Pyridinyloxy pyridines as modulators of ATP-binding cassette transporters and their use in the treatment of medical conditions

Abstract

The present invention provides pyridyloxy pyridines and related compounds as modulators of ATP-binding cassette ("ABC") transporters. Also disclosed are pharmaceutical compositions comprising the pyridyloxy pyridines and the use of the pyridyloxy pyridines in the treatment of medical conditions associated with ABC transporter dysfunction.

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application Serial No. 63 / 620,311, filed January 12, 2024, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0002] This invention provides pyridyloxypyridine and related compounds, pharmaceutical compositions, and their use in treating medical conditions. Background Technology

[0003] ATP-binding cassette (ABC) transporters are a large, phylogenetically conserved family of genes with broad physiological and pathological relevance. [1,2] They are expressed systemically and transport a wide variety 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 the lipid membrane to the other. [2,3]

[0004] At least 21 ABC transporters are fundamental to rare monogenic genetic diseases, and many more are involved in the susceptibility and symptomatology of common and complex diseases. This broad (patho)physiological relevance places these proteins at the intersection of pathogenicity and therapeutic potential, highlighting them as promising targets for drug discovery. Based on a few characteristic disorders, including cystic fibrosis (CF), progressive familial intrahepatic cholestasis 2 (PFIC2), and STGD, there are mechanistic commonalities with pathogenic ABC transporter missense mutations, primarily their effects on protein folding (leading to endoplasmic reticulum (ER) degradation) (transport defects) or their effects on protein function (leading to reduced substrate transport) (transport defects). Importantly, small molecule compounds could enable the treatment of disease symptoms not directly caused by ABC transporter gene mutations.

[0005] There is a need for small molecule compounds that can positively regulate the function of ABC transporters and thus be used to treat diseases in which such enhancement is predicted to have therapeutic value in improving the condition or in treating the symptom response. For example, there is a need for regulators that can resolve 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] Therefore, there is a need for novel treatment methods and compounds for treating ABC transporter dysfunction. This invention addresses the aforementioned needs and provides other related advantages. Summary of the Invention

[0007] This invention provides pyridyloxypyridines and related compounds, pharmaceutical compositions, and their use in treating medical conditions. In particular, one aspect of the invention provides a collection of pyridyloxypyridine compounds, such as those represented by formula I: (I) Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the specific embodiments. Further description of an additional set of pyridyloxypyridine compounds is described in the specific embodiments. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0008] Another aspect of the present invention provides a method for treating ABC transporter dysfunction. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of formula I, to a subject in need to treat the ABC transporter dysfunction, as further described in the detailed embodiments.

[0009] Another aspect of the present invention provides a method for modulating the function of proteins selected from the group consisting of ABCB11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, ABCD1, and ABCD2 in a subject. The method comprises administering an effective amount of the compound described herein, such as a compound of formula I, to a subject in need, thereby modulating the function of the protein, as further described in the detailed embodiments. Detailed Implementation

[0010] This invention provides pyridyloxypyridine and related compounds, pharmaceutical compositions, and their use in treating medical conditions. Unless otherwise indicated, the practice of this invention employs 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” (BM Trost & I. Fleming, eds., 1991–1992); “Handbook of experimental immunology” (DM Weir and CC Blackwell, eds.); “Current protocols in molecular biology” (FM Ausubel et al., eds., 1987, and regularly updated); and “Current protocols in immunology” (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0011] The various aspects of the invention are described in sections below; however, the aspects of the invention described in a particular section are not limited to any particular section. Furthermore, when a variable is not defined, its prior definition shall prevail. definition

[0012] The compounds of this invention include those generally described herein, and are further described according to the categories, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. Unless otherwise indicated, these definitions apply whether the terms are used alone or in combination with other terms. Thus, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portion of “-O-alkyl”, etc. For the purposes of this invention, chemical elements are identified according to the periodic table (CAS edition, Handbook of Chemistry and Physics, 75th edition). Furthermore, the general principles of organic chemistry are described in the following references: “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999; and “March's Advanced Organic Chemistry”, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0013] As used herein, the term "aliphatic" or "aliphatic group" means a fully saturated or branched linear (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a fully saturated or branched monocyclic or bicyclic hydrocarbon (also referred to herein as "alicyclic") containing one or more unsaturated units but not aromatic, having a single attachment point to the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in yet another embodiment, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "aliphatic" refers to a fully saturated or branched monocyclic C3-C6 hydrocarbon containing one or more unsaturated units but not aromatic, having a single attachment point to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0014] As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system having one or more common atoms between the two rings, i.e., a carbocyclic or heterocyclic system, saturated or having one or more unsaturated units. Therefore, the term includes any permitted ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicyclic system. Such heteroatoms may be present at ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridging bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbocyclic or heterocyclic system, saturated or partially unsaturated. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or valence bonds connecting two bridgeheads, wherein a “bridgehead” is any skeletal atom in a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those groups described below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridging bicyclic group is optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group is optionally substituted. Exemplary bicycles include:

[0015] Exemplary bridging dual-ring classes include: .

[0016] The term "lower alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0017] The term "lower haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0018] The term "heteroatom" means one or more of the following: oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. +(e.g., in N-substituted pyrroleyl groups).

[0019] As used in this article, the term "unsaturated" means that a portion of a part has one or more unsaturated units.

[0020] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and ynylene chains as defined herein.

[0021] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0022] The term "-(C0 alkylene)-" refers to a bond. Therefore, the term "-(C0 alkylene)-" refers to a bond. 0-3 alkylene)-” encompasses both the bond (i.e., C0) and the bond (-(C) 1-3 (alkylene) group.

[0023] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene chain containing at least one double bond, wherein one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0024] The terms “halogenated group” and “halogen” refer to F, Cl, Br or I.

[0025] The term "aryl," used alone or as part of a larger part (such as in "aralkyl," "arylalkoxy," or "aryloxyalkyl"), refers to a monocyclic or bicyclic cyclic system 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 some embodiments of the invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc. When used herein, the term "aryl" also includes groups in its scope where the aromatic ring is fused with one or more non-aromatic groups, such as indanyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl. The term "phenylene" refers to a polyvalent phenyl having an appropriate number of open valences to account for the groups attached to it. For example, "phenylene" is a divalent phenyl when it has two groups attached to it (e.g., "Phenylidene" is a trivalent phenyl group when it has three groups attached to it (e.g., The term "triaryl" refers to a divalent aryl group.

[0026] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger portion (e.g., "heteroarylalkyl" or "heteroarylalkoxy") refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, indoleazinyl, purine, naphthidyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein, unless otherwise specified, the attachment group or attachment site is located on the heteroaryl ring or on one of the rings fused with the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene," any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0027] The term "heteroarylene" refers to a polyvalent heteroarylene with an appropriate number of open valences to account for the groups attached to it. For example, a "heteroarylene" is a divalent heteroarylene when it has two groups attached to it; a "heteroarylene" is a trivalent heteroarylene when it has three groups attached to it.

[0028] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (preferably one to four) heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or... + NR (as in N-substituted pyrroleyl groups).

[0029] Heterocycles can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxalyl, dioxopentyl, diazapyrrolyl, oxazpyrrolyl, thioazpyrrolyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromyl, phenanthridine, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moiety are independently and optionally substituted. The term “oxo-heterocyclic group” refers to a heterocyclic group substituted with one or more oxo groups. The term “heterocyclic subcyclic group” refers to a polyvalent heterocyclic group having an appropriate number of open valences to account for the groups attached to it. For example, a “heterocyclic subcyclic group” is a divalent heterocyclic group when it has two groups attached to it; a “heterocyclic subcyclic group” is a trivalent heterocyclic group when it has three groups attached to it. The term "oxo-heterocyclic group" refers to a polyvalent oxo-heterocyclic group with an appropriate number of open valences to explain the groups to which it is attached.

[0030] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0031] The term "partially aromatic double ring" refers to a double ring in which one ring is an aromatic molecule and the other ring is not.

[0032] As used herein, the term "pyridyl-N-oxide" refers to... .

[0033] As described herein, the compounds of the present invention may contain an “optionally substituted” portion. Generally, regardless of whether the term “optionally” is preceding it, the term “substituted” means that one or more hydrogens of the specified portion are replaced by suitable substituents. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term “stable” means a compound that remains substantially unchanged when subjected to conditions that allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] Each optional substituent on the substituted carbon is independently selected from the following monovalent substituents: halogen; -(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°,-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph can be substituted by R°; -CH=CHPh can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted by R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(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) 0-4 C(O)R°;-C(S)R°;-(CH2)0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, SC(S)SR°; -(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-S(O)(NR°)R°;-S(O)2N=C(NR°2)2;-(CH2) 0-4 S(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; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (Straight-chain or branched alkylene)C(O)ON(R°)2.

[0035] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -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 foregoing definition, two independently occurring R° together with one or more of their intermediate atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atom of R° with a divalent substituent selected from =O and =S; or each R° may optionally be substituted independently with a monovalent substituent selected from: halogen, -(CH2) 0-2 R ● -(halogenated R) ● -(CH2) 0-2OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2;-O(halogenated R ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0- 2SH、-(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● .

[0036] Each R ● Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either unsubstituted or, in the case of a preceding halogenation, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are independently selected from the following divalent substituents: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-; or a divalent substituent bonded to an ortho-substituted carbon atom of an "optionally substituted" group is -O(CR). * 2) 2-3 O-, where each independently occurring R *Selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6 saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0037] When R * It is C 1-6 When aliphatic, R * Optionally replaced by: halogen, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either unsubstituted or, in the case of prior halogenation, substituted by only one or more halogens.

[0038] The optional substituent on the substituted nitrogen is independently -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, it is hydrogen and C 1-6 Aliphatic, unsubstituted -OPh or unsubstituted 5-6 member saturated, partially unsaturated or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or two independently occurring R... † Together with one or more of their intermediate atoms, they form unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; wherein when R † It is C 1-6 When aliphatic, R †Optionally replaced by: halogen, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either unsubstituted or, in the case of prior halogenation, substituted by only one or more halogens.

[0039] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues within a reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate-heptyl sulfate, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0040] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed in, for example, the following literature: P. Stahl et al., Camille G. (ed.) 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. ofPharmaceutics (1986) 33 References 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on its website). These publications are incorporated herein by reference.

[0041] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using anti-charge ions (such as halide ions, hydroxide ions, carboxyl ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions).

[0042] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers) of the structures; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetry center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. The present invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (including those with hydrogen replaced by deuterium or tritium, or those with enriched isotopic atoms) 13 C or 14(Carbon substitution for carbon) is within the scope of this invention. According to the invention, such compounds can be used, for example, as analytical tools, as probes in bioassays, or as therapeutic agents.

[0043] A mixture of diastereomers can be separated into their individual diastereomers based on physicochemical differences using methods known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), converting the diastereomers, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Further still, in the case where the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), a diastereomer salt is formed with a suitable optically active acid or base, and the resulting diastereomers are then resolved by fractional crystallization or chromatographic means known to those skilled in the art, followed by recovery of the pure enantiomers.

[0044] Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all other or other alternative stereoisomers. One or more chiral centers in the compounds of the present invention may have an S or R configuration as defined in IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as transisomers (e.g., substituted biaryl compounds), all such transisomers are considered part of the present invention.

[0045] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both chemical structure and chemical name are used to refer to a chemical compound, and there is ambiguity between the structure and name, the structure takes precedence. It should also be noted that any carbon atoms and heteroatoms that do not satisfy a valence in the text, schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy a valence.

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

[0047] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group with 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C1, respectively. 12 Alkyl, C1-C 10Alkyl and C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0048] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group derived from cycloalkanes of 3-12, 3-8, 4-8, or 4-6 carbons, and is referred to herein as, for example, "C3-C6 cycloalkyl". Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0049] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

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

[0051] The terms “alkenyl” and “alkynyl” are recognized in the art and refer to unsaturated aliphatic groups that are similar to the alkyl groups described above in length and possible substitutions, but each contains at least one double or triple bond.

[0052] The term "alkoxyl" or "alkoxy" is recognized in the art and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc.

[0053] The term "oxo" is recognized in the art and refers to an "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0054] symbol" "Instruction attachment point."

[0055] Unless otherwise indicated, when any substituent or variable appears more than once in any ingredient or compound of the present invention, its definition at each occurrence is independent of its definition at each other occurrence.

