmol, 1.0 eq.), TBSC1 (3.7 g, 24.6 mmol, 1.2 eq.), imidazole (2.8 g, 41.0 mmol, 2.0 eq.) in DCM (50 mL) was stirred at r.t. under N2 atmosphere for 16 hrs. After completion, the mixture was diluted with H2O (300 mL) and extracted with DCM (100 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 4: 1) to afford Int-70 (3.9 g, 15.0 mmol, 73.2%) as a white solid. LCMS (ESI): m / z = 261 [M+H]+.

[0322] Step 2: To a stirred solution of Int-70 (3.0 g, 11.5 mmol, 1.0 eq.) in ACN (50 mL) was added NBS (2.3g, 12.7 mmol, 1.1 eq.). After stirred at r.t. for 1 hrs, the mixture was diluted withAttorney Docket No. 255944.001402H2O (130 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-71 (1.6 g, 4.7 mmol, 41.2 %) as a yellow solid. LCMS (ESI): m / z = 339 [M+H]+.

[0323] Step 3: A mixture of Int-71 (1.5 g, 4.4 mmol, 1.0 eq.), cyclopropylboronic acid (1.1 g, 13.2 mmol, 3.0 eq.), cataCXium A Pd G3 (640 mg, 0.88 mmol, 0.2 eq.) and K2CO3 (1.82 g, 13.2 mmol, 3.0 eq.) in dioxane (150 mL) and H2O (30 mL) was stirred at 110 °C under N2 atmosphere for 16 hrs. After completion, the mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-72 (710 mg, 2.4 mmol, 53.8%) as a yellow oil.LCMS (ESI): m / z = 301 [M+H]+.

[0324] Step 4: To a solution of Int-72 (700 mg, 2.3 mmol, 1.0 eq.) in THF (40 mL) was added TBAF (720 mg, 2.8 mmol, 1.2 eq.) and kept stirred at r.t. under N2 atmosphere for 24 hrs. After completion, the mixture was diluted with H2O (150 mL) and extracted with EtOAc (60 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-73 (350 mg, 1.9 mmol, 81.8%) as a white solid. LCMS (ESI): m / z = 187 [M+H]+.

[0325] Step 5 through Step 9: From Int-73, analogous conditions as used in Steps 3-7 from Method A to provide Compound 1-30 as a white solid.

[0326] Compound 1-30: Retention time: 1.357 min; LCMS (ESI): m / z = 459.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ10.03 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.87 (d, J= 1.8 Hz, 1H), 8.85 (d, J= 1.6 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.35 (t, J= 2.0 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 3.27 (s, 3H), 3.16 - 3.09 (m, 1H), 1.21 - 1.13 (m, 2H), 0.98-0.90 (m, 2H).

[0327] The following compounds were synthesized from the appropriate reagents using Method I: Compound 1-66.Attorney Docket No. 255944.001402Example 10: Method J: Synthesis of Compound 1-23Compound 1-23

[0328] Step 1: To a stirred solution of 1, 5-naphthyridin-3-amine (R-16, 1.0 g, 6.9 mmol, 1.0 eq.) in DMF (30 mL) was added NIS (1.7 g, 7.6 mmol, 1.1 eq.). After stirred at r.t. for 2 hrs, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with H2O (50 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 3) to afford Int-78 (1.2 g, 4.4 mmol, 64.2%) as a yellow solid.LCMS (ESI): m / z = 272 [M+H]+.

[0329] Step 2: A mixture of Int-78 (1.2 g, 4.4 mmol, 1.0 eq.), cyclopropylboronic acid (568 mg, 6.6 mmol, 1.5 eq.), cataCXium A Pd G3 (320 mg, 0.44 mmol, 0.1 eq.) and K2CO3 (1.8 g, 13.2 mmol, 3.0 eq.) in dioxane (50 mL) and H2O (10 mL) was stirred at 100 °C under N2 atmosphere for 5 hrs. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAcAttorney Docket No. 255944.001402(50 mL x 3), the combined organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 4) to afford Int-79 (430 mg, 2.3 mmol, 52.7%) as a white solid.LCMS (ESI): m / z= 186 [M+H]+.

[0330] Step 3 through 8: From Int-79, analogous conditions as used in Steps 2-7 from Method A to provide Compound 1-23 as a white solid.

[0331] Compound 1-23: Retention time: 1.131 min; LC-MS (ESI) m / z = 459.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.11 - 8.87 (m, 4H), 8.82 (s, 1H), 8.61 - 8.53 (m, 1H), 8.45 (dd, J = 8.4, 1.7 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.5, 4.1 Hz, 1H), 3.26 (s, 1H), 2.83 (tt, J = 8.8, 5.5 Hz, 1H), 1.70 (dd, J = 5.9, 3.3 Hz, 1H), 1.05 (dt, J = 6.2, 3.4 Hz, 1H).Example 11: Method K: Synthesis of Compound 1-19Attorney Docket No. 255944.001402

[0332] Step 1: A mixture of 6-bromo-4-methylpyridin-3-amine (R-5, 3.0 g, 16.1 mmol, 1.0 eq.), 3-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine (R-2, 5.0 g, 24.2 mmol, 1.5 eq.), Pd(PPh3)4(930 mg, 0.8 mmol, 0.05 eq.) and K2CO3 (6.7 g, 48.3 mmol, 3.0 eq.) in dioxane (80 mL) and H2O (16 mL) was stirred at 100 °C under N2 atmosphere for 6 hrs. After completion, the mixture was diluted with H2O (120 mL) and extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 2: 1) to afford Int-85 (920 mg, 5.0 mmol, 30.9%) as a white solid. LCMS (ESI): m / z = 186 [M+H]+.

[0333] Step 2: To a stirred solution of Int-85 (900 mg, 4.9 mmol, 1.0 eq.) in MeCN (40 mL) was added NBS (952 mg, 5.4 mmol, 1.1 eq.). After stirred at r.t. for 2 hrs, the mixture was diluted with H2O (70 mL) and extracted with EtOAc (50 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 through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-86 (220 mg, 0.84 mmol, 17.1%) as a white solid. LCMS (ESI): m / z = 264 [M+H]+.Attomey Docket No. 255944.001402

[0334] Step 3: A mixture of Int-86 (220 mg, 0.84 mmol, 1.0 eq.), cyclopropylboronic acid (146 mg, 1.7 mmol, 2.0 eq.), cataCXium A Pd G3 (61 mg, 0.08 mmol, 0.1 eq.) and K2CO3 (348 mg, 2.5 mmol, 3.0 eq.) in dioxane (20 mL) and H2O (4 mL) was stirred at 100 °C under N2 atmosphere for 16 hrs. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-87 (163 mg, 0.72 mmol, 86.2%) as a yellow solid. LCMS (ESI): m / z = 226 [M+H]+.

[0335] Step 4: To a stirred solution of Int-87 (133 mg, 0.59 mmol, 1.0 eq.) in water (5 mL) was added concentrated H2SO4 (1 mL) and aqueous solution of NaNO2(61.2 mg, 0.89 mmol, 1.5 eq.) at 0 °C slowly. After stirred at r.t. overnight, the mixture was poured into ice water (15 mL) and the reaction mixture was adjusted to pH = 7-8 with saturated NaHCO3. After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-88 (45 mg, 0.20 mmol, 34%) as a white solid. LCMS (ESI): m / z = 227 [M+H]+.

[0336] Steps 5 through 7: From Int-88, analogous conditions as used in Steps 3-5 from Method A to provide Int-91 as a white solid, which was used directly in the next step. LCMS (ESI): m / z = 421 [M+H]+.