[0056] One or more compounds of the present invention can exist in a non-solventized form and in a pharmaceutically acceptable solvent (such as water, ethanol, etc.), and the present invention is intended to include both solvated and non-solventized forms. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses both solution phases and separable solvates. Non-limiting examples of suitable solvates include ethanolides, methanolides, etc. "Hydrate" is a solvate with H₂O as the solvent molecule.

[0057] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rats, apes, horses, cattle, pigs, dogs, cats, etc.), and most preferably include humans.

[0058] The term "IC" 50 "is recognized in the field and refers to the compound concentration required to achieve 50% target inhibition."

[0059] The term "EC" 50 "is recognized in the field and refers to the concentration of compounds required to achieve 50% of the maximum target effect relative to the baseline."

[0060] Term "E" max "is recognized in the field and refers to the concentration of compounds required to achieve the maximum target effect."

[0061] As used herein, the term "effective amount" means an amount of compound sufficient to achieve a beneficial or desired outcome (e.g., therapeutic, ameliorative, inhibitory, or preventative outcome). An effective amount may be administered in one or more applications, doses, or administrations and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "therapeutic" includes any effect that results in the improvement of a symptom, disease, disorder, etc., or improves its symptoms, such as by alleviating, reducing, moderating, improving, or eliminating it.

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

[0063] As used herein, the term “pharmaceuticalally acceptable carrier” refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solutions, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. Compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA

[1975] .

[0064] For therapeutic purposes, salts of the compounds of the present invention are considered pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds.

[0065] Furthermore, when the compounds of the present invention contain both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acid), zwitterions (“internal salts”) can be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts. Such salts of the compounds of the present invention can be formed, for example, by reacting the compounds of the present invention with a certain amount (such as an equivalent amount) of an acid or base in a medium (such as a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0066] Throughout this specification, when a composition is described as having, including, or containing specific components, or when a process or method is described as having, including, or containing specific steps, it is contemplated that there are additional compositions of the invention that are substantially composed of or comprised of the listed components, as well as processes and methods of the invention that are substantially composed of or comprised of the listed processing steps.

[0067] Generally, unless otherwise specified, the specified percentage of the composition is by weight. I. Pyridyloxypyridine compounds I.1 Pyridyloxypyridine compounds of formula (I)

[0068] One aspect of the present invention provides pyridyloxypyridine compounds. These compounds can be used in the pharmaceutical compositions and treatment methods described herein. Exemplary compounds and exemplary procedures for preparing these compounds are described in the following sections. One aspect of the present invention provides compounds represented by Formula I: (I) Or its pharmaceutically acceptable salt, wherein: Ring A 1It is (i) a 6-membered heteroarylene having one or two heteroatoms selected from nitrogen; (ii) a phenylene; or (iii) a 5- to 7-membered saturated or partially unsaturated monocyclic oxy-heterocyclic group having one to two heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic group containing 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 Replacement; or ring B 1 It is k R 3 Substituted phenyl; Ring C 1 It is a phenylene oxide, a 5- or 6-membered heteroarylene or pyridinyl-N-oxide containing one or two heteroatoms selected from nitrogen, oxygen and sulfur; R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -SO2-N(R) 7 )2、-S(NR 9 (O)-R 6 -N=S(O)(R 9 )2 or -S(O2)-R 6 or ; R 2 Each time it appears, it independently represents the hydroxyl group and C. 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, C 3-4 cycloalkyl, -OR 11 , a 3-5 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-12 membered bridging or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two adjacent R groups. 2 Together with the atoms to which they are attached, they form 3-6 membered rings with 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur; R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 2-3alkynyl group, C 1-6 Halogenated alkyl, hydroxyl, (C 0-2 (alkylene)-C 1-6 Alkoxy, C 1-3 Hydroxyalkyl, -CON(R) 4 )2、-C(O)-R 5 -C(O)-OR 5 -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 -S(NR) 4 (O)-R 5 C 1-6 Halogenated alkoxy groups, C 3-4 Cycloalkyl groups, or 3-6 membered heterocyclic groups having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl group and heterocyclic group is divided by r R groups. 13 replace; R 4 Each time it appears, it independently represents hydrogen and C. 1-4 Alkyl or cyclopropyl; R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 cycloalkyl, -(C 0-2 alkylene)-phenyl, -(C 0-2 Alkylene)-(a 3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or -(C 0-2 Alkylene group (5-10-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are separated by m R 8 Substitution, and wherein each alkylene group is replaced by n R groups. 8 replace; R 7 It is hydrogen, or two R atoms attached to the same nitrogen atom. 7 The groups, together with the nitrogen to which they are attached, form a 3- to 6-membered saturated monocycle having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen atom. R 8 C is represented independently each time it appears. 1-4 Alkyl, Halogenated, C 1-3 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, cyano, or cyclopropyl; R 9 Each time it appears, it independently represents hydrogen and C. 1-3 Alkyl or cyclopropyl; R 10It is C 1-3 Alkyl, C 1-3 Haloalkyl, halogroup, hydroxyl or cyclopropyl; R 11 It is C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyclopropyl, or 3- to 5-membered saturated heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 It is C 1-3 Alkyl, halogroup, cyano, or -SO2-(C 1-3 alkyl); R 13 It is a halogenated group, C 1-3 Alkyl or C 1-3 Alkyl group; h is 0, 1, or 2; j is 0, 1, or 2; k is 1 or 2; m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 1, 2, 3, or 4 q is 0, 1, or 2; and r is 0, 1, or 2.

[0069] The definition of the variable in Formula I above covers multiple chemical groups. This application contemplates embodiments in which, for example, i) the variable is defined as a single chemical group selected from those chemical groups, ii) the variable is defined as a set of two or more chemical groups selected from those chemical groups, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0070] In some embodiments, the compound is a compound of formula I.

[0071] As generally defined above, ring A 1 It is (i) a 6-membered heteroarylene having one or two heteroatoms selected from nitrogen; (ii) a phenylene; or (iii) a 5- to 7-membered saturated or partially unsaturated monocyclic oxy-heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A 1 It is a phenylene oxide. In some embodiments, cyclic A 1 It is a 6-membered monocyclic heteroaromatic ring containing one or two heteroatoms selected from nitrogen. In some embodiments, ring A... 1 It is a 5-7 member saturated or partially unsaturated monocyclic oxy-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A... 1 It is pyridyl or pyrimidinyl. In some embodiments, ring A 1It is a pyridyl group. In some embodiments, ring A... 1 It is a pyrimidine group. In some embodiments, cyclic A... 1 The groups are selected from the compounds described in Table 1 below.

[0072] As roughly defined above, ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic group containing 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 Replacement; or ring B 1 It is a phenyl group that has been substituted with k R atoms.

[0073] In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is separated by j R 3 Replacement; or ring B 1 It is k R 3 Substituted phenylene.

[0074] In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is separated by j R 3 Replacement. In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0075] In some implementations, ring B 1 It was by j R 3 The substituted group is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It was by j R3 The substituted 5-6 membered monocyclic heteroaryl group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It was by j R 3 The substituted heterocyclic group is a 7-12 bridging heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0076] In some implementations, ring B 1 It was by j R 3 The substituted 3-7 membered monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0077] In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It is a 7-12 bridging heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0078] In some implementations, ring B 1 It was by j R 3 The substituted heterocyclic group is a 7-12 bridging or spirocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0079] In some implementations, ring B 1 It was by j R 3 Substituted 9-10 membered bicyclic aromatics containing 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0080] In some implementations, ring B 1 It is k R 3 Substituted phenyl groups. In some embodiments, cyclic B... 1 It is a phenylene oxide.

[0081] In some implementations, ring B 1 It is pyridinyl, pyrazolyl, imidazolyl, piperazinyl, 2,5,-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl or azacyclobutyl, wherein each ring is divided by j R 3 Replacement. In some implementations, ring B 1 It was by j R 3Substituted pyridinyl group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted pyrazol group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted imidazole group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted piperazine group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted 2,5,-diazabicyclo[2.2.1]heptyl. In some embodiments, ring B... 1 It was by j R 3 Substituted 3,6-diazabicyclo[3.1.1]heptyl. In some embodiments, ring B... 1 It was by j R 3 Substituted 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl. In some embodiments, cyclic B... 1 It was by j R 3 Substituted 2,6-diazaspiro[3,4]octyl. In some embodiments, cyclic B 1 It was by j R 3 Substituted 2,6-diazaspiro[3.3]heptyl. In some embodiments, cyclic B... 1 It was by j R 3 Substituted nitrogen-containing heterocyclic butyl groups.

[0082] In some implementations, ring B 1 The groups are selected from the compounds described in Table 1 below.

[0083] As generally defined above, ring C 1 It is a phenylene oxide, a 5- or 6-membered heteroarylene or pyridylene-N-oxide containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a phenylene oxide. In some embodiments, the cyclic C 1 It is a 5- or 6-membered heteroarylene containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a pyridyl-N-oxide. In some embodiments, the cyclic C 1 It is a 5-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen. In some embodiments, the cyclic C 1It is phenylene or pyridylene. In some embodiments, the cyclic C 1 It is a pyridyl group. In some embodiments, the cyclic C 1 It is a pyridyl group. In some embodiments, the cyclic C 1 It is a pyrimidine group. In some embodiments, the cyclic C 1 It is pyridyl or pyrimidinyl. In some embodiments, the cyclic C 1 The groups are selected from the compounds described in Table 1 below.

[0084] As generally defined above, R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -SO2-N(R) 7 )2、-S(NR 9 (O)-R 6 -N=S(O)(R 9 )2、-S(O2)-R 6 or In some implementations, R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -S(NR) 9 (O)-R 6 or -S(O2)-R 6 In some implementations, R 1 It is -N(R) 9 )-SO2-R 6 In some implementations, R 1 It is -SO2-N(R) 9 )-R 6 In some implementations, R 1 It is -SO2-N(R) 7 2. In some implementations, R 1 It is -S(NR) 9 (O)-R 6 In some implementations, R 1 It is -N=S(O)(R 9 ) 2。 In some implementations, R 1 It is -S(O2)-R 6 In some implementations, R 1 yes In some implementations, R 1It is -NH-SO2-CH3. In some implementations, R 1 The groups are selected from the compounds described in Table 1 below.

[0085] As generally defined above, R 2 Each time it appears, it independently represents the hydroxyl group and C. 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, C 3-4 cycloalkyl, -OR 11 A 3-5 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl group and heterocyclic group is separated by q R 12 Replacement; or two adjacent Rs 2 Together with the atoms to which they are attached, they form 3-6 membered rings having 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 C is represented independently each time it appears. 1-3 Alkyl, Halogenated, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyl alkyl or cyano.

[0086] In some implementations, R 2 C is represented independently each time it appears. 1-3 Alkyl group. In some embodiments, R 2 The halogen group is represented independently each time it appears. In some implementations, R 2 C is represented independently each time it appears. 1-3 Alkyl group. In some embodiments, R 2 C is represented independently each time it appears. 1-3 Halogenated alkyl groups. In some embodiments, R 2 C is represented independently each time it appears. 1-3 Hydroxyalkyl. In some embodiments, R 2 Each occurrence independently represents being represented by q R's. 12 The substituted 3- to 5-membered heterocyclic group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 It was q R 12 Replacement C 3-4 Cycloalkyl. In some embodiments, R 2 Represent -OR independently each time it appears. 11 In some implementations, R 2 Each occurrence independently represents being represented by q R's.12 The substituted heterocyclic group is a 7-12 membered bridging or spirocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 It is cyano. In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is a hydroxyl group. In some embodiments, R 2 Each occurrence of the R group independently represents either methyl or cyclopropyl. In some embodiments, or two adjacent R groups, the R group is used to represent either methyl or cyclopropyl. 2 Together with the atoms to which they are attached, they form 3- to 6-membered rings with 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some implementations, R 2 C is represented independently each time it appears. 1-3 Alkyl, C 1-3 Haloalkyl, -O-(C 1-4 (halogenated alkyl) or C 3-4 Cycloalkyl. In some embodiments, R 2 Each time it appears, it independently represents methyl, cyclopropyl, O-cyclopropyl, -CHF2, -CF3 or -O-CF3.