[0337] Steps 8 and 9: To a stirred Int-91 (34 mg, crude, about 0.08 mmol, 1.0 eq.) in concentrated HC1 (3 mL) and glacial acetic acid (1 mL) was added aqueous solution of NaNO2(2.0 M, 0.08 mL, 2.0 eq.) at 0 °C slowly (Kept T < 5°C). After stirred for 30 min, to the mixture was added CuCl₂ (27 mg, 0.2 mmol, 1.0 eq.), then SO2 was bubbled through the mixture at 0 °C for 15 min. After completion, the mixture was poured into ice water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed by saturated aq. NaHCOs (20 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide Int-92. The crude Int-92 dissolved with DCM (5 mL), then to the resulting mixture was added cyclopropylamine hydrochloride (37.2 mg, 0.4 mmol, 5.0 eq.) and TEA (0.5 mL) at 0 °C. After stirring at r.t. for 30 min, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 20-Attorney Docket No. 255944.00140285% MeCN in H2O (with 0.1% FA)) to afford Compound 1-19 (5.5 mg, 10.5 pmol, 13.1%) as a white solid.

[0338] Compound 1-19: Retention time: 1.412 min; LCMS (ESI): m / z = 525.3 [M+H]+;1H NMR (400 MHz, DMSO-6) 5 (ppm) 9.37 (s, 1H), 9.07 (d, J= 1.9 Hz, 1H), 9.04 (d, J= 1.8 Hz, 1H), 8.79 - 8.66 (m, 3H), 8.59 (d, J= 2.3 Hz, 1H), 8.49 (d, J= 7.9 Hz, 1H), 8.12 (d, J= 8.0 Hz, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 2.43-2.38 (m, 1H), 2.25 (s, 3H), 2.18-2.12 (m, 1H), 1.29 - 1.15 (m, 1H), 0.94-0.91 (m, 2H), 0.82-0.75 (m, 1H), 0.62 - 0.49 (m, 3H), 0.47 - 0.35 (m, 1H).

[0339] The following compounds were synthesized from the appropriate reagents using Method K: Compound 1-11, 1-12, 1-13, 1-14, 1-15, 1-16 and 1-21.Example 12: Compound Characterization

[0340] The compounds of the invention were characterized with LCMS. The methods used are outlined below in Table 2.Table 2: LCMS Analytical Characterization Methods UsedCompound No. LCMS Method1-1 A1-2 A1-3 A1-4 B1-5 B1-6 A1-7 A1-8 P1-9 B1-10 A1-11 A1-12 A1-13 A1-14 A1-15 A1-16 B1-17 A1-18 A1-19 A1-20 B1-21 AAttorney Docket No. 255944.001402Compound No. LCMS Method1-22 A1-23 B1-24 C1-25 A1-26 A1-27 A1-28 B1-29 A1-30 A1-31 B1-32 A1-33 B1-34 A1-35 A1-36 A1-37 A1-38 A1-39 B1-40 B1-41 A1-42 N1-43 C1-44 B1-45 B1-46 A1-47 C1-48 C1-49 o1-50 o1-51 A1-52 A1-53 A1-54 O1-55 O1-56 o1-57 o1-58 A1-59 A1-60 A1-61 B1-62 B1-63 B1-64 B1-65 AAttorney Docket No. 255944.001402Compound No. LCMS Method1-66 A1-67 B1-68 A1-69 B1-70 N1-71 N1-72 A1-73 A1-74 A1-75 A1-76 A1-77 A1-78 O1-79 A1-80 A1-81 A1-82 A1-83 A1-84 A1-85 A1-86 A1-87 B1-88 BExample 13: ABCC6 WT Assay

[0341] To assess activity against ABCC6, compounds were screened in an assay measuring protein expression, using cells transfected with cDNA encoding HiBit-tagged ABCC6 wild-type.

[0342] Described here is an assay for measuring the expression of the wild type of human ABCC6 (henceforth referred to as ABCC6 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCC6 WT. The assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCC6 WT by calculating an Emaxand ECso value. HEK-293 cells transiently expressing ABCC6 WT (HEK-293 / ACC6 WT) were used for this assay and were cultured at 37°C (5% CO2, humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product #11965-092) supplemented with 10% fetal bovine serum. For the assay, HEK-293 cells were transfected with 0.24 mg / 10 cm plate of cDNA encoding HiBit- tagged ABCC6 wild-type using Lipofectamine 2000 (Thermo Fisher, product # 11668019). Twenty-four hours after transfection, the HEK-293 / ACC6 WT cells were seeded in white / opaqueAttorney Docket No. 255944.001402384-well plates (PerkinElmer, cat. No. 6007688) at 10,000 cells / well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO2, humidified). Compound serial dilutions are prepared in growth medium as ten times (lOx) the final concentration and using a dilution factor of 2. After the four-hour incubation period, 2.2 pL of the lOx dilutions are transferred to the assay plate.

[0343] Dose response curves include ten doses with the top final concentration at 20 pM in 0.15% DMSO. Liquid handling is performed with an Integra mini96-tip head (INTEGRA). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO2, humidified). After the 24-hour treatment, plates are allowed to equilibrate for 15 minutes at room temperature. Using Integra mini-96, 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 10 minutes and luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).

[0344] Results are presented below in Table 3 for ABCC6 WT. Compounds having an activity designated as " A" provided an EC50 less <1 pM, Emax (fold) >1.2; compounds having an activity designated as " B" provided an EC50 >1 pM and <10 pM, Emax (fold) >1.2; compounds having an activity designated as " C" provided an ECso>lO pM and <25 pM, Emax (fold) >1.2; compounds having an activity designated as " D" provided an EC50 >25 pM, Emax (fold) <1.2; compounds having an activity designated as " E" provided an EC50 >25 pM, Emax (fold) >1.2; and compounds having an activity designated as " F" provided an EC50 less than 25 pM, Emax (fold) <1.2.Table 3: Efficacy and Potency of Compounds In Increasing the Expression of ABCC6 WT Compound No. ABCC6 WT EC50, Emax1-1 A1-2 A1-3 A1-4 A1-5 B1-6 A1-7 B1-8 A1-9 A1-10 B1-11 B1-12 B1-13 EAttorney Docket No. 255944.001402Compound No. ABCC6 WT EC5O, Emax1-14 B1-15 A1-16 B1-17 E1-18 E1-19 B1-20 A1-21 B1-22 D1-23 A1-24 B1-25 B1-26 A1-27 E1-28 A1-29 E1-30 A1-31 B1-32 B1-33 A1-34 A1-35 B1-36 C1-37 B1-38 A1-39 B1-40 E1-41 B1-42 B1-43 D1-44 C1-45 B1-46 B1-47 E1-48 D1-49 B1-50 B1-51 E1-52 B1-53 C1-54 B1-55 B1-56 A1-57 AAttorney Docket No. 255944.001402Compound No. ABCC6 WT EC50, Emax1-58 A1-59 A1-60 A1-61 A1-62 A1-63 A1-64 A1-65 A1-66 A1-67 A1-68 A1-69 A1-70 A1-71 A1-72 A1-73 A1-74 A1-75 B1-76 B1-77 A1-78 A1-79 A1-80 A1-81 B1-82 A1-83 A1-84 A1-85 A1-86 A1-87 A1-88 A1-131 A1-136 A1-134 A1-135 A1-132 A1-140 A1-125 A1-102 A1-107 A1-141 A1-149 A1-157 A1-126 AAttorney Docket No. 255944.001402Compound No. ABCC6 WT EC50, Emax1-129 A1-98 A1-119 B1-89 A1-90 A1-92 A1-158 A1-147 E1-148 A1-159 A1-146 A1-160 A1-128 A1-97 A1-161 A1-162 A1-142 A1-163 A1-150 A1-99 B1-106 A1-109 A1-116 A1-120 B1-164 A1-165 A1-105 A1-118 A1-153 A1-166 E1-167 D1-168 A1-169 A1-170 D1-171 A1-172 A1-173 D1-174 A1-155 E1-175 AAttorney Docket No. 255944.001402Example 14: ABCB4 WT Assay

[0345] To assess activity against ABCB4, compounds were screened in an assay measuring protein expression, using cells transfected with cDNA encoding HiBit-tagged ABCB4 wild-type.

[0346] Described here is an assay for measuring the expression of the wild type of human ABCB4 (henceforth referred to as ABCB4 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCB4 WT. The assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCB4 WT by calculating an Emaxand EC50 value. HEK-293 cells stably expressing ABCB4 WT (HEK-293 / ABCB4 WT) were used for this assay and were maintained at 37°C (5% CO2, humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product # 12100) supplemented with 10% fetal bovine serum (Biosera product # FB-1058 / 500), 1% PenStrep (HDB product # 15140-122), and 0.5 mg / mL puromycin (Gibco product # A11138-03). For the assay, the HEK-293 / ABCB4 WT cells were seeded in white / opaque 384-well plates (Corning product # 3570) at 10,000 cells / well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO2, humidified). Compound serial dilutions are prepared in DMSO as three hundred times (333x) the final concentration and using a dilution factor of 3 using Bravo (Agilent). After the four-hour incubation period, 60 nL of DMSO solutions are transferred to the assay plate.

[0347] Dose response curves include eleven doses with the top final concentration at 30 pM in 0.3% DMSO. Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO2, humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).

[0348] Results are presented below in Table 4 for ABCB4 WT. Compounds having an activity designated as " A" provided an EC5O<1 pM, Emax (fold) >1.2; compounds having an activity designated as " B" provided an EC50 >1 and <10 pM, Emax (fold) >1.2; compounds having an activity designated as " C" provided an EC50 >10 and <25 pM, Emax(fold) >1.2; compounds havingAttorney Docket No. 255944.001402an activity designated as " D" provided an EC50 >25 pM, Emax (fold) <1.2; compounds having an activity designated as " E" provided an EC50 >25 pM, Emax(fold) >1.2; and compounds having an activity designated as " F" provided an EC50 <25 pM, Emax (fold) <1.2.Table 4: Efficacy and Potency of Compounds In Increasing the Expression of ABCB4 WT ABCB4 WTCompound No.EC50, Emax1-1 D1-2 A1-3 A1-4 F1-5 D1-6 A1-7 E1-8 A1-9 E1-10 F1-11 B1-12 B1-13 F1-14 F1-15 A1-16 F1-17 E1-18 B1-19 B1-20 B1-21 B1-22 F1-23 A1-24 B1-25 B1-26 E1-27 E1-28 A1-29 E1-30 B1-31 B1-32 B1-33 A1-34 A1-35 C1-36 EAttorney Docket No. 255944.001402ABCB4 WTCompound No.EC50, Emax1-37 E1-38 A1-39 B1-40 E1-41 F1-42 C1-43 F1-44 C1-45 B1-46 B1-47 E1-48 D1-49 A1-50 B1-51 D1-52 B1-53 B1-54 B1-55 B1-56 E1-57 A1-58 A1-59 A1-60 A1-61 A1-62 A1-63 A1-64 C1-65 C1-66 A1-67 E1-68 A1-69 F1-70 E1-71 F1-72 A1-73 A1-74 A1-75 F1-76 F1-77 A1-78 F1-79 EAttorney Docket No. 255944.001402ABCB4 WTCompound No.EC50, Emax1-80 B1-81 E1-82 B1-83 E1-84 E1-85 A1-86 A1-87 A1-88 B1-131 D1-136 D1-134 D1-135 F1-132 D1-140 D1-125 F1-102 D1-107 F1-141 A1-149 E1-157 E1-126 A1-129 A1-98 C1-119 F1-89 A1-90 A1-92 A1-158 A1-147 F1-148 F1-159 D1-146 A1-160 A1-128 D1-97 A1-161 A1-162 D1-142 A1-163 F1-150 D1-99 D1-106 AAttorney Docket No. 255944.001402ABCB4 WTCompound No.EC50, Emax1-109 A1-116 F1-120 B1-164 A1-165 F1-105 A1-118 F1-153 A1-166 F1-167 D1-168 F1-169 F1-170 D1-171 F1-172 F1-173 D1-174 A1-155 F1-175 AExample 15: ABCA4 P1380L Assay

[0349] Exemplary compounds were evaluated in an ABCA4 P1380L correction dose-response assay. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0350] To assess activity against ABCA4 P1380L, the compounds were screened in an assay measuring protein expression, using cells transfected with cDNA encoding HiBit-tagged ABCA4 P1380L. Here we describe an assay for measuring the expression of the P1380L variant of human ABCA4 (henceforth referred to as ABCA4 P1380L) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCA4 P1380L. The assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCA4 P1380L by calculating an Emax and EC50 value. HEK-293 cells stably expressing ABCA4 P1380L (HEK-293 / ABCA4 P1380L) were used for this assay and were maintained at 37°C (5% CO2, humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product # 12100) supplemented with 10% fetal bovine serum (Biosera product # FB-1058 / 500), 1% PenStrep (HDB product # 15140-122), and 0.5 mg / mL puromycin (Gibco product # A11138-03). For the assay, the HEK-293 / ABCA4Attorney Docket No. 255944.001402P1380L cells were seeded in white / opaque 384-well plates (Corning product # 3570) at 10,000 cells / well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO2, humidified). Compound serial dilutions are prepared in DMSO as three hundred times (333x) the final concentration and using a dilution factor of 3 using Bravo (Agilent). After the four-hour incubation period, 60 nL of DMSO solutions are transferred to the assay plate.

[0351] Dose response curves include eleven doses with the top final concentration at 30 pM in 0.3% DMSO. Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO2, humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).Part II - Results

[0352] Results are shown in Table 5 below. Compounds having an activity designated as " A" provided an ECso<l pM, Emax(fold) >1.2; compounds having an activity designated as " B" provided an EC50 >1 and <10 pM, Emax (fold) >1.2; compounds having an activity designated as " C" provided an ECso>lO and <25 pM, Emax(fold) >1.2; compounds having an activity designated as " D" provided an EC 50 >25 pM, Emax (fold) <1.2; compounds having an activity designated as " E" provided an EC50 >25 pM, Emax (fold) >1.2; and compounds having an activity designated as " F" provided an EC50 <25 pM, Emax(fold) <1.2.Table 5: Efficacy and Potency of Compounds In Increasing the Expression of ABCB4 WT ABCA4Compound No. P1380L EC50,Emax1-1 A1-2 A1-3 F1-4 A1-5 DAttorney Docket No. 255944.001402ABCA4Compound No. P1380L EC50,Emax1-6 A1-7 E1-8 A1-9 E1-10 B1-11 B1-12 B1-13 D1-14 F1-15 B1-16 D1-17 E1-18 C1-19 B1-20 A1-21 B1-22 D1-23 A1-24 B1-25 B1-26 A1-27 E1-28 A1-29 E1-30 A1-31 A1-32 A1-33 A1-34 A1-35 B1-36 B1-37 B1-38 A1-39 B1-40 E1-41 D1-42 B1-43 D1-44 B1-45 D1-46 B1-47 EAttorney Docket No. 255944.001402ABCA4Compound No. P1380L EC50,Emax1-48 D1-49 D1-50 B1-51 D1-52 F1-53 D1-54 E1-55 E1-56 A1-57 F1-58 F1-59 A1-60 A1-61 A1-62 F1-63 B1-64 A1-65 A1-66 D1-67 B1-68 A1-69 A1-70 F1-71 A1-72 A1-73 A1-74 B1-75 B1-76 A1-77 A1-78 A1-79 A1-80 E1-81 E1-82 A1-83 C1-84 A1-85 A1-86 A1-87 A1-88 F1-131 AAttorney Docket No. 255944.001402ABCA4Compound No. P1380L EC50,Emax1-136 A1-134 A1-135 F1-132 F1-140 F1-125 A1-102 E1-107 A1-141 A1-149 F1-157 A1-126 E1-129 A1-98 D1-119 D1-89 E1-90 E1-92 A1-158 A1-147 F1-148 F1-159 A1-146 A1-160 A1-128 B1-97 A1-161 A1-162 A1-142 A1-163 A1-150 D1-99 D1-106 A1-109 E1-116 F1-120 B1-164 A1-165 A1-105 A1-118 F1-153 A1-166 DAttorney Docket No. 255944.001402ABCA4Compound No. P1380L EC50,Emax1-167 D1-168 C1-169 F1-170 D1-171 A1-172 F1-173 D1-174 B1-155 F1-175 AExample 16: ABCD2 WT Assay