[0088] In some implementations, p is 3 and at least one R 2 It is C 1-3 Halogenated alkyl group. In some embodiments, p is 3 and at least two R groups are present. 2 It is C 1-3 Halogenated alkyl group. In some embodiments, p is 3 and at least two R groups are present. 2 It is methyl. In some embodiments, p is 3 and at least one R 2 It is cyclopropyl. In some embodiments, p is 3 and there are at least two R groups. 2 It is cyclopropyl.

[0089] In some implementations, R 2 The groups are selected from the compounds described in Table 1 below.

[0090] As generally defined above, R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, (C 0-2 (alkylene)-C 1-6 Alkoxy, C 1-3 Hydroxyalkyl, -CON(R) 4 )2、-C(O)-R 5 -C(O)-OR 5 -S(O)2-R5 -N(R) 4 )-C(O)-R 5 -S(NR) 4 (O)-R 5 Or C 1-6 Halogenated alkoxy groups, C 3-4 Cycloalkyl groups, or 3-6 membered heterocyclic groups having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl group and heterocyclic group is divided by r R groups. 13 Replacement. In some implementations, R 3 The halogen group is represented independently each time it appears. In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl group. In some embodiments, R 3 C is represented independently each time it appears. 1-6 Halogenated alkyl groups. In some embodiments, R 3 Represented independently each time it appears (C) 0-2 (alkylene)-C 1-6 Alkyl group. In some embodiments, R 3 C is represented independently each time it appears. 1-3 Hydroxyalkyl. In some embodiments, R 3 Represent -CON(R) independently each time it appears. 4 2. In some implementations, R 3 -C(O)-R is represented independently each time it appears. 5 In some implementations, R 3 Represent -C(O)-OR independently each time it appears. 5 In some implementations, R 3 Represent -S(O)2-R independently each time it appears. 5 In some implementations, R 3 Represent -N(R) independently each time it appears. 4 )-C(O)-R 5 In some implementations, R 3 -S(NR) is represented independently each time it appears. 4 (O)-R 5 In some implementations, R 3 C is represented independently each time it appears. 1-6 Haloalkoxy. In some embodiments, R 3 Each occurrence independently represents being represented by r R. 13 Replacement C 3-4 Cycloalkyl. In some embodiments, R 3 Each occurrence independently represents being represented by r R. 13The substituted 3-6 membered heterocyclic group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 It is cyano. In some embodiments, R 3 It is a hydroxyl group. In some embodiments, R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl or C 1-6 Alkyl group. In some embodiments, R 3 The halogen group is represented independently each time it appears. In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl, -CON(R) 4 )2、-C(O)-R 5 or -C(O)-OR 5 In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl, -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 Or C 1-6 Haloalkoxy. In some embodiments, R 3 Each time it appears, it independently represents a halogenated group or a cyano group.

[0091] In some implementations, R 3 The groups are selected from the compounds described in Table 1 below.

[0092] As generally defined above, R 4 Each time it appears, it independently represents hydrogen and C. 1-4 Alkyl or cyclopropyl. In some embodiments, R 4 It is hydrogen. In some implementations, R 4 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 4 It is cyclopropyl. In some embodiments, R 4 The groups are selected from the compounds described in Table 1 below.

[0093] As generally defined above, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 cycloalkyl, -(C 0-2 alkylene)-phenyl, -(C 0-2 Alkylene)-(a 3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or -(C0-2 Alkylene group (5-10-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are separated by m R 8 Substitution, and wherein each alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl group. In some embodiments, R 5 and R 6 Each occurrence independently represents being represented by m R's. 8 Replacement C 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each occurrence of C is represented independently. 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 alkylene)-phenyl, wherein the phenyl group is m R 8 Substitution, and the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 (alkylene)-phenyl.

[0094] In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene)-(a 5-10 membered heteroaryl group having 1-3 independent heteroatoms selected from nitrogen, oxygen and sulfur), wherein the heteroaryl group is surrounded by m R 8 Substitution, and wherein the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (5-10 heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (a 3-6 membered monocyclic heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur), wherein the heterocyclic group is surrounded by m R atoms. 8 Substitution, and wherein the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0095] In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, phenyl, heterocyclic and heteroaryl group is surrounded by m R 8 Replacement. In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl or C 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each represents a methyl group independently. In some embodiments, R 5 and R 6 The groups are selected from the compounds described in Table 1 below.

[0096] As generally defined above, R 7 It is hydrogen, or two R atoms attached to the same nitrogen atom. 7 The groups, together with the nitrogen atom to which they are attached, form a 3-6 membered saturated monocyclic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the nitrogen atom. In some embodiments, R 7 It is hydrogen. In some embodiments, two R atoms attached to the same nitrogen atom... 7 The groups, together with the nitrogen atom to which they are attached, form a 3-6 membered saturated monocyclic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the nitrogen atom. In some embodiments, R 7 The groups are selected from the compounds described in Table 1 below.

[0097] As generally defined above, R 8 C is represented independently each time it appears. 1-4 Alkyl, Halogenated, C 1-3 Halogenated alkyl, hydroxyl, C 1-4 Alkyl, cyano, or cyclopropyl. In some embodiments, R 8 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 8The halogen group is represented independently each time it appears. In some implementations, R 8 C is represented independently each time it appears. 1-3 Halogenated alkyl groups. In some embodiments, R 8 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 8 It is cyano. In some embodiments, R 8 It is a hydroxyl group. In some embodiments, R 8 It is cyclopropyl. In some embodiments, R 8 The groups are selected from the compounds described in Table 1 below.

[0098] As generally defined above, R 9 Each time it appears, it independently represents hydrogen and C. 1-3 Alkyl or cyclopropyl. In some embodiments, R 9 It is hydrogen. In some implementations, R 9 C is represented independently each time it appears. 1-3 Alkyl group. In some embodiments, R 9 It is cyclopropyl. In some embodiments, R 9 The groups are selected from the compounds described in Table 1 below.

[0099] As generally defined above, R 10 It is C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, hydroxyl, or cyclopropyl. In some embodiments, R 10 It is C 1-3 Alkyl group. In some embodiments, R 10 It is C 1-3 Halogenated alkyl groups. In some embodiments, R 10 It is a halogenated group. In some implementations, R 10 It is a hydroxyl group. In some embodiments, R 10 It is cyclopropyl. In some embodiments, R 10 It is methyl. In some embodiments, R 10 It is trifluoromethyl. In some embodiments, R 10 It is fluorine. In some implementations, R 10 The groups are selected from the compounds described in Table 1 below.

[0100] As generally defined above, R 11 It is C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyclopropyl, or 3- to 5-membered saturated heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 11It is C 1-4 Alkyl group. In some embodiments, R 11 It is C 1-4 Halogenated alkyl groups. In some embodiments, R 11 It is cyclopropyl. In some embodiments, R 11 It is a 3- to 5-membered saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 11 It is methyl. In some embodiments, R 11 It is trifluoromethyl. In some embodiments, R 11 It is an oxetane-butyl group. In some embodiments, R 11 The groups are selected from the compounds described in Table 1 below.

[0101] As generally defined above, R 12 It is C 1-3 Alkyl, halogroup, cyano, or -SO2-(C 1-3 Alkyl). In some embodiments, R 12 It is a halogenated group. In some implementations, R 12 It is C 1-3 Alkyl group. In some embodiments, R 12 It is cyano. In some embodiments, R 12 It is -SO2-(C 1-3 Alkyl). In some embodiments, R 12 The groups are selected from the compounds described in Table 1 below.

[0102] As generally defined above, R 13 It is a halogenated group, C 1-3 Alkyl or C 1-3 Alkyl group. In some embodiments, R 13 It is a halogenated group. In some implementations, R 13 It is C 1-3 Alkyl group. In some embodiments, R 13 It is C 1-3 Alkyl group. In some embodiments, R 13 The groups are selected from the compounds described in Table 1 below.

[0103] As generally defined above, h is 0, 1, or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0104] As generally defined above, j is 0, 1, or 2. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, j is 2. In some embodiments, j is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0105] As generally defined above, k is 1 or 2. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0106] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0107] As generally defined above, n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0108] As generally defined above, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0109] As generally defined above, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0110] As generally defined above, r is 0, 1, or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0111] In some embodiments, the compound of formula I is further defined by formula IA or a pharmaceutically acceptable salt thereof: IA.

[0112] In some embodiments, the compound of formula I is further defined by formula IB, IC, or ID or a pharmaceutically acceptable salt thereof:

[0113] In some embodiments, the compound of formula I is further defined by formula IE or a pharmaceutically acceptable salt thereof: IE.

[0114] In some embodiments, the compound of formula I is further defined by formula IF or a pharmaceutically acceptable salt thereof: IF.

[0115] In some embodiments, the compound of formula I is further defined by formula IG, IH, IJ, IK, or IL or a pharmaceutically acceptable salt thereof:

[0116] In some embodiments, the compound of formula I is further defined by formula IM, IN, IO, IP, or IQ or a pharmaceutically acceptable salt thereof:

[0117] In some embodiments, compounds of formula I are further defined by formula IR, IS, IT, or IU, or pharmaceutically acceptable salts thereof:

[0118] In some embodiments, the compound of formula I is further defined by formula IV or a pharmaceutically acceptable salt thereof:

[0119] In some embodiments, the compound of formula I is further defined by formula IW or a pharmaceutically acceptable salt thereof:

[0120] In some embodiments, the compound of formula I is further defined by formula IX or a pharmaceutically acceptable salt thereof:

[0121] In some embodiments, the compound of formula I is further defined by formula IY or a pharmaceutically acceptable salt thereof:

[0122] In some embodiments, the compound of formula I is further defined by formula IZ or a pharmaceutically acceptable salt thereof: I.2 Pyridyloxypyridine compounds of formula (II)

[0123] One aspect of the present invention provides pyridyloxypyridine compounds. These compounds can be used in the pharmaceutical compositions and treatment methods described herein. Exemplary compounds and exemplary procedures for preparing these compounds are described in the following sections. One aspect of the present invention provides compounds represented by Formula II: (II) Or its pharmaceutically acceptable salt, wherein: Ring A 1 It is (i) a 6-membered heteroarylene having one or two heteroatoms selected from nitrogen or (ii) a phenylene; Ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic partially aromatic group containing 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 Replacement; or ring B 1 It is k R 3 Substituted phenyl; Ring C 1 It is a phenylene group or a 5- or 6-membered heteroarylene group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur; R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -SO2-N(R) 7 )2、-S(NR 9 (O)-R 6 or -S(O2)-R 6 ; R 2 Each time it appears, it independently represents the hydroxyl group and C. 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, cyclopropyl, -OR 11 Or a 3- to 5-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R atoms appearing in the adjacent position. 2 Together with the atoms to which they are attached, they form 3-6 membered rings with 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur; R 3Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Alkyl groups, -CON(R) 4 )2、-C(O)-R 5 -C(O)-OR 5 -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 -S(NR) 4 (O)-R 5 Or C 1-6 Halogenated alkoxy groups; R 4 Each time it appears, it independently represents hydrogen and C. 1-4 Alkyl or cyclopropyl; R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 cycloalkyl, -(C 0-2 alkylene)-phenyl, -(C 0-2 Alkylene)-(a 3-5 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or -(C 0-2 Alkylene group (5-10-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are separated by m R 8 Substitution, and wherein each alkylene group is replaced by n R groups. 8 replace; R 7 It is hydrogen, or two R atoms attached to the same nitrogen atom. 7 The groups, together with the nitrogen to which they are attached, form 3-6 membered saturated monocycles having 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 8 C is represented independently each time it appears. 1-4 Alkyl, Halogenated, C 1-3 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, cyano, or cyclopropyl; R 9 It is hydrogen, C 1-3 Alkyl or cyclopropyl; R 10 It is C 1-3 Alkyl, C 1-3 Haloalkyl, halogroup or cyclopropyl; R 11 It is C 1-4 Alkyl, C 1-4Halogenated alkyl, cyclopropyl, or 3- to 5-membered saturated heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; h is 0, 1, or 2; j is 0, 1, or 2; k is 1 or 2; m is 0, 1, or 2; n is 0, 1, 2, or 3; and p is 1, 2, 3 or 4.

[0124] The definition of the variable in Formula II above covers multiple chemical groups. This application contemplates embodiments in which, for example, i) the variable is defined as a single chemical group selected from those chemical groups, ii) the variable is defined as a set of two or more chemical groups selected from those chemical groups, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0125] In some embodiments, the compound is a compound of formula II.

[0126] As generally defined above, ring A 1 It is (i) a 6-membered heteroarylene having one or two heteroatoms selected from nitrogen, or (ii) a phenylene. In some embodiments, cycloatom A... 1 It is a phenylene oxide. In some embodiments, cyclic A 1 It is a 6-membered monocyclic heteroaromatic ring containing one or two heteroatoms selected from nitrogen. In some embodiments, ring A... 1 It is pyridyl or pyrimidinyl. In some embodiments, ring A 1 It is a pyridyl group. In some embodiments, ring A... 1 It is a pyrimidine group. In some embodiments, cyclic A... 1 The groups are selected from the compounds described in Table 1 below.

[0127] As roughly defined above, ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic partially aromatic group containing 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 Replacement; or ring B 1 It is a phenyl group that has been substituted with k R atoms.

[0128] In some implementations, ring B1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is separated by j R 3 Replacement; or ring B 1 It is k R 3 Substituted phenylene.

[0129] In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is separated by j R 3 Replacement. In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-12 membered bridging heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0130] In some implementations, ring B 1 It was by j R 3 The substituted group is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It was by j R 3 The substituted 5-6 membered monocyclic heteroaryl group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It was by j R 3 The substituted heterocyclic group is a 7-12 bridging heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0131] In some implementations, ring B 1 It was by j R 3 The substituted 3-7 membered monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0132] In some implementations, ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B... 1It is a 7-12 bridging heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0133] In some implementations, ring B 1 It was by j R 3 The substituted heterocyclic group is a 7-12 bridging or spirocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0134] In some implementations, ring B 1 It was by j R 3 Substituted 9-10 membered bicyclic aromatics containing 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0135] In some implementations, ring B 1 It is k R 3 Substituted phenyl groups. In some embodiments, cyclic B... 1 It is a phenylene oxide.

[0136] In some implementations, ring B 1 It is pyridinyl, pyrazolyl, imidazolyl, piperazinyl, 2,5,-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl or azacyclobutyl, wherein each ring is divided by j R 3 Replacement. In some implementations, ring B 1 It was by j R 3 Substituted pyridinyl group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted pyrazol group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted imidazole group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted piperazine group. In some embodiments, cyclic B... 1 It was by j R 3 Substituted 2,5,-diazabicyclo[2.2.1]heptyl. In some embodiments, ring B... 1 It was by j R 3 Substituted 3,6-diazabicyclo[3.1.1]heptyl. In some embodiments, ring B... 1 It was by j R 3 Substituted 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl. In some embodiments, cyclic B... 1 It was by j R 3Substituted 2,6-diazaspiro[3,4]octyl. In some embodiments, cyclic B 1 It was by j R 3 Substituted 2,6-diazaspiro[3.3]heptyl. In some embodiments, cyclic B... 1 It was by j R 3 Substituted nitrogen-containing heterocyclic butyl groups.

[0137] In some implementations, ring B 1 The groups are selected from the compounds described in Table 1 below.

[0138] As generally defined above, ring C 1 It is a phenylene group or a 5- or 6-membered heteroarylene group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a phenylene oxide. In some embodiments, the cyclic C 1 It is a 5- or 6-membered heteroarylene containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a 5-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen. In some embodiments, the cyclic C 1 It is phenylene or pyridylene. In some embodiments, the cyclic C 1 It is a pyridyl group. In some embodiments, the cyclic C 1 It is a pyridyl group. In some embodiments, the cyclic C 1 The groups are selected from the compounds described in Table 1 below.

[0139] As generally defined above, R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -SO2-N(R) 7 )2、-S(NR 9 (O)-R 6 or -S(O2)-R 6 In some implementations, R 1 It is -N(R) 9 )-SO2-R 6 -SO2-N(R) 9 )-R 6 -S(NR) 9 (O)-R 6 or -S(O2)-R6 In some implementations, R 1 It is -N(R) 9 )-SO2-R 6 In some implementations, R 1 It is -SO2-N(R) 9 )-R 6 In some implementations, R 1 It is -SO2-N(R) 7 2. In some implementations, R 1 It is -S(NR) 9 (O)-R 6 In some implementations, R 1 It is -S(O2)-R 6 In some implementations, R 1 It is -NH-SO2-CH3. In some implementations, R 1 The groups are selected from the compounds described in Table 1 below.

[0140] As generally defined above, R 2 Each time it appears, it independently represents the hydroxyl group and C. 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, cyclopropyl, -OR 11 Or a 3- to 5-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R atoms appearing in the adjacent position. 2 Together with the atoms to which they are attached, they form 3-6 membered rings having 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 C is represented independently each time it appears. 1-3 Alkyl, Halogenated, C 1-4 Alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyl alkyl or cyano.

[0141] In some implementations, R 2 C is represented independently each time it appears. 1-3 Alkyl group. In some embodiments, R 2 The halogen group is represented independently each time it appears. In some implementations, R 2 C is represented independently each time it appears. 1-3 Alkyl group. In some embodiments, R 2 C is represented independently each time it appears. 1-3 Halogenated alkyl groups. In some embodiments, R 2 C is represented independently each time it appears. 1-3Hydroxyalkyl. In some embodiments, R 2 Each occurrence independently represents a 3-5 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 It is cyclopropyl. In some embodiments, R 2 Represent -OR independently each time it appears. 11 In some implementations, R 2 It is cyano. In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is a hydroxyl group. In some embodiments, R 2 Each occurrence of the R group independently represents either methyl or cyclopropyl. In some embodiments, or two adjacent R groups, the R group is used to represent either methyl or cyclopropyl. 2 Together with the atoms to which they are attached, they form 3-6 membered rings having 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 The groups are selected from the compounds described in Table 1 below.

[0142] As generally defined above, R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Alkyl groups, -CON(R) 4 )2、-C(O)-R 5 -C(O)-OR 5 -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 -S(NR) 4 (O)-R 5 Or C 1-6 Haloalkoxy. In some embodiments, R 3 The halogen group is represented independently each time it appears. In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl group. In some embodiments, R 3 C is represented independently each time it appears. 1-6 Halogenated alkyl groups. In some embodiments, R 3 C is represented independently each time it appears. 1-6 Alkyl group. In some embodiments, R 3 Represent -CON(R) independently each time it appears. 4 2. In some implementations, R 3 -C(O)-R is represented independently each time it appears. 5In some implementations, R 3 Represent -C(O)-OR independently each time it appears. 5 In some implementations, R 3 Represent -S(O)2-R independently each time it appears. 5 In some implementations, R 3 Represent -N(R) independently each time it appears. 4 )-C(O)-R 5 In some implementations, R 3 -S(NR) is represented independently each time it appears. 4 (O)-R 5 In some implementations, R 3 C is represented independently each time it appears. 1-6 Haloalkoxy. In some embodiments, R 3 It is cyano. In some embodiments, R 3 It is a hydroxyl group. In some embodiments, R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl or C 1-6 Alkyl group. In some embodiments, R 3 The halogen group is represented independently each time it appears. In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl, -CON(R) 4 )2、-C(O)-R 5 or -C(O)-OR 5 In some implementations, R 3 C is represented independently each time it appears. 1-6 Alkyl, -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 Or C 1-6 Halogenated alkoxy groups.

[0143] In some implementations, R 3 The groups are selected from the compounds described in Table 1 below.

[0144] As generally defined above, R 4 Each time it appears, it independently represents hydrogen and C. 1-4 Alkyl or cyclopropyl. In some embodiments, R 4 It is hydrogen. In some implementations, R 4 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 4It represents cyclopropyl independently each time it appears. In some embodiments, R 4 The groups are selected from the compounds described in Table 1 below.

[0145] As generally defined above, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 cycloalkyl, -(C 0-2 alkylene)-phenyl, -(C 0-2 Alkylene)-(a 3-5 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or -(C 0-2 Alkylene group (5-10-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are separated by m R 8 Substitution, and wherein each alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl group. In some embodiments, R 5 and R 6 Each occurrence independently represents being represented by m R's. 8 Replacement C 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each occurrence of C is represented independently. 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 alkylene)-phenyl, wherein the phenyl group is m R 8 Substitution, and the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 (alkylene)-phenyl.

[0146] In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene)-(a 5-10 membered heteroaryl group having 1-3 independent heteroatoms selected from nitrogen, oxygen and sulfur), wherein the heteroaryl group is surrounded by m R 8 Substitution, and wherein the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (5-10 heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (3-5 membered monocyclic heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur), wherein the heterocyclic group is surrounded by m R atoms. 8 Substitution, and wherein the alkylene group is replaced by n R groups. 8 Replacement. In some implementations, R 5 and R 6 Each occurrence is represented independently as -(C) 0-2 Alkylene group (3-5 membered monocyclic heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur).

[0147] In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl, 3-5 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, phenyl, heterocyclic and heteroaryl group is surrounded by m R 8 Replacement. In some implementations, R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl or C 3-5 Cycloalkyl. In some embodiments, R 5 and R 6 Each represents a methyl group independently. In some embodiments, R 5 and R 6 The groups are selected from the compounds described in Table 1 below.

[0148] As generally defined above, R 7 It is hydrogen, or two R atoms attached to the same nitrogen atom. 7 The groups, together with the nitrogen atoms to which they are attached, form a 3-6 membered saturated monocyclic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 It is hydrogen. In some embodiments, two R atoms attached to the same nitrogen atom... 7 The groups, together with the nitrogen atoms to which they are attached, form a 3-6 membered saturated monocyclic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7The groups are selected from the compounds described in Table 1 below.

[0149] As generally defined above, R 8 C is represented independently each time it appears. 1-4 Alkyl, Halogenated, C 1-3 Halogenated alkyl, hydroxyl, C 1-4 Alkyl, cyano, or cyclopropyl. In some embodiments, R 8 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 8 The halogen group is represented independently each time it appears. In some implementations, R 8 C is represented independently each time it appears. 1-3 Halogenated alkyl groups. In some embodiments, R 8 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 8 It is cyano. In some embodiments, R 8 It is a hydroxyl group. In some embodiments, R 8 It is cyclopropyl. In some embodiments, R 8 The groups are selected from the compounds described in Table 1 below.

[0150] As generally defined above, R 9 It is hydrogen, C 1-3 Alkyl or cyclopropyl. In some embodiments, R 9 It is hydrogen. In some implementations, R 9 It is C 1-3 Alkyl group. In some embodiments, R 9 It is cyclopropyl. In some embodiments, R 9 The groups are selected from the compounds described in Table 1 below.

[0151] As generally defined above, R 10 It is C 1-3 Alkyl, C 1-3 Halogenated alkyl, halogenated, or cyclopropyl. In some embodiments, R 10 It is C 1-3 Alkyl group. In some embodiments, R 10 It is C 1-3 Halogenated alkyl groups. In some embodiments, R 10 It is a halogenated group. In some implementations, R 10 It is cyclopropyl. In some embodiments, R 10 It is methyl. In some embodiments, R 10 It is trifluoromethyl. In some embodiments, R 10 It is fluorine. In some implementations, R10 The groups are selected from the compounds described in Table 1 below.

[0152] As generally defined above, R 11 It is C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyclopropyl, or 3- to 5-membered saturated heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 11 It is C 1-4 Alkyl group. In some embodiments, R 11 It is C 1-4 Halogenated alkyl groups. In some embodiments, R 11 It is cyclopropyl. In some embodiments, R 11 It is a 3- to 5-membered saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 11 It is methyl. In some embodiments, R 11 It is trifluoromethyl. In some embodiments, R 11 It is an oxetane-butyl group. In some embodiments, R 11 The groups are selected from the compounds described in Table 1 below.

[0153] As generally defined above, h is 0, 1, or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0154] As generally defined above, j is 0, 1, or 2. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, j is 2. In some embodiments, j is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0155] As generally defined above, k is 1 or 2. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0156] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0157] As generally defined above, n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0158] As generally defined above, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is selected from the corresponding values ​​represented by the compounds in Table 1 below.

[0159] In some embodiments, the compound of formula II is further defined by formula II-A or a pharmaceutically acceptable salt thereof: II-A.

[0160] In some embodiments, the compound of formula II is further defined as a pharmaceutically acceptable salt of formula II-B, II-C, or II-D:

[0161] In some embodiments, the compound of formula II is further defined by formula II-E or a pharmaceutically acceptable salt thereof: II-E.