[0353] Exemplary compounds were evaluated in a ABCD2 WT correction dose-response assay. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0354] To assess activity against ABCD2 WT, the compounds were screened in an assay measuring protein expression, using cells transfected with cDNA encoding HiBit-tagged ABCD2 wild-type. Here we describe an assay for measuring the expression of the wild type of human ABCD2 (henceforth referred to as ABCD2 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCD2 WT. The assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCD2 WT by calculating an Emax and ECso value. HEK-293 cells transiently expressing ABCD2 WT (HEK-293 / ABCD2 WT) were used for this assay and were maintained at 37°C (5% CO2, humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product # 12100) supplemented with 10% fetal bovine serum (Biosera product # FB-1058 / 500). For the assay, HEK-293 cells were transfected with 0.24 mg / 10 cm plate of cDNA encoding HiBit-tagged ABCD2 wild-type using Lipofectamine 3000 (Thermo Fisher, L3000-015). Twenty-four hours after transfection, the HEK-293 / ABCD2 WT cells were seeded in white / opaque 384-well plates (Corning product # 3570) at 10,000 cells / well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO2, humidified). Compound serial dilutions are prepared in DMSO as three hundred times (333x) the finalAttorney Docket No. 255944.001402concentration and using a dilution factor of 3 using Bravo (Agilent). After the four-hour incubation period, 60 nL of DMSO solutions are transferred to the assay plate.

[0355] Dose response curves include eleven doses with the top final concentration at 30 pM in 0.3% DMSO. Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO2, humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).Part II - Results

[0356] Results are shown in Table 6 below. Compounds having an activity designated as " A" provided an ECso<l pM, Emax(fold) >1.2; compounds having an activity designated as " B" provided an EC 50 >1 and <10 pM, Emax (fold) >1.2; compounds having an activity designated as " C" provided an ECso>lO and <25 pM, Emax (fold) >1.2; compounds having an activity designated as " D" provided an EC50 >25 pM, Emax (fold) <1.2; compounds having an activity designated as " E" provided an EC50 >25 pM, Mean Emax (fold) >1.2; and compounds having an activity designated as " F" provided an EC50 <25 pM, Emax (fold) ) <1.2.Table 6: Efficacy and Potency of Compounds In Increasing the Expression of ABCD2 WT ABCD2 WTCompound No.EC50, Emax1-1 A1-2 E1-3 A1-4 A1-5 E1-6 A1-7 C1-8 A1-9 EAttorney Docket No. 255944.001402ABCD2 WTCompound No.EC50, Emax1-10 B1-11 C1-12 B1-13 B1-14 B1-15 B1-16 B1-17 E1-18 E1-19 B1-20 B1-21 B1-22 D1-23 E1-24 B1-25 B1-26 E1-27 E1-28 A1-29 E1-30 E1-31 C1-32 B1-33 B1-34 A1-35 B1-36 E1-37 B1-38 B1-39 B1-40 E1-41 B1-42 B1-43 D1-44 B1-45 B1-46 B1-47 E1-48 D1-49 C1-50 E1-51 E1-52 BAttorney Docket No. 255944.001402ABCD2 WTCompound No.EC50, Emax1-53 E1-54 E1-55 C1-56 E1-57 A1-58 E1-59 A1-60 A1-61 A1-62 A1-63 A1-64 A1-65 A1-66 A1-67 A1-68 A1-69 B1-70 E1-71 A1-72 E1-73 E1-74 E1-75 B1-76 B1-77 A1-78 A1-79 E1-80 B1-81 E1-82 B1-83 E1-84 A1-85 A1-86 A1-87 A1-88 E1-131 A1-136 A1-134 A1-135 A1-132 E1-140 E1-125 EAttorney Docket No. 255944.001402ABCD2 WTCompound No.EC50, Emax1-102 A1-107 A1-141 A1-149 B1-157 E1-126 E1-129 A1-98 A1-119 B1-89 B1-90 A1-92 A1-158 A1-147 B1-148 C1-159 A1-146 A1-160 A1-128 B1-97 A1-161 E1-162 E1-142 E1-163 A1-150 F1-99 E1-106 A1-109 A1-116 B1-120 B1-164 A1-165 A1-105 E1-118 A1-153 E1-166 B1-167 D1-168 B1-169 A1-170 D1-171 A1-172 A1-173 DAttorney Docket No. 255944.001402ABCD2 WTCompound No.EC50, Emax1-174 A1-155 E1-175 AExample 17: Synthesis of Compound 1-171Attorney Docket No. 255944.001402DAST, DCM, Pd / C. Ha. was. 0*Cto RT MeOH ACNR-26Int-186

[0357] Step 1: To a stirred solution of 5-nitropicolinaldehyde (R-26, 3.0 g, 19.7 mmol, 1.0 eq.) in DCM (50 mL) was added DAST (6.3 g, 39.5 mmol, 2.0 eq.) at 0 °C slowly. After addition, the mixture was added to r.t., then kept stirring at r.t. for 1 hrs, the mixture was diluted with H2O (120 mL) and extracted with DCM (60 mL x 3). The organic phase was washed with brine, driedAttorney Docket No. 255944.001402over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 5: 1) to afford Int-179 (2.4 g, 13.8 mmol, 70.1%) as a yellow oil. LCMS (ESI): m / z = 175.1 [M+H]+.

[0358] Step 2: To a stirred solution of Int-179 (2.4 g, 13.8 mmol) in MeOH (100 mL) was added Pd / C (wet, 240 mg, 10 wt%). The resulting mixture was stirred under H2 atmosphere (in balloon) at r.t. for 16 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (50 mL x 3). The combined filtrates were concentrated under reduced pressure to give Int-180 (1.9 g, 13.2 mmol, 95.6%) as a brown oil. LCMS (ESI): m / z = 145.2[M+H]+.

[0359] Step 3: To a stirred solution of Int-180 (1.9 g, 13.2 mmol,, 1.0 eq.) in ACN (50 mL) was added NBS (2.6 g, 14.5 mmol, 1.1 eq.). After stirred at r.t. for 4 hrs, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 3: 1) to afford Int-181 (1.4 g, 6.3 mmol, 47.7%) as a white solid. LCMS (ESI): m / z = 223.1 [M+H]+.

[0360] Step 4: A mixture of Int-181 (128 mg, 1.0 mmol, 1.0 eq.), pyridin-3-ylboronic acid (R-7, 147.6 mg, 1.2 mmol, 1.2 eq.), Pd(PPh3)4(115.4 mg, 0.1 mmol, 0.1 eq.) and K2CO3 (414.0 mg, 3.0 mmol, 3.0 eq.) in dioxane (30 mL) and H2O (6 mL) was stirred at 100 °C under N2 atmosphere for 1 hrs. After completion, the mixture was diluted with H2O (80 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 1) to afford Int-182 (110 mg, 0.5 mmol, 49.8%) as a colorless solid. LCMS (ESI): m / z = 222.2 [M+H]+.

[0361] Step 5: To a stirred solution of Int-182 (110 mg, 0.5 mmol, 1.0 eq.) in ACN (15 mL) was added NBS (97.9 mg, 0.6 mmol, 1.1 eq.) at r.t. After stirred at r.t. for 4 hrs, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (30 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 2: 3) to afford Int-183 (80 mg, 0.3 mmol, 53.5%) as a white solid. LCMS (ESI): m / z = 300.1 [M+H]+.