[0162] In some embodiments, the compounds of formula II are further defined by formula II-F or pharmaceutically acceptable salts thereof: II-F.

[0163] In some embodiments, the compounds of formula II are further defined as those of formula II-G, II-H, II-J, II-K, or II-L, or pharmaceutically acceptable salts thereof:

[0164] In some embodiments, the compounds of formula II are further defined as those of formula II-M, II-N, II-O, II-P, or II-Q, or pharmaceutically acceptable salts thereof:

[0165] In some embodiments, the compound of formula II is further defined as a product of formula II-R, II-S, II-T, or II-U, or a pharmaceutically acceptable salt thereof:

[0166] In some embodiments, the compound of formula II is further defined by formula II-V or a pharmaceutically acceptable salt thereof: Exemplary specific compounds

[0167] In some embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is selected from compounds I-1 to I-132 in Table 1 or pharmaceutically acceptable salts thereof. Table 1. Exemplary Compounds

[0169] In some 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 mediator, said compound or pharmaceutical composition being used as a pharmaceutical agent.

[0170] In some embodiments, the present invention provides pharmaceutical compositions comprising the compounds shown in Table 1 above or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or diluents. II. Therapeutic applications

[0171] In some embodiments, the present invention provides a method for treating a disorder that has clinical benefit in enhancing ABC transporter function. For example, in some embodiments, the disorder is one in which ABC transporter dysfunction is a cause of disease. In some embodiments, correction of one or more potential mutations associated with ABC transporter dysfunction is rationalized. In some embodiments, the method of the present invention provides enhancement of one or more non-mutant forms of the ABC transporter.

[0172] In some embodiments, the present invention provides a method for treating a clinically beneficial impairment of ABC transporter function, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound described herein (such as a compound of formula I or II) to treat the clinically beneficial impairment of ABC transporter function. In some embodiments, the specific compound of formula I or II is a compound defined in one of the embodiments described in Section I of the preceding document.

[0173] In some embodiments, the present invention provides a method for treating a disorder associated with ABC transporter dysfunction, wherein the method comprises administering a therapeutically effective amount of a compound described herein (such as a compound of formula I or II) to a subject in need to treat the disorder associated with ABC transporter dysfunction. In some embodiments, the specific compound of formula I or II is a compound defined in one of the embodiments described in Section I above.

[0174] In some embodiments, the present invention provides a method for modulating the function of ABC transporters in a subject, the method comprising administering to the subject an effective amount of a compound of formula I or II, thereby modulating the function of ABC transporters in the subject. In some embodiments, the ABC transporters are selected from one or more of the following: ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0175] Another aspect of the present invention provides a method for increasing the expression of proteins selected from ABCB11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, and ABCD2 in a subject. This method comprises administering an effective amount of a compound described herein (such as a compound of formula I or II) to a subject in need, thereby increasing the expression of said protein, as further described in the detailed embodiments.

[0176] In some embodiments, the present invention provides a method for alleviating one or more symptoms of a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound described herein (such as a compound of formula I or II) to treat the disorder associated with ABC transporter dysfunction. In some embodiments, the specific compound of formula I or II is a compound defined in one of the embodiments described in Section I above.

[0177] In some implementations, the impairment associated with ABC transporter dysfunction is characterized by dysfunction of one or more transporters selected from the following: 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.

[0178] In some embodiments, the present invention provides a method for treating disorders selected from the following: Tangier disease, pulmonary surfactant metabolic dysfunction type 3, autosomal recessive congenital ichthyosis 4A (ARCI), naked lymphocyte syndrome type I, naked lymphocyte syndrome type I due to TAP2 deficiency, hereditary generalized pigmentary disorder type 3, X-linked sideroblastic anemia with ataxia, Durbin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis disorder type 5, methylmalonic aciduria and homocystinuria cblJ, sitosterolemia, Staggart disease, PFIC3, PFIC2, pseudoxanthoma elastica, X-linked adrenoleukodystrophy (ALD), cholestasis, high... Hyperbilirubinemia, intrahepatic cholestasis of pregnancy, biliary atresia, Aragerhee syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hill's-Sprolon disease, brain-hepatorenal syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile generalized arterial calcification, calcification defense, autosomal recessive cone-rod dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, hypophospholipid-associated cholelithiasis, intrahepatic microlithiasis, intrahepatic bile duct stones, non-anastomotic biliary stricture, benign recurrent intrahepatic cholestasis, vascular calcification, vascular calcification associated with CKD, vascular calcification associated with T2D, and calcified uremic arteriopathy.

[0179] In some embodiments, the present invention provides methods for treating or preventing disorders selected from: Tangier disease, pulmonary surfactant metabolic dysfunction type 3, autosomal recessive congenital ichthyosis 4A (ARCI), naked lymphocyte syndrome type I, naked lymphocyte syndrome type I due to TAP2 deficiency, hereditary generalized pigmentary disorder type 3, X-linked sideroblastic anemia with ataxia, Durbin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis disorder type 5, methylmalonic aciduria and homocystinuria cblJ, sitosterolemia, Staggart disease, PFIC3. PFIC2, pseudoxanthoma elastica, X-linked adrenoleukodystrophy (ALD), cholestasis, hyperbilirubinemia, intrahepatic cholestasis of pregnancy, biliary atresia, Arager's syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hill's-Sprolon disease, brain-hepatorenal syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile generalized arterial calcification, calcification defense, autosomal recessive cone-rod dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, and hypophospholipid-associated cholelithiasis.

[0180] In some embodiments, the present invention provides methods for treating or preventing disorders selected from: Tangier disease, pulmonary surfactant metabolic dysfunction type 3, autosomal recessive congenital ichthyosis 4A (ARCI), naked lymphocyte syndrome type I, naked lymphocyte syndrome type I due to TAP2 deficiency, hereditary generalized pigmentary disorder type 3, X-linked sideroblastic anemia with ataxia, Durbin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis disorder type 5, methylmalonic aciduria and homocystinuria cblJ, sitosterolemia, Staggart disease, PFIC3, PFIC2, pseudoxanthomas elastica, X-linked adrenoleukodystrophy Adverse events (ALD), cholestasis, hyperbilirubinemia, intrahepatic cholestasis of pregnancy, biliary atresia, Aragerhee syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hill's-Sprolon disease, brain-hepatorenal syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile generalized arterial calcification, calcification defense, autosomal recessive cone-rod dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, hypophospholipid-associated cholelithiasis, chronic kidney disease, progeria (Hargee-Gilles syndrome), hemodialysis, end-stage renal disease, aortic stenosis, peripheral artery disease, or ischemic stroke.

[0181] In some embodiments, the present invention provides a method for treating a disorder selected from the following: calcification defense, elastic pseudoxanthoma, infantile generalized arterial calcification, chronic kidney disease, progeria (Harge's progeria syndrome), hemodialysis, end-stage renal disease, aortic stenosis, peripheral artery disease, or ischemic stroke.

[0182] In some embodiments, the disorder associated with ABC transporter dysfunction is cystic fibrosis (CF). Therefore, in some embodiments, the present invention provides a method for treating cystic fibrosis, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound described herein, such as a compound of formula I or II. In some such embodiments, the method further comprises administering one or more additional therapeutic agents described below and further herein.

[0183] In some embodiments, the disorder associated with ABC transporter dysfunction is cholestasis. Therefore, in some embodiments, the present invention provides a method for treating cholestasis, wherein the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of formula I or II, to a subject in need. Those skilled in the medical field will recognize that various forms of cholestasis exist, all of which are covered herein within the therapeutic scope of the methods and compounds of the present invention. In some embodiments, the cholestasis is intrahepatic. In some embodiments, the cholestasis is extrahepatic. In some embodiments, the cholestasis is any of those described above and herein. Subjects

[0184] In some implementations, the subject is a person. In some implementations, the subject is an adult. In some implementations, the subject is a child. Medical use

[0185] Another aspect of the invention provides the use of the compounds described herein (such as compounds of Formula I or II, or other compounds in Section I) in the manufacture of pharmaceutical agents. In some embodiments, the pharmaceutical agents are used to treat disorders described herein, such as disorders associated with ABC transporter dysfunction. Exemplary such disorders have been described above and herein.

[0186] Another aspect of the invention provides the use of the compounds described herein (such as compounds of Formula I or II or other compounds in Section I) for the treatment of medical disorders, such as disorders associated with ABC transporter dysfunction. Exemplary such disorders have been described above and herein. III. Combination Therapy

[0187] Another aspect of the invention provides combination therapies. The compounds described herein (such as compounds of Formula I or II, or other compounds in Section I) or pharmaceutically acceptable salts thereof can be used in combination with additional therapeutic agents to treat medical disorders, such as autoimmune disorders, cancer, etc.

[0188] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, the method comprising administering to a patient in need an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, as described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the disclosed compound works synergistically in combination with one or more additional therapeutic agents.

[0189] One or more other therapeutic agents may be administered separately from the compounds or compositions of the present invention as part of a multiple-dosing regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered in a multiple-dosing regimen, one or more other therapeutic agents and the compounds or compositions of the present invention may be administered simultaneously, sequentially, or at intervals between each other over a period of time (e.g., intervals of 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). In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are administered in a multiple-dosing regimen at intervals greater than 24 hours.

[0190] In some embodiments, the present invention provides a method for treating cystic fibrosis (CF), the method comprising administering a compound of the present invention together with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, cystic fibrosis transmembrane conduction (CFTR) modulators, nutritional agents, or any agent known for treating CF.

[0191] In some embodiments, one or more additional therapeutic agents are antibiotics. In some embodiments, the antibiotic is selected from penicillin, cephalosporins, tetracyclines, macrolides, fluoroquinolones, sulfonamides, glycopeptides, or rifamycin. In some implementations, the antibiotic is selected from phenoxymethylpenicillin, dicloxacillin, amoxicillin-clavulanic acid, ampicillin, nafcillin, oxacillin, penicillin V, penicillin G, cefaclor, cefazolin, cefadroxil, cefalexin, cefuroxime, cefixime, cefoxitin, ceftriaxone sodium, doxycycline, minocycline, sarecycline, erythromycin, clarithromycin, azithromycin, fendamycin, roxithromycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, sulfamethoxazole-trimethoprim, sulfasalazine, sulfacetamide, silver sulfadiazine, vancomycin, dapavancin, orivancin, terabancin, and rifaximin.

[0192] In some embodiments, one or more additional therapeutic agents are S-nitrosoglutathione reductase (GSNOR) inhibitors. In some embodiments, the GSNOR inhibitor is selected from the GSNOR inhibitors disclosed in the following documents: WO2010 / 019903, U.S. Patent No. 8,470,857, U.S. Patent No. 8,642,628, WO2010 / 019910, U.S. Patent No. 8,586,624, WO2011 / 100433, U.S. Patent No. 8,481,590, WO2012 / 048181, WO2012 / 083165, WO2012 / 083171, or WO 2012 / 170371.

[0193] In some embodiments, one or more additional therapeutic agents are ileal bile transport (IBAT) inhibitors. In some embodiments, the IBAT inhibitor is selected from the IBAT inhibitors disclosed in the following literature: AU2011326873, US2020 / 0330545, WO2012 / 064266, WO2020 / 167964, or Front. Pharmacol. 2018; 9: 931 (Al-Dury et al., published online August 21, 2018). Exemplary IBAT inhibitors include, but are not limited to, odevixibat, elobixivat, maralixibat, linerixibat, GSK2330672, SHP626 (volixibat), A4250, etc.

[0194] In some embodiments, one or more additional therapeutic agents are ileal bile transport (IBAT) inhibitors. In some embodiments, the IBAT inhibitor is selected from the IBAT inhibitors disclosed in the following literature: AU2011326873, US2020 / 0330545, WO2012 / 064266, WO2020 / 167964, or Front. Pharmacol. 2018; 9: 931 (Al-Dury et al., published online August 21, 2018). Exemplary IBAT inhibitors include, but are not limited to, odexibare, elocitabine, macitabine, linecitabine, GSK2330672, SHP626 (voricitabine), A4250, etc. In some embodiments, one or more additional therapeutic agents are selected from odexibare, elocitabine, macitabine, linecitabine, GSK2330672, SHP626 (voricitabine), and A4250.