[0362] Step 6: A mixture of Int-183 (80 mg, 0.3 mmol, 1.0 eq.), cyclopropylboronic acid (51.6 mg, 0.6 mmol, 2.0 eq.), Pd(PPh3)4(34.4 mg, 0.03 mmol, 0.1 eq.) and K2CO3 (442.1 mg, 3.2Attorney Docket No. 255944.001402mmol, 3.0 eq.) in dioxane (20 mL) and H2O (4 mL) was stirred at 100 °C under N2 atmosphere for 16 hrs. After completion, the mixture was diluted with H2O (40 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 column chromatography through silica gel (eluted with PE: EtOAc = 2: 3) to afford Int-184 (42 mg, 0.16 mmol, 53.6%) as a brown oil.LCMS (ESI): m / z = 262.2 [M+H]+.

[0363] Step 7: To a stirred solution of Int-184 (42 mg, 0.16 mmol, 1.0 eq.) in water (5 mL) was added concentrated H2SO4 (1 mL) and aqueous solution of NaNO2(20.7 mg in 0.5 mL H2O, 0.3 mmol, 2 eq.) at 0 °C slowly. After stirred at r.t. for 1 hr, then stirred at 60 °C for 2 hrs, the mixture was poured into ice water (30 mL) and adjusted to pH = 7-8 with saturated NaHCO3. After completion, the resulting mixture was extracted with EtOAc (20 mL x 3), and the organic phase was combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography through silica gel (eluted with PE: EtOAc = 1: 5) to afford Int-185 (35 mg, 0.13 mmol, 83.5%) as a light yellow solid. LCMS (ESI): m / z = 263.1 [M+H]+.

[0364] Steps 8-12: From Int-185, analogous conditions as used in Steps 3-7 from Method A were used to provide Compound 1-171 as a white solid. The final compound was purified by Prep-HPLC (column: YMC-Actus Triart C18 250 x 20mm x 5um, gradient: 10-95% MeCN in H2O (with 0.1% TFA)).Compound 1-171: Retention time: 1.438 min; LC-MS (ESI) m / z = 535.2 [M+H]+;1H NMR (400 MHz, DMSO-6) 89.03 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.82 (s, 1H), 8.48 (dd, J = 4.8, 1.5 Hz, 1H), 8.36 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.02 (t, J = 55.0 Hz, 1H), 2.92 (s, 3H), 2.10 (td, J = 8.3, 4.3 Hz, 1H), 0.97 (d, J = 7.0 Hz, 2H), 0.89 - 0.83 (m, 2H);19F NMR (376 MHz, DMSO-d6) 8 -114.33 (s).Attorney Docket No. 255944.001402Example 18: Synthesis of Compounds 1-163 & 1-92Attorney Docket No. 255944.001402

[0365] Step 1: To a solution of Int-106 (5.0 g, 21.4 mmol) in dioxane (50 mL) and H2O (10 mL), then was added pyridin-3-ylboronic acid (R-7, 2.6 g, 21.4 mmol, 1.0 eq.) and Pd(PPh3)4(cat., 1.2 g, 1.1 mmol) and K2CO3 (8.9 g, 64.2 mmol, 3.0 eq.), the mixture was stirred at 100 °C for 16 hrs. LCMS showed 1 was consumed completely and desired mass was detected. The resulting solution was poured to H2O (100 mL), extract with EA (50 mL * 3), dried over with Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel using PE / EA = 1: 1 to afford Int-190 (3.6 g, 15.1 mmol, 70.6%) as a white solid. LCMS (ESI): m / z = 240.1 [M+H]+.

[0366] Step 2: To a solution of Int-190 (1.0 g, 4.2 mmol, 1.0 eq.) in DMF (20 mL), then was added NBS (820 mg, 4.6 mmol, 1.1 eq.) at 0 °C, the mixture was warmed to r.t. and kept stirred for 2 hrs. LCMS showed 3 was consumed completely and desired mass was detected. The resulting solution was poured into H2O (80 mL), extract with EA (50 mL * 3), dried over with Na2SO4 filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel using PE / EA = 1:1. Afford Int-191 (686 mg, 2.2 mmol, 51.5%) as a white solid. LCMS (ESI): m / z = 317.1 [M+H]+.

[0367] Step 3: To a solution of Int-191 (686 mg, 2.2 mmol, 1.0 eq.) in dioxane (60 mL) and H2O (12 mL), then was added cyclopropylboronic acid (378.4 mg, 4.4 mmol, 2.0 eq.) and cataCXium A Pd G3 (cat., 72.8 mg, 0.1 mmol) and K2CO3 (910.8 mg, 6.6 mmol, 3.0 eq.), the mixture was stirred at 100 °C for 16 hrs. LCMS showed Int-191 was consumed completely and desired mass was detected. The resulting solution was poured into H2O (60 mL), extracted with EA (40 mL * 3), dried over with Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using PE / EA = 2:3 to afford Int-192 (512 mg, 1.8 mmol, 83.4%) as a white solid. LCMS (ESI): m / z = 280.2 [M+H]+.

[0368] Step 4: To a solution of Int-192 (250 mg, 0.9 mmol, 1.0 eq.) in H2O (20 mL), then was added H2SO4 (cone., 2 mL) and sodium nitrite (124.2 mg, 1.8 mmol, 2.0 eq.) at 0 °C, after addition, the mixture was warmed to 60 °C and stirred for 4 hrs. LCMS showed Int-192 was consumed completely and desired mass was detected. The resulting solution was neutralized by cooled NaOH (aq.) to adjust pH to pH =7, then extracted with EA (40 mL * 4). The combined organic layers were dried over Na2SO4 filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using PE / EA = 1:3 to afford Int-193 (165 mg, 0.6 mmol, 65.5%) as a white solid. LCMS (ESI): m / z = 281.2 [M+H]+.Attorney Docket No. 255944.001402

[0369] Step 5: To a solution of Int-193 (165 mg, 0.6 mmol, 1.0 eq.) in DMF (10 mL), then was added NaH (36.0 mg, 60% dispersed in mineral oil, 0.9 mmol, 1.5 eq.) at 0 °C and kept stirred for 1 hr, 2,6-dichloro-3-nitropyridine (R-3, 138.2 mg, 0.7 mmol, 1.2 eq.) in DMF (0.5 mL) was added, then warmed to r.t. and stirred at 25 °C for 2 hrs. LCMS showed Int-193 was consumed completely and desired mass was detected. The resulting solution was poured into H2O (50 mL), extracted with (30 mL * 3), and the combined organic layers were washed by water (*3) and brine successively, then dried over with Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using PE / EA = 1: 1 to afford Int-194 (72 mg, 0.17 mmol, 27.5%) as a yellow solid. LCMS (ESI): m / z = 437.1 [M+H]+.

[0370] Steps 6-10: From Int-194, Compound 1-163 was generated as a white solid and Compound 1-92 was generated as a white solid.Compound 1-163: Retention time: 1.4505 min; LC-MS (ESI) m / z = 553.2 [M+H]+;1H NMR (400 MHz, DMSO-6) 5 10.20 (s, 1H), 9.05 (d, J= 5.5 Hz, 1H), 8.96 (s, 1H), 8.93 (s, 1H), 8.64 - 8.53 (m, 1H), 8.45 (d, J= 1.6 Hz, 1H), 8.35-8.28 (m, 1H), 7.94 (d, J= 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.58 - 7.42 (m, 1H), 3.20 (s, 3H), 2.17-2.13 (m, 1H), 1.08-0.90 (m, 4H).Compound 1-92: Retention time: 1.44 min; LC-MS (ESI) m / z = 567.1 [M+H]+;XH NMR (400 MHz, DMSO-cfc) 3 9.01 (d, J = 1.8 Hz, 1H), 9.01-8.98 (m, 1H), 8.92 (s, 1H), 8.62-8.58 (m, 1H), 8.54 (d, J = 1.9 Hz„ 1H), 8.23 - 8.11 (m, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.53-7.48 (m, 1H), 3.25 (s, 3H), 3.21 (s, 3H), 2.16-2.12 (m, 1H), 1.06-0.94 (m, 4H);19F NMR (376 MHz, DMSO-6) δ -65.76 (s).INCORPORATION BY REFERENCE

[0371] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0372] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoingAttorney Docket No. 255944.001402description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.References:1. Vauthier, V. et al. (2017) Targeted pharmacotherapies for defective ABC transporters. Biochem Pharmacol 136, 1-11. 10.1016 / j.bcp.2017.02.0202. Dean, M. et al. (2022) The human ATP -binding cassette (ABC) transporter superfamily. Hum Mutat 43, 1162-1182. 10.1002 / humu.244183. Liu, X. (2019) ABC Family Transporters. Adv Exp Med Biol 1141, 13-100. 10.1007 / 978-981-13-7647-4 24. Molday, R. S. et al. (2022) Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration. Prog Retin Eye Res 89, 101036.10.1016 / j.preteyeres.2021.1010365. Kroll, T. et al. (2021) Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. ChemRev 121, 5240-5288. 10.1021 / acs.chemrev.0c006596. Wanders, R. J. et al. (2007) The peroxisomal ABC transporter family. Pflugers Arch 453, 719-734. 10.1007 / s00424-006-0142-x7. Shaughnessy, C. A. et al. (2021) Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment. Sci Rep 11, 19810.10.1038 / s41598-021-99184-18. Thomas, C. and Tampe, R. (2020) Structural and Mechanistic Principles of ABC Transporters. Annu Rev Biochem 89, 605-636. 10.1146 / annurev-biochem-011520-105201 9. Byrne, J. A. et al. (2009) Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 49, 553-567. 10.1002 / hep.2268310. Gunaydin, M. and Bozkurter Cil, A. T. (2018) Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med 10, 95-104.10.2147 / HMER.S137209Attorney Docket No. 255944.00140211. Bosma, P.J. et al. (2020) Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects. IntJ Mol Sci 22. 10.3390 / ijms2201027312. Boyer, J. L. (2013) Bile formation and secretion. Compr Physiol 3, 1035-1078.10.1002 / cphy.c 12002713. Gerloff, T. et al. (1998) The sister of P -glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273, 10046-10050. 10.1074 / jbc.273.16.10046 14. van der Woerd, W. L. et al. (2017) Current and future therapies for inherited cholestatic liver diseases. World J Gastroenterol 23, 763-775. 10.3748 / wjg.v23.i5.76315. Wang, L. et al. (2020) Cryo-EM structure of human bile salts exporter ABCB11. Cell Res 30, 623-625. 10.1038 / s41422-020-0302-016. Boyer, J. L. and Soroka, C. J. (2021) Bile formation and secretion: An update. J Hepatol 75, 190-201. 10.1016 / j.jhep.2021.02.01117. Al-Dury, S. and Marschall, H. U. (2018) Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH. Front Pharmacol 9, 931.10.3389 / fphar.2018.0093118. van Wessel, D. B. E. et al. (2020) Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol 73, 84-93. 10.1016 / j.jhep.2020.02.00719. Stattermayer, A. F. et al. (2020) Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol 73, 651-663. 10.1016 / j.jhep.2020.04.03620. Nayagam, J. S. et al. (2022) Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol Commun. 10.1002 / hep4.2051 21. Stapelbroek, J. M. et al. (2010) Liver disease associated with canalicular transport defects: current and future therapies. J Hepatol 52, 258-271. 10.1016 / j.jhep.2009.11.01222. Thompson, R. J. et al. (2022) Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 7, 830-842. 10.1016 / S2468-1253(22)00093-023. Le Saux, O. et al. (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25, 223-227. 10.1038 / 76102Attorney Docket No. 255944.00140224. Iwanaga, A. and Murota, H. (2022) Author reply to comment on " Clinical practice guidelines for pseudoxanthoma elasticum (2017)": The importance of mutation analysis. J Dermatol 49, e250. 10.1111 / 1346-8138.1637925. Borst, P. et al. (2019) PXE, a Mysterious Inborn Error Clarified. Trends Biochem Sci 44, 125-140. 10.1016 / j.tibs.2018.10.00526. Nitschke, Y. and Rutsch, F. (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum: two sides of the same coin. Front Genet 3, 302.10.3389 / fgene.2012.0030227. Ferreira, C. R. et al. (2021) Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. J Bone Miner Res 36, 2193-2202.10.1002 / jbmr.441828. Bartstra, J. W. et al. (2021) Genotype-phenotype correlation in pseudoxanthoma elasticum. Atherosclerosis 324, 18-26. 10.1016 / j.atherosclerosis.2021.03.01229. Matsuzaki, Y. et al. (2005) Tissue-specific expression of the ABCC6 gene. J Invest Dermatol 125, 900-905. 10.1111 / j.0022-202X.2005.23897.x30. Scheffer, G. L. et al. (2002) MRP6 (ABCC6) detection in normal human tissues and tumors. Lab Invest 82, 515-518. 10.1038 / labinvest.378044431. Jansen, R. S. et al. (2014) ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol 34, 1985-1989. 10.1161 / ATVBAHA.114.30401732. Jansen, R. S. et al. (2013) ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci USA 110, 20206-20211. 10.1073 / pnas.131958211033. Iwanaga, A. et al. (2022) Clinical practice guidelines for pseudoxanthoma elasticum (2017): Clinical Practice Guidelines for Pseudoxanthoma Elasticum Drafting Committee. J Dermatol 49, e91-e98. 10.1111 / 1346-8138.1630134. Fong, V. and Patel, S. B. (2021) Recent advances in ABCG5 and ABCG8 variants. Curr Opin Lipidol 32, 117-122. 10.1097 / MOL.0000000000000734Attorney Docket No. 255944.00140235. Hooper, A. J. et al. (2017) Clinical utility gene card for: Sitosterolaemia. Eur J Hum Genet 25. 10.1038 / ejhg.2016.18736. Bhattacharyya, A. K. and Connor, W. E. (1974) Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 53, 1033-1043.10.1172 / JCI10764037. Patel, S. B. et al. (1998) Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J Lipid Res 39, 1055-106138. Williams, K. et al. (2021) Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8. Int J Mol Sci 22. 10.3390 / ijms2205264139. Graf, G. A. et al. (2002) Coexpression of ATP -binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest 110, 659-669.10.1172 / JCI1600040. Jakulj, L. et al. (2016) Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion. Cell Metab 24, 783-794. 10.1016 / j.cmet.2016.10.00141. Zein, A. A. et al. (2019) ABCG5 / G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion. Biochem Soc Trans 47, 1259-1268. 10.1042 / BST20190130 42. Chen, Z. C. et al. (2008) Significant association of ABCG8: D19H gene polymorphism with hypercholesterolemia and insulin resistance. J Hum Genet 53, 757-763. 10.1007 / s10038-008-0310-243. Rust, S. et al. (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22, 352-355. 10.1038 / 1192144. Schaefer, E. J. et al. (2016) Diagnosis and treatment of high density lipoprotein deficiency. Prog Cardiovasc Dis 59, 97-106. 10.1016 / j.pcad.2016.08.00645. Maranghi, M. et al. (2019) A novel splicing mutation in the ABCA1 gene, causing Tangier disease and familial HDL deficiency in a large family. Biochem Biophys Res Commun 508, 487-493. 10.1016 / j.bbrc.2018.11.064Attorney Docket No. 255944.00140246. Koseki, M. et al. (2021) Current Diagnosis and Management of Tangier Disease. J Atheroscler Thromb 23, 802-810. 10.5551 / jat.RV1705347. Langmann, T. et al. (1999) Molecular cloning of the human ATP-binding cassette transporter 1 (hABCl): evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun 257, 29-33. 10.1006 / bbrc.1999.040648. Hoekstra, M. et al. (2003) Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells. J Biol Chem 278, 25448-25453. 10.1074 / jbc.M30118920049. Wang, X. et al. (2007) Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest 117, 2216-2224.10.1172 / JCI3205750. Oram, J. F. and Lawn, R. M. (2001) ABCA1. The gatekeeper for eliminating excess tissue cholesterol. J Lipid Res 42, 1173-117951. Oram, J. F. et al. (2000) ABCA1 is the cAMP -inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem 275, 34508-34511.10.1074 / jbc.M00673820052. Brunham, L. R. et al. (2007) Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 13, 340-347. 