[0195] In some embodiments, one or more additional therapeutic agents are peroxisome proliferator-activated receptor (PPAR) agonists. In some embodiments, one or more additional therapeutic agents are dual PPAR agonists, PPAR-α agonists, PPAR-γ agonists, or PPAR-δ agonists. In some embodiments, one or more additional therapeutic agents are PPAR-α agonists. In some embodiments, one or more additional therapeutic agents are PPAR-γ agonists. In some embodiments, one or more additional therapeutic agents are PPAR-δ agonists. In some embodiments, the PPAR agonist is selected from elafibrinor, clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, GW-9662, GW501516, GFT1007, agliflozin, mogliflozin, ticaglipizide, salroglipizide, and sradpar.

[0196] In some embodiments, one or more additional therapeutic agents are HMG-CoA reductase inhibitors. In some embodiments, the HMG-CoA reductase inhibitor is a statin. In some embodiments, the statin is selected from atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0197] In some embodiments, one or more additional therapeutic agents are disease-modifying antirheumatic drugs (DMARDs). In some embodiments, the DMARD is selected from azathioprine, hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine.

[0198] In some embodiments, one or more additional therapeutic agents are DNA methyltransferase inhibitors. In some embodiments, the DNA methyltransferase inhibitor is selected from azacitidine, decitabine, zabraline, hydralazine, procaine, MG98, genistein, bobcat339 hydrochloride, hinokitiol, CM-272, and larsucosterol.

[0199] In some embodiments, one or more additional therapeutic agents are anti-interleukin-17A biologics. In some embodiments, the anti-interleukin-17A biologic is selected from secukinumab, ixekizumab, bisemegzizumab, budarumab, and nicarimab.

[0200] In some embodiments, one or more additional therapeutic agents are anti-interleukin-23 inhibitors. In some embodiments, the anti-interleukin-23 inhibitor is selected from glucocortizumab, resalizumab, tiregrinizumab, and ustekinumab.

[0201] In some embodiments, one or more additional therapeutic agents are neutrophil elastase inhibitors. In some embodiments, the neutrophil elastase inhibitor is selected from cevelexatol sodium, AvKTI, and flavonoids.

[0202] In some embodiments, one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is selected from fluoroprogesterone, fluorometholone, medroxyprogesterone acetate, prebediolone, chlorprednisolone, difluprednisolone, fludrocortisone, fluocinolone, flusperidone, fluprednisolone, chlorteprednisolone, methylprednisolone, prednicarbamate, prednisolone, prednisone, tecortisone, triamcinolone, and dexamethasone. 、 Aclomethasone, beclomethasone, betamethasone, clobetasol, clobetasol, clobetasol, clocotropin, deshydroxymethasone, dexamethasone, difluralasone, diflucolone, fluclosonide, flumethasone, flucodone, flucodone, fluprednisolone, fluticasone, fluticasone furoate, halometasone, methylprednisolone, mometasone, mometasone furoate, peramisone, prednisolone, limexolone, ubetasol, ancinonide, budesonide, ciclopidine, dextromethorphan, formococcal, fluclomethasone, flunisolone, fluocinolone acetonide, fluocinolone acetate, halcinonide, triamcinolone acetonide, cortivazole and RU-28362.

[0203] In some embodiments, one or more additional therapeutic agents are protein arginine deiminase 4 (PAD4) inhibitors. In some embodiments, the PAD4 inhibitor is selected from JBI-589, GSK484, Cl-amidine, azithromycin, clindamycin, leflunomide, and methotrexate.

[0204] In some embodiments, one or more additional therapeutic agents are apical sodium-dependent BA transporter (ASBT) inhibitors. In some embodiments, the ASBT inhibitor is A3907.

[0205] In some embodiments, one or more additional therapeutic agents are thyroid hormone receptor β (THR-β) agonists. In some embodiments, the THR-β agonist is selected from resmetirox, VK2809, and CS27109.

[0206] In some embodiments, one or more additional therapeutic agents are immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cimiprimab, ipilimumab, atezolizumab, avelumab, and durvalumab.

[0207] In some embodiments, one or more additional therapeutic agents are bile acid conjugates. In some embodiments, the bile acid conjugates are berberine ursodeoxycholate, ursodeoxycholate, and norursodeoxycholate.

[0208] In some embodiments, one or more additional therapeutic agents are integrin inhibitors. 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, natezumab, vedolzumab, PLN-1474, risuteganib, THR-687, OT-166, AXT107, tirofiban, eptifibatide, abciximab, MORF-057, 7HP349, efalizumab, and ristatin.

[0209] In some embodiments, one or more additional therapeutic agents are endocrine fibroblast growth factor (FGF) analogs. In some embodiments, the endocrine FGF analog is selected from FGF19, FGF21, and FGF23. In some embodiments, the endocrine FGF analog is odavmin.

[0210] In some embodiments, one or more additional therapeutic agents are monoclonal antibodies. In some embodiments, the monoclonal antibody targets CCL24, lysyl oxidase-like protein 2 (LOXL2), or vascular adhesion protein (VAP). In some embodiments, the monoclonal antibody is CM-101, simtuzumab, or BTT1023.

[0211] In some embodiments, one or more additional therapeutic agents are antagonists of MAS-associated GPR family member X4 (MRGPRX4). In some embodiments, the monoclonal antibody is EP547.

[0212] In some embodiments, one or more additional therapeutic agents are apical sodium-dependent bile acid transporter (ASBT) inhibitors. In some embodiments, the ASBT inhibitor is selected from resveratrol, icoxibate, A4250, 264W94, 216U90, GSK2330672, clomacibate, SC-435, S-1647, IMB17-15, baribixibat, S-8921, S-8921G, R-146224, BRL-39924A, S0960 volixibat, and ritivixibat.

[0213] In some embodiments, one or more additional therapeutic agents are farnesoid X receptor (FXR) agonists. In some embodiments, the FXR agonist is selected from OCA, CS0159, tropifexor, vonafexor, and cilofexor.

[0214] In some embodiments, one or more additional therapeutic agents are glucagon-like peptide-1 receptor agonists (GLP-1RAs). In some embodiments, the GLP-1RA is selected from dulaglutide, exenatide, liraglutide, liraglutide / degludec insulin, lixilamide / glargine insulin, smegglutide, and telpoxetine.

[0215] In some embodiments, one or more additional therapeutic agents are bile acids or analogues thereof. In some embodiments, the bile acids or analogues thereof are selected from ursodeoxycholic acid and 24-norursodeoxycholic acid.

[0216] In some embodiments, one or more additional therapeutic agents are dihydroorotate dehydrogenase inhibitors. In some embodiments, the dihydroorotate dehydrogenase inhibitor is selected from buquina sodium, ASLAN003, ML390, BAY2402234, PTC299, leflunomide, vidofludimus calcium, teriflunomide, and IMU-838.

[0217] In some implementations, one or more additional therapeutic agents are sodium thiosulfate.

[0218] In some embodiments, one or more additional therapeutic agents are calcium reducing agents. In some embodiments, one or more additional therapeutic agents are cinacalcet.

[0219] In some embodiments, one or more additional therapeutic agents are phosphorus reducing agents. In some embodiments, one or more additional therapeutic agents are sevelamer.

[0220] In some embodiments, one or more additional therapeutic agents are enzymes. In some embodiments, one or more additional therapeutic agents are recombinant human ENPP1 protein. In some embodiments, one or more additional therapeutic agents are INZ-701.

[0221] In some embodiments, one or more additional therapeutic agents are TNAP inhibitors. In some embodiments, the TNAP inhibitor is selected from MLS-0038949, levamisole, and DS-1211.

[0222] In some embodiments, one or more additional therapeutic agents are GLP1 agonists or dual GLP1 agonists. In some embodiments, the GLP1 agonist or dual GLP1 agonist is selected from exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), abiglutide (Tanzeum), dulaglutide (Trulicity), semaglutide (Ozempic, Rybelsus), and telpoglutide (Mounjaro).

[0223] In some embodiments, one or more additional therapeutic agents are SGLT2 inhibitors. In some embodiments, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, etoragliflozin, bexagliflozin, and soragliflozin.

[0224] In some embodiments, one or more additional therapeutic agents are anticoagulants. In some embodiments, the anticoagulant is selected from apixaban (Eliquis), dabigatran etexilate (Pradaxa), edoxaban (Lixiana), rivaroxaban (Xarelto), and warfarin (Coumadin).

[0225] In some embodiments, one or more additional therapeutic agents are statins. In some embodiments, the statin is selected from atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin, pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin calcium (Crestor), and simvastatin (Zocor).

[0226] In some embodiments, one or more additional therapeutic agents are angiotensin-converting enzyme inhibitors. In some embodiments, the angiotensin-converting enzyme inhibitor is selected from benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Zestril, Prinivil), moxipril (Univasc), perindopril (Coversyl), quinapril (Accupril), ramipril (Altace), and quindopril (Mavik).

[0227] In some embodiments, one or more additional therapeutic agents are renin-angiotensin inhibitors. In some embodiments, the renin-angiotensin inhibitor is selected from aliskiren, ciproskiren, deteskiren, etanerskiren, remiskiren, rasilez, traskiren, and zanjiren.

[0228] In some embodiments, one or more additional therapeutic agents are aldosterone inhibitors. In some embodiments, the aldosterone inhibitor is selected from systemic spironolactone, systemic eplerenone, and systemic fenelinone. Other considerations

[0229] The dosage and dosing regimen of the active ingredient used in combination therapy can be determined by the attending physician. In some embodiments, the compounds described herein (such as compounds of Formula I or II or other compounds in Section I) and one or more additional therapeutic agents are administered at the dosage commonly used when such agents are used as a monotherapy to treat the disorder. In other embodiments, the compounds described herein (such as compounds of Formula I or II or other compounds in Section I) and one or more additional therapeutic agents are administered at a lower dosage than commonly used when such agents are used as a monotherapy to treat the disorder. In some embodiments, the compounds described herein (such as compounds of Formula I or II or other compounds in Section I) and one or more additional therapeutic agents are present in the same composition suitable for oral administration.

[0230] In some embodiments, the compounds described herein (such as compounds of Formula I or II, or other compounds in Section I) and one or more additional therapeutic agents may act additively or synergistically. Synergistic combinations may allow for lower doses and / or lower frequencies of administration of one or more agents in a combination therapy. Lower doses or lower frequencies of administration of one or more agents may reduce therapeutic toxicity without diminishing therapeutic efficacy.

[0231] Another aspect of the invention is a kit comprising a therapeutically effective amount of the compound described herein (such as a compound of formula I or II or other compounds in section I), a pharmaceutically acceptable carrier, medium or diluent, and optionally at least one of the additional therapeutic agents listed above. IV. Pharmaceutical Composition and Dosage Considerations

[0232] As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above compounds formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. Pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, for example, enemas (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those for buccal, sublingual and systemic absorption), pills, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, as a sterile solution or suspension or sustained-release formulation administered via subcutaneous, intramuscular, intravenous or epidural injection; (3) topical application, for example, as a cream, ointment or controlled-release patch or spray applied to the skin; (4) intravaginal or rectal administration, for example, as a vaginal suppository, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (such as a compound of formula I or II or other compounds in section I) and a pharmaceutically acceptable carrier.

[0233] As used herein, the phrase "therapeutic effective amount" means an amount of compound, material, or composition comprising the compounds of the present invention that, in order to provide a reasonable benefit / risk ratio for any medical treatment, effectively produces a desired therapeutic effect in at least a subpopulation of cells in animals.

[0234] The phrase “pharmaceutically acceptable” in this document refers to compounds, materials, compositions, and / or dosage forms that, to a reasonable extent medical judgment, are suitable for use in contact with human or animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0235] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may also be present in the composition.

[0236] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0237] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can be conveniently presented in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount will range from about 0.1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0238] In some embodiments, the formulations of the present invention comprise excipients selected from cyclodextrins, cellulose, liposomes, micelle forming agents (e.g., bile acids) and polymeric carriers (e.g., polyesters and polyanhydrides); and the compounds of the present invention. In some embodiments, the aforementioned formulations impart oral bioavailability to the compounds of the present invention.

[0239] Methods for preparing these formulations or compositions include the step of combining the compounds of the present invention with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and adequately combining the compounds of the present invention with a liquid carrier or a fine solid carrier, or both, and then (if necessary) shaping the product.