10.1038 / nml546 53. Wang, N. et al. (2000) Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem 275, 33053-33058. 10.1074 / jbc.M00543820054. Jacobo-Albavera, L. et al. (2021) The Role of the ATP-Binding Cassette Al (ABCA1) in Human Disease. Int J Mol Sci 22. 10.3390 / ijms2204159355. Al-Khuzaei, S. et al. (2021) An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story. Genes (Basel) 12. 10.3390 / genesl208124156. Tsang, S. and Sharma, T. (2018) Stargardt disease. In Atlas of Inherited Retinal Diseases (Tsang, S. and Sharma, T., eds), pp. 140-151, Springer International Publishing AGAttorney Docket No. 255944.00140257. Tanna, P. et al. (2017) Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 101, 25-30. 10.1136 / bjophthalmol-2016-30882358. Kawaguchi, K. and Morita, M. (2016) ABC Transporter Subfamily D: Distinct Differences in Behavior between ABCD1-3 and ABCD4 in Subcellular Localization, Function, and Human Disease. Biomed Res Int 2016, 6786245. 10.1155 / 2016 / 678624559. Turk, B. R. et al. (2020) X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev Neurosci 80, 52-72.10.1002 / jdn.1000360. Barthel, A. et al. (2019) An Update on Addison's Disease. Exp Clin Endocrinol Diabetes 127, 165-175. 10.1055 / a-0804-271561. Kawaguchi, K. et al. (2016) Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. Sci Rep 6, 30183. 10.1038 / srep3018362. Weinhofer. I. et al. (2018) Impaired plasticity of macrophages in X-linked adrenoleukodystrophy. Brain 141, 2329-2342. 10.1093 / brain / awy12763. Beers, M. F. and Mulugeta, S. (2017) The biology of the ABCA3 lipid transporter in lung health and disease. Cell Tissue Res 367, 481-493. 10.1007 / s00441-016-2554-z64. Flamein, F. et al. (2012) Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum Mol Genet 21, 765-775. 10.1093 / hmg / ddr50865. Hammel, M. et al. (2007) Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies. Biochem Biophys Res Commun 359, 947-951. 10.1016 / j.bbrc.2007.05.21966. Wambach, J. A. et al. (2022) First Steps toward Personalized Therapies for ABCA3 Deficiency. Am J Respir Cell Mol Biol 66, 349-350. 10.1165 / rcmb.2021-0405ED67. Sanders, M. et al. (2021) Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis. Hum Genet 140, 423-439. 10.1007 / s00439-020-02211-wAttorney Docket No. 255944.00140268. Amaral, M. D. (2015) Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients. J Intern Med 277, 155-166. 10.1111 / joim.1231469. Breijyeh, Z. and Karaman, R. (2020) Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules 25. 10.3390 / molecules2524578970. Anstey, K. J. et al. (2017) Updating the Evidence on the Association between Serum Cholesterol and Risk of Late-Life Dementia: Review and Meta- Analysis. J Alzheimers Dis 56, 215-228. 10.3233 / JAD-16082671. Torrandell-Haro, G. et al. (2020) Statin therapy and risk of Alzheimer's and age-related neurodegenerative diseases. Alzheimers Dement (N Y) 6, el2108. 10.1002 / trc2.1210872. Bossaerts, L. et al. (2022) The role of ATP-binding cassette subfamily A in the etiology of Alzheimer's disease. Mol Neurodegener 17, 31. 10.1186 / s13024-022-00536-w73. Koldamova, R. P. et al. (2005) The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem 280, 4079-4088. 10.1074 / jbc.M41142020074. Koldamova, R. et al. (2005) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280, 43224-43235.10.1074 / jbc.M50451320075. Zhu, X. et al. (2010) Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J Lipid Res 51, 3196-3206.10.1194 / jlr.M00648676. Sviridov, D. et al. (2020) Lipid rafts as a therapeutic target. J Lipid Res 61, 687-695. 10.1194 / jlr.TR12000065877. Ehehalt, R. et al. (2003) Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 160, 113-123. 10.1083 / jcb.200207113 78. Choy, R. W. et al. (2012) Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network. Proc Natl Acad Sci USA 109, E2077-2082. 10.1073 / pnas.1208635109Attorney Docket No. 255944.00140279. Marquer, C. et al. (2011) Local cholesterol increase triggers amyloid precursor protein-Bacel clustering in lipid rafts and rapid endocytosis. FASEB J 25, 1295-1305. 10.1096 / fj.10-16863380. Wahrle, S. E. et al. (2005) Deletion of Abcal increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280, 43236-43242.10.1074 / jbc.M50878020081. Lefterov. I. et al. (2009) Memory deficits in APP23 / Abcal+ / - mice correlate with the level of Abeta oligomers. ASN Neuro 1. 10.1042 / AN2009001582. Jiang, Q. et al. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681-693. 10.1016 / j.neuron.2008.04.01083. Leissring, M. A. et al. (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087-1093. 10.1016 / s0896-6273(03)00787-684. Husain, M. A. et al. (2021) APOE and Alzheimer's Disease: From Lipid Transport to Physiopathology and Therapeutics. Front Neurosci 15, 630502. 10.3389 / fnins.2021.630502 85. Wahrle, S. E. et al. (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118, 671-682. 10.1172 / JCI33622 86. Boehm-Cagan, A. et al. (2016) ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. J Alzheimers Dis 54, 1219-1233. 10.3233 / JAD-16046787. Noveir, S. D. et al. (2022) Effect of the ABCA1 agonist CS-6253 on amyloid-beta and lipoprotein metabolism in cynomolgus monkeys. Alzheimers Res Ther 14, 87. 10.1186 / s13195-022-01028-188. Reitz, C. et al. (2013) Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4, and the risk of late-onset Alzheimer disease in African Americans. JAMA 309, 1483-1492. 10.1001 / jama.2013.297389. Cukier, H. N. et al. (2016) ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol Genet 2, e79. 10.1212 / NXG.0000000000000079Attorney Docket No. 255944.00140290. Bellenguez, C. et al. (2017) Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59, 220 e221-220 e229. 10.1016 / j.neurobiolaging.2017.07.00191. De Roeck, A. et al. (2017) Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease. Acta Neuropathol 134, 475-487.10.1007 / s00401 -017- 1714-x92. Apostolova, L. G. et al. (2018) Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis. JAMA Neurol 75, 328-341. 10.1001 / jamaneurol.2017.4198 93. Stage, E. et al. (2016) The effect of the top 20 Alzheimer disease risk genes on graymatter density and FDG PET brain metabolism. Alzheimers Dement (Amst) 5, 53-66.10.1016 / j.dadm.2016.12.00394. Lyssenko, N. N. and Pratico, D. (2021) ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease. Alzheimers Dement 17, 164-174. 10.1002 / alz.1222095. Lamartiniere, Y. et al. (2018) ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-beta Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. J Alzheimers Dis 64, 1195-1211. 10.3233 / JAD-17088396. Tanaka, N. et al. (2010) Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP -binding cassette transporter A7. J Lipid Res 51, 2591-2599. 10.1194 / jlr. M00604997. Jehle, A. W. et al. (2006) ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol 174, 547-556.10.1083 / jcb.20060103098. Aikawa, T. et al. (2019) ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain. Proc Natl Acad Sci USA 116, 23790-23796. 10.1073 / pnas.1908529116 99. Satoh, K. et al. (2015) ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing. J Biol Chem 290, 24152-24165. 10.1074 / jbc.M115.655076Attorney Docket No. 255944.001402100. Sakae, N. et al. (2016) ABCA7 Deficiency Accelerates Amyloid-beta Generation and Alzheimer's Neuronal Pathology. J Neurosci 36, 3848-3859. 10.1523 / JNEUROSCI.3757-15.2016101. Kim, W. S. et al. (2013) Deletion of Abca7 increases cerebral amyloid-beta accumulation in the J20 mouse model of Alzheimer's disease. J Neurosci 33, 4387-4394.10.1523 / JNEUROSCI.4165-12.2013

Claims

Attorney Docket No. 255944.001402We Claim:

1. A compound represented by Formula I:,(R2A)P(R2B)q( B1H A12or a pharmaceutically acceptable salt thereof, wherein:Ring A1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene;Ring B1is a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl;Ring C1is a 5- or 6-membered monocyclic heteroarylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered monocyclic heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenylene;NiSR1is -N(R6)-SO2-R4, -SO2-N(R6)-R4, -S(NR6)(O)-R4, or 0R2Arepresents independently for each occurrence Ci -3 alkyl, halo, Ci -3 haloalkyl, C3-5 cycloalkyl, or -O-R7, wherein each cycloalkyl is substituted with k instances of R8;R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a saturated or partially unsaturated 6-10 membered bicyclic heterocyclyl containing 1-4Attorney Docket No. 255944.001402heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9; or two vicinal occurrences of R2Bare taken together with the atoms to which they are attached to form a 6-membered saturated, partially unsaturated, or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3represents independently for each occurrence halo, cyano, Ci-6 alkyl, C1-4 haloalkyl, or a C3-5 cycloalkyl substituted with m instances of R10;R4is CM alkyl or a C3-5 cycloalkyl substituted with n instances of R5;R5represents independently for each occurrence C1-4 alkyl, halo, C1-3 haloalkyl, or hydroxyl;R6is hydrogen, C1-3 alkyl, C3-5 cycloalkyl, or-(Co-3alkylene)-O-(Ci-3alkyl);R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, cyclopropyl, a 3-5 membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R8represents independently for each occurrence C1-3 alkyl, C1-4 haloalkyl, or halo;R9represents independently for each occurrence C1-3 alkyl, halo, C1.4 haloalkyl, cyano, -C(O)-(Ci.3 alkyl), -(C0-3 alkylene)-O-(Ci.3alkyl), –(C0-3alkylene)-O-(C1-3haloalkyl), or -SO2- (Ci_3alkyl);R10represents independently for each occurrence halo, Ci-3alkyl, or C1-4 haloalkyl; k is 0, 1, or 2;m is 0, 1, or 2;n is 0, 1, or 2;o is 0, 1, or 2;p is 0, 1, or 2;q is 1 or 2; andr is 0, 1, 2, or 3.

2. The compound of claim 1, wherein the compound is a compound of Formula I.Attorney Docket No. 255944.0014023. The compound of claim 1 or 2, wherein r is 1.

4. The compound of claim 1 or 2, wherein r is 2.

5. The compound of any one of claims 1-4, wherein Ring A1is a 6-membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

6. The compound of any one of claims 1-4, wherein Ring A1is pyridinylene.

7. The compound of any one of claims 1-6, wherein Ring B1is a 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound of any one of claims 1-6, wherein Ring B1is pyridinyl.

9. The compound of claim 1, wherein the compound is a compound of Formula I-A, or a pharmaceutically acceptable salt thereof:(R2A)PC1I-A.

10. The compound of any one of claims 1-9, wherein Ring C1is a 6-membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of claims 1-9, wherein Ring C1is pyridinylene.

12. The compound any one of claims 1-9, wherein Ring C1is pyrimidinylene.

13. The compound any one of claims 1-9, wherein Ring C1is a 5-membered monocyclic heteroarylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

14. The compound any one of claims 1-9, wherein Ring C1is pyrazolylene.Attorney Docket No. 255944.00140215. The compound of claim 1, wherein the compound is a compound of Formula I-B, I-C, or I-D, or a pharmaceutically acceptable salt thereof:I-B I-C I-D.

16. The compound of any one of claims 1-15, wherein R1is -N(R6)-SO2-R4.

17. The compound of any one of claims 1-15, wherein R1is -SO2-N(R6)-R4.

18. The compound of any one of claims 1-15, wherein R1is -S(NR6)(O)-R4.

19. The compound of claim 1, wherein the compound is a compound of Formula I-E, I-F, or I-G, or a pharmaceutically acceptable salt thereof:I-E I-F I-G.

20. The compound of any one of claims 1-19, wherein R6is hydrogen.

21. The compound of any one of claims 1-20, wherein R4is Ci-4 alkyl.

22. The compound of any one of claims 1-20, wherein R4is methyl.

23. The compound of any one of claims 1-22, wherein R3represents independently for each occurrence halo, cyano, C1-6alkyl, or Ci-4 haloalkyl.

24. The compound of any one of claims 1-22, wherein R3is cyano.

25. The compound of claim 1, wherein the compound is a compound of Formula I-H, or a pharmaceutically acceptable salt thereof:Attorney Docket No. 255944.00140226. The compound of claim 1, wherein the compound is a compound of Formula I-J or a pharmaceutically acceptable salt thereof:I-J.

27. The compound of claim 1, wherein the compound is a compound of Formula I-K or a pharmaceutically acceptable salt thereof:N-NH(R2B)qX (R2A)P{JHXCNHONC^I-K.

28. The compound of any one of claims 1-27, wherein q is 1.

29. The compound of any one of claims 1-27, wherein q is 2.

30. The compound of any one of claims 1-29, wherein p is 1.

31. The compound of any one of claims 1-29, wherein p is 2.Attorney Docket No. 255944.00140232. The compound of any one of claims 1-31, wherein R2Arepresents independently for each occurrence C1-3 alkyl, C1-3 haloalkyl, or C3-5 cycloalkyl.

33. The compound of any one of claims 1-31, wherein R2Arepresents independently for each occurrence methyl, cyclopropyl, -CHF2, or -CF3.

34. The compound of any one of claims 1-33, wherein R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each heteroaryl and heterocyclyl is substituted with o instances of R9.

35. The compound of any one of claims 1-33, wherein R2Brepresents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

36. The compound of any one of claims 1-33, wherein R2Brepresents independently for each occurrence a 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

37. The compound of any one of claims 1-33, wherein R2Brepresents independently for each occurrence pyridinyl, tetrahydropyranyl, morpholinyl, pyrazolyl, imidazolyl, or piperidinyl.

38. The compound of any one of claims 1-33, wherein R2Brepresents independently for each occurrence pyridinyl or piperidinyl.

39. A compound in Table 1 or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound of any one of claims 1-39 and a pharmaceutically acceptable carrier.

41. A method of treating a disorder associated with ABC transporter dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-39 to treat the disorder.

42. The method of claim 41, wherein the disorder associated with ABC transporter dysfunction is characterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6,Attorney Docket No. 255944.001402ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

43. A method of treating or preventing a disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-39 to treat or prevent 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, 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, chronic kidney disease, Progeria (Hutchinson-Gilford progeria syndrome), hemodialysis, end stage renal disease, aortic stenosis, peripheral arterial disease, and ischemic stroke.

44. The method of claim 43, wherein the disorder is selected from calciphylaxis, pseudoxanthoma elasticum, generalized arterial calcification of infancy, chronic kidney disease, Progeria (Hutchinson-Gilford progeria syndrome), hemodialysis, end stage renal disease, aortic stenosis, peripheral arterial disease, and ischemic stroke.

45. A method of modulating the function of an ABC transporter in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-39 to thereby modulate the function of the ABC transporter in the subject.Attorney Docket No. 255944.00140246. The method of claim 45, wherein 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.

47. The method of any of claims 41-46 wherein the subject is a human.

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