[0240] Formulations of the present invention suitable for oral administration may be in the following forms: capsules, flat capsules, pills, tablets, lozenges (using a flavoring base, typically sucrose and gum arabic or astragalus gum), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as soft lozenges (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as large pills, granules, or pastes.

[0241] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, tablets, etc.) of the present invention for oral administration, 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 starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; (5) solution blockers, 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 cetyl alcohol, glyceryl monostearate and nonionic surfactants; (8) (9) Absorbents, such as kaolin and bentonite; (10) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (11) Colorants; and (12) Controlled-release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0242] Tablets can be prepared by compression or molding (optionally with one or more excipients). Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0243] The pharmaceutical compositions of the present invention in tablet and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) may optionally be scored or prepared to have a coating and shell, such as enteric coating and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile, to provide sustained or controlled release of the active ingredient therein. They may be formulated for rapid release, for example, lyophilization. They may be sterilized, for example, by filtration via a bacterial trapping filter or by incorporation with a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium just before use. These compositions may also optionally contain a light-blocking agent and may have a composition that releases one or more active ingredients only or preferably in a portion of the gastrointestinal tract, optionally in a delayed manner. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in a microencapsulated form, if appropriate, microencapsulated together with one or more of the excipients described above.

[0244] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof.

[0245] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0246] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum and mixtures thereof.

[0247] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, and the suppositories are solid at room temperature but liquid at body temperature, thus melting and releasing the active compounds in the rectum or vaginal cavity.

[0248] The formulations of the present invention suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing suitable carriers known in the art.

[0249] Dosage forms for topical or transdermal application of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds can be mixed under sterile conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0250] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0251] In addition to the compounds of this invention, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may additionally contain custom propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0252] Transdermal patches offer the additional advantage of controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0253] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also considered to be within the scope of this invention.

[0254] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, which may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0255] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0256] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action on the subject compound can be ensured by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It is also desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0257] In some cases, to prolong the action of a drug, it may be desirable to slow down the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily medium.

[0258] Injectable depot formulations are prepared by forming microcapsule matrices of the subject compound within a biodegradable polymer, such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot-type injectable formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0259] When the compounds of the present invention are administered as drugs to humans and animals, they may be administered either on their own or as a pharmaceutical composition containing, for example, 0.1% to 99% (more preferably 10% to 30%) of an active ingredient in combination with a pharmaceutically acceptable carrier.

[0260] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. Of course, the formulations are administered in a form suitable for each route of administration. For example, they can be administered in tablet or capsule form, by injection, inhalation, eye wash, ointment, suppository, etc.; by injection, infusion, or inhalation; by topical application as a wash or ointment; and by rectal suppository. Oral administration is preferred.

[0261] As used in this article, the phrases “parenteral administration” and “extraterrestrial administration” refer to administration methods other than intravenous and local administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-sacral, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0262] As used herein, the phrases “systemic administration,” “systemic application,” “peripheral application,” and “peripheral application” refer to the administration of a compound, drug, or other material other than direct entry into the central nervous system, such that the compound, drug, or other material enters the patient’s system and thus undergoes metabolism and other similar processes, such as subcutaneous administration.

[0263] These compounds can be administered to humans and other animals for therapeutic purposes via any suitable route of administration, including oral, nasal (e.g., via spray), rectal, vaginal, parenteral, intracerebrospinal, and topical (e.g., via powder, ointment, or drops, including buccal and sublingual).

[0264] Regardless of the chosen route of administration, 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 using conventional methods known to those skilled in the art.

[0265] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a specific patient, composition and administration method without being toxic to the patient.

[0266] The selected dosage level will depend on a variety of factors, including the activity of the specific compound of the invention or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

[0267] A physician or veterinarian with ordinary skills in the art can readily determine and specify the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound of the invention used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0268] Generally, the appropriate daily dose of the compounds of the present invention will be the minimum dose at which the compounds effectively produce a therapeutic effect. This effective dose will typically depend on the factors described above. Preferably, the compounds are administered at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as a sensitizer), the effective amount may be less than the amount used when the agent is used alone.

[0269] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-dose administered at appropriate intervals throughout the day, optionally in unit dosage form. Preferred administration is once daily.

[0270] The present invention further provides a unit dosage form (such as a tablet or capsule) for treating the medical disorders described herein, said unit dosage form comprising a therapeutically effective amount of the compounds described herein. Example

[0271] The present invention, which is generally described, will be more readily understood by referring to the following embodiments, which are for illustrative purposes only and are not intended to limit the invention. Synthesis method

[0272] The methods for preparing the compounds described herein are shown in the following synthetic schemes. These schemes are given for illustrative purposes and are not intended to limit the scope or spirit of the invention. The starting materials shown in the schemes are available from commercial sources or can be prepared based on procedures described in the literature.

[0273] In this scheme, those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods (e.g., using protecting groups or alternative reactions) will be indicated. Protecting group chemistry and strategies are well known in the art, for example, as detailed in the following literature: “Protecting Groups in Organic Synthesis”, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. The modular synthetic route shown in Scheme 1 can also be readily modified by those skilled in the art to provide additional compounds by functional group transformations of intermediates and the final compound. Such functional group transformations are well known in the art, as described, for example, in the following literature: “Comprehensive Organic Synthesis” (BMTrost and I. Fleming, eds., 1991–1992).

[0274] The abbreviation "TFA" refers to trifluoroacetic acid. The abbreviation "FA" refers to formic acid. Preparative HPLC methods:

[0275] HPLC Method 1: Instrumentation: Shimadzu LCMS system equipped with UV and MS detectors. Mobile phase: 0.225% formic acid (solvent A) and CH3CN (solvent B) in water. Gradient: Use an elution gradient of 30%-70% (solvent B) for 10 minutes. Flow rate: 35 ml / min; Column: Phenomenex Gemini-NX 150*30mm*5um Wavelengths: UV 220 nm and 254 nm Column temperature: 30ºC; MS ionization: ESI

[0276] HPLC Method 2: Instruments: GILSON 215 and Shimadzu LCMS 2010A Column: Agela Durashell C18 250*20mm *5um Mobile phase A: 0.1% ammonium bicarbonate in water (m / m) Mobile phase B: Acetonitrile Gradient: linear from 80% A / 20% B to 60% A / 40% B within 10.0 min, and held at 0% A / 100% B until 12.0 min. Flow rate: 35 mL / min or 30 mL / min

[0277] HPLC Method 3: Instrument: Shimadzu LCMS system equipped with a DAD detector Mobile phase: 1.5 mL TFA / 4 L water (solvent A) and 0.75 mL TFA / 4 L CH3CN (solvent B). Gradient: Use an elution gradient of 5%-95% (solvent B) for 0.7 min and maintain at 95% for 0.4 min, at a flow rate of 1.5 ml / min; Column: Chromolish.Flash RP-18e 25-2 mm Wavelength: UV 220 nm (or 215 nm, 254 nm) Column temperature: 50ºC; MS ionization: ESI

[0278] HPLC Method 4A: Instrument: Gilson-GX281 Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 5%-95% (solvent B) for 25 minutes. Flow rate: 25 ml / min; Column: Nanomicro-UniSil 5-120 C18, 5 um, 30*150 mm Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0279] HPLC Method 4B: Instrument: Gilson-GX281 Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 5%-95% (solvent B) for 25 minutes. Flow rate: 25 ml / min; Column: YMC-Actus Triart C18 250*20mm*5um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0280] HPLC Method 4C: Instrument: Gilson-GX281 Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 5%-95% (solvent B) for 25 minutes. Flow rate: 25 ml / min; Column: YMC-Actus Triart C18 250*20mm*5um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0281] HPLC Method 4D: Instrument: LH-40 Mobile phase: H2O (0.1% NH4HCO3) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 20%-95% (solvent B) for 15 minutes. Flow rate: 18 ml / min; Column: YMC-Actus Triart C18 250*20mm*5um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0282] HPLC Method 5A: Instrument: LC-8A Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 20%-95% (solvent B) for 18 minutes. Flow rate: 18 ml / min; Column: Metasil Cloak C18 21.2*250 mm, 5 μm Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0283] HPLC Method 5B: Instrument: LC-8A Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 30%-95% (solvent B) for 18 minutes. Flow rate: 15 ml / min; Column: Metasil Cloak C18 21.2*250 mm, 5 μm Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0284] HPLC Method 6A: Instrument: LH-40 Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 5%-95% (solvent B) for 30 minutes. Flow rate: 15 ml / min; Column: YMC-Actus TriartC18 250*20 mm*5 um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0285] HPLC Method 6B: Instrument: LH-40 Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 40%-95% (solvent B) for 20 minutes. Flow rate: 20 ml / min; Column: YMC-Actus TriartC18 250*20 mm*5 um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0286] HPLC Method 6C: Instrument: LH-40 Mobile phase: H2O (0.1% NH4OH) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 30%-98% (solvent B) for 20 minutes. Flow rate: 18 ml / min; Column: YMC-ActusTriart C18 250*20 mm S-5 um, 12 nm Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0287] HPLC Method 7A: Instrument: LC-LHS Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 40%-95% (solvent B) for 22 minutes. Flow rate: 15 ml / min; Column: YMC-Actus Triart C18 / S-5 μm / 12 nm, Lot No. 18849 Wavelengths: UV 220 nm and 254 nm Column temperature: room temperature; MS ionization: ESI.

[0288] HPLC Method 7B: Instrument: LC-LHS Mobile phase: H2O (0.1% NH4OH) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 30%-95% (solvent B) for 22 minutes. Flow rate: 15 ml / min; Column: YMC-Actus Triart C18 / S-5 μm / 12 nm, Lot No. 18849 Wavelengths: UV 220 nm and 254 nm Column temperature: room temperature; MS ionization: ESI.

[0289] HPLC Method 8A: Instrument: LC-LHS Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 20%-95% (solvent B) for 18 minutes. Flow rate: 18 ml / min; Column: Shim-pack Scepter C18 50*4.6 mm, 5 um, 5 um Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0290] HPLC Method 9: Instrument: LC-8A Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 35%-95% (solvent B) for 21 minutes. Flow rate: 15 ml / min; Column: welch xbidge xb 5um 21.2*250mm Wavelengths: UV 220 nm and 254 nm Column temperature: 25ºC; MS ionization: ESI.

[0291] HPLC Method 10A: Instrument: LC-8A Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B). Gradient: Use an elution gradient of 30%-95% (solvent B) for 22 minutes. Flow rate: 15 ml / min; Column: welch xbidge xb 5um 21.2*250mm Wavelengths: UV 220 nm and 254 nm Column temperature: room temperature; MS ionization: ESI. Analytical LCMS methods:

[0292] Analytical LC / MS analysis method A: ESI + / - ion mode 150-850 Da Wavelength: UV 220 nm Column: Waters, Xbridge C18 50*2.1 mm, 5 um Temperature: 40ºC gradient:

[0293] Analytical LC / MS analysis method B: ESI + / - ion mode 150-850 Da Wavelength: UV 220 nm Column: Waters, Xbridge C18 50*2.1 mm, 5 um Temperature: 40ºC gradient:

[0294] Analytical LC / MS analysis method C: (0-70% positive - negative) ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Pillars: Shim-pack C18, 50*4.6 mm, 5 μm or Welch Xtimate C18, 250*4.6 mm, 5 μm or YMC-Triart C18, 50*4.6 mm, 5 μm Temperature: 40ºC gradient:

[0295] Analytical LC / MS analysis method D: (plus - min-3 min-1) ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Column: YMC-Triart C18, 50*4.6 mm, 5 μm or Shim-pack C18, 50*4.6 mm, 5 μm Temperature: 40ºC gradient:

[0296] Analytical LC / MS analysis method E: ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Column: YMC-Triart C18, 50*4.6 mm, 5 um Temperature: 40ºC gradient:

[0297] Analytical LC / MS analysis method F: ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Column: YMC-Triart C18, 50*4.6 mm, 5 um Temperature: 40ºC gradient:

[0298] Analytical LC / MS analysis method G: (0-50% positive 3 min) ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Column: YMC-Triart C18, 50*4.6 mm, 5 μm or Shim-Pack Scepter C18, 33*3.0 mm, 3 μm Temperature: 40ºC gradient:

[0299] Analytical LC / MS analysis method H: ESI + / - ion mode 100-1000 Da Wavelength: UV 220 nm / 254 nm Column: YMC-Triart C18, 50×4.6 mm, 5 um Temperature: 40ºC gradient:

[0300] Analytical LC / MS analysis method J: ESI + / - ion mode 100-1000 Da Column: Shim-Pack Scepter C18, 33*3.0 mm, 3 um Temperature: 40ºC gradient:

[0301] Analytical LC / MS analysis method K: ESI + / - ion mode 100-1000 Da Columns: Kromasil-C18, 50*4.6 mm, 5 μm or YMC-Triart C18, 50*4.6 mm, 5 μm Temperature: 40ºC gradient:

[0302] Analytical LC / MS analysis method M: ESI + / - ion mode 100-1000 Da Column: Shim-Pack Scepter C18, 33*3.0 mm, 3 um Temperature: 40ºC gradient:

[0303] Analytical LC / MS analysis method N: ESI + / - ion mode 100-1000 Da Column: YMC-Triart C18, 50*4.6 mm, 5 um Temperature: 40ºC gradient:

[0304] Analytical LC / MS analysis method O: ESI + / - ion mode 100-1000 Da Column: YMC-Triart C18, 50*4.6 mm, 5 um Temperature: 40ºC gradient: Example 1Method A: Synthesis of Compound I-55

[0305] Step 1: At 0ºC, NaH (480 mg, 12.0 mmol, 1.2 equivalent) was slowly added to a stirred solution of 2,4,6-trimethylphenol (R-2, 1.36 g, 10.0 mmol, 1.0 equivalent) in THF (20 mL). The resulting mixture was stirred at 0ºC under a N2 atmosphere for 30 min, and then 2,6-dichloro-3-nitropyridine (R-1, 1.92 g, 10.0 mmol, 1.0 equivalent) was added to the reaction mixture. The mixture was stirred at room temperature for 2 h, and then the reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL). The layers were separated, and the aqueous layer was 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-1 as a yellow solid (2.50 g, 8.56 mmol, 86%). LCMS (ESI): m / z = 293 [M+H] + .

[0306] Step 2: Pd(PPh3)4 (989 mg, 0.856 mmol, 0.1 equivalent) was added to a mixture of Int-1 (2.50 g, 8.56 mmol, 1 equivalent), (5-chloropyridin-3-yl)boronic acid (R-3, 2.1 g, 12.8 mmol, 1.5 equivalent), and Na2CO3 (2.7 g, 25.7 mmol, 3.0 equivalent) in dioxane (15 mL) and water (3 mL). The resulting mixture was stirred overnight at 80ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-2 as a yellow solid (1.6 g, 4.34 mmol, 51%). LCMS (ESI): m / z = 370 [M+H] + .

[0307] Step 3: At room temperature, Fe powder (1.2 g, 21.7 mmol, 5 equivalents) and ammonium chloride (1.3 g, 21.7 mmol, 5 equivalents) were added to a stirred solution of Int-2 (1.6 g, 4.34 mmol, 1.0 equivalents) in 20 mL of EtOH and 5 mL of H2O. The resulting mixture was then warmed to 90ºC and stirred at that temperature for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness, and the residue was diluted with water (30 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 2:1) to give Int-3 as a gray solid (1.2 g, 3.52 mmol, 82%). LCMS (ESI): m / z = 340 [M+H] + .

[0308] Step 4: Cool the stirred solution of Int-3 (100 mg, 0.29 mmol, 1.0 equivalent) and TEA (0.3 mL) in DCM (5 mL) to 0ºC and slowly add methanesulfonyl chloride (R-4, 84 mg, 0.73 mmol, 2.5 equivalent). Stir the resulting mixture at room temperature for 20 min. After completion, dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (10 mL x 3). Combine the organic layers, dry with anhydrous Na2SO4, and concentrate under reduced pressure. Dissolve the residue with THF (10 mL), and then add an aqueous solution of KOH (1 M, 5 mL) to the solution. Stir the resulting mixture at room temperature for 30 min. After completion, dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers, dry with anhydrous Na2SO4, and concentrate under reduced pressure. The residue was purified by preparative HPLC (Method 4B) to give compound I-55 (35 mg, 84 µmol, 28%) as a white solid. Compound I-55: Retention time: 1.613 min. LC-MS (ESI) m / z = 418.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.78 (d, J = 1.6 Hz,1H), 8.56 (d, J = 1.9 Hz, 1H), 8.11 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.81(d, J = 8.0 Hz, 1H), 6.98 (s, 2H), 3.18 (s, 3H), 2.29 (s, 3H), 2.04 (s, 6H).

[0309] Use Method A to synthesize the following compounds using the appropriate alcohol, boric acid / borate, and sulfonyl chloride: Compounds I-1, I-3, I-4, I-37, I-40, I-46, I-49, I-50, I-51 , I-54, I-56, I-57, I-58, I-60, I-62, I-63, I-65, I-68, I-71, I-72, I-252, I-253 and I-283. Example 2 Method B: Synthesis of Compound I-35

[0310] Step 1: At room temperature, Cs₂CO₃ (168 mg, 0.51 mmol, 1.5 equivalent) was added to a stirred solution of 6-chloro-2-(trimethoxy)-3-nitropyridine (Int-1, 100 mg, 0.34 mmol, 1.0 equivalent) and R-5 (81 mg, 0.41 mmol, 1.2 equivalent) in DMF (5 mL). The resulting mixture was stirred at 80ºC for 2 h, then the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give Int-4 (141 mg, quantified) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI): m / z = 455 [M+H] + .

[0311] Step 2: At room temperature, TFA (2 mL) was slowly added to a stirred solution of Int-4 (141 mg, crude) in DCM (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was concentrated under reduced pressure to obtain Int-5 (110 mg, quantified) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI): m / z = 355 [M+H]+ .

[0312] Step 3: At 0ºC, TEA (0.1 mL) and cyclopropane carbonyl chloride (R-6, 0.5 mL) were slowly added to a stirred solution of Int-5 (110 mg, crude) in DCM (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 100:1 to 3:1) to give Int-6 (85 mg) as a yellow solid. LCMS (ESI): m / z = 423 [M+H] + .

[0313] Step 4: Under nitrogen atmosphere at room temperature, add Pd / C (10 mg, 10 wt%) to a stirred solution of Int-6 (85 mg, 0.20 mmol, 1.0 equivalence) in MeOH (20 mL). Degas the suspension under vacuum and purge with H2 several times. Stir the resulting mixture at room temperature for 0.5 h. After completion, filter the suspension through a diatomaceous earth mat, wash the filter cake with MeOH (20 mL), and concentrate the combined filtrates to dryness to obtain Int-7 (62 mg, quantified) as a brown solid. LCMS(ESI): m / z = 393 [M+H] + .

[0314] Step 5: The solution of Int-7 (62 mg, crude) and TEA (0.3 mL) in DCM (5 mL) was cooled to 0ºC, and then methanesulfonyl chloride (R-4, 0.5 mL) was slowly added. The resulting mixture was stirred at room temperature for 20 min, then the reaction mixture was diluted with H2O (10 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 preparative HPLC (Method 4B) to give compound I-35 (7.5 mg) as a white solid. Compound I-35: Retention time: 1.486 min. LCMS (ESI): m / z = 471 [M+H] + ; 1H NMR(400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 6.88 (s, 2H), 6.21 (d, J = 8.3 Hz, 1H), 4.14-4.03 (m, 1H), 3.98-3.93 (m, 1H), 3.92-3.84 (m,1H), 3.69-3.61 (m, 1H), 3.55-3.46 (m, 1H), 3.21-3.12 (m, 1H), 3.01 (s, 3H),2.55-2.51 (m, 1H), 2.23 (s, 3H), 1.95 (s, 6H), 1.69-1.57 (m, 1H), 1.40 (d, J= 8.7 Hz, 1H), 0.76-0.62 (m, 3H), 0.62-0.52 (m, 1H).

[0315] Method B involves synthesizing the following compounds using appropriate amines, alcohols, boric acids / borates, and sulfonyl chlorides: compounds I-15, I-18, I-19, I-22, I-24, I-25, I-31, I-38, I-43, and I-44. Example 3 Method C: Synthesis of compound I-77

[0316] Step 1: CataCXium A Pd G3 (1.8 g, 2.5 mmol, 0.05 equivalent) was added to a mixture of 2-bromo-4,6-dimethylphenol (R-7, 10.0 g, 50.0 mmol, 1 equivalent), cyclopropylboronic acid (R-8, 12.9 g, 150.0 mmol, 3 equivalent) and Cs₂CO₃ (48.9 g, 150 mmol, 3 equivalent) in dioxane (300 mL) and water (60 mL). The resulting mixture was stirred overnight at 100ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H₂O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-8 as a white solid (5.84 g, 36 mmol, 72%). LCMS (ESI): m / z = 163 [M+H] + .

[0317] Step 2: The solution of Int-8 (500 mg, 3.09 mmol, 1.0 equivalent) in THF (20 mL) was cooled to 0ºC, and NaH (148 mg, 3.71 mmol, 1.2 equivalent) was slowly added. The resulting mixture was stirred at room temperature under a N2 atmosphere for 30 min, and then 2,6-dichloro-3-nitropyridine (R-1, 592 mg, 3.09 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 2 h, and then quenched with a saturated aqueous solution of ammonium chloride (20 mL). The layers were separated, and the aqueous layer was 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-9 as a yellow solid (687 mg, 2.16 mmol, 70%). LCMS (ESI): m / z = 319 [M+H] + .

[0318] Step 3: Pd(PPh3)4 (249 mg, 0.216 mmol, 0.1 equivalent) was added to a mixture of Int-9 (687 mg, 2.16 mmol, 1 equivalent), (5-chloropyridin-3-yl)boronic acid (R-3, 407 mg, 2.59 mmol, 1.2 equivalent), and Na2CO3 (687 mg, 6.48 mmol, 3.0 equivalent) in toluene (18 mL), EtOH (18 mL), and water (6 mL). The resulting mixture was stirred overnight at 60ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-10 as a white solid (427 mg, 1.08 mmol, 50%). LCMS (ESI): m / z = 396 [M+H] + .

[0319] Step 4: At room temperature, Fe powder (302 mg, 5.4 mmol, 5 equivalents) and ammonium chloride (292 mg, 5.4 mmol, 5 equivalents) were added to a stirred solution of Int-10 (427 mg, 1.08 mmol, 1.0 equivalents) in 10 mL of EtOH and 5 mL of H2O. The resulting mixture was stirred at 80ºC for 5 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat, the filter cake was washed with MeOH (20 mL), and the combined filtrates were concentrated to dryness. The residue was diluted with water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 2:1) to give Int-11 (296 mg, 0.81 mmol, 75%) as a gray solid. LCMS (ESI): m / z = 366 [M+H] + .

[0320] Step 5: The solution of Int-11 (300 mg, 0.82 mmol, 1.0 equivalent) in HCl (10 mL) and HOAc (30 mL) was cooled to -10ºC and then treated with sodium nitrite (113 mg, 1.64 mmol, 2.0 equivalent). The resulting mixture was stirred at -10ºC for 1 h, then CuCl2 (112 mg, 0.66 mmol, 0.80 equivalent) was added and the mixture was stirred at -10ºC for 0.5 h. Next, SO2 gas was bubbled through the reaction mixture for 10 min. The resulting mixture was stirred at -10ºC for another 0.5 h. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a yellow solid, Int-12 (300 mg, quantified), which was used directly in the next step without further purification. LCMS (ESI): m / z = 415 [M+H] + .

[0321] Step 6: Add 1,3-dichloro-4,4-dimethyl-2-oxotetrahydro-1H-imidazol-5-one (R-9, 71 mg, 0.36 mmol, 0.5 equivalence) to a solution of Int-12 (300 mg, 0.72 mmol, 1.0 equivalence) in DCM (3 mL). Stir the resulting mixture at 25ºC for 10 min, then dilute the reaction mixture with H2O (20 mL) and extract with DCM (20 mL x 3). Wash the combined organic layers with brine (15 mL), dry to anhydrous Na2SO4, and concentrate under reduced pressure. Purify the residue on silica gel by rapid column chromatography (eluting with PE:EtOAc = 5:1 to 4:1) to give Int-13 (50 mg, 0.11 mmol, 15%) as a yellow oil.

[0322] Step 7: Add MeNH2 . A solution of HCl (4 mg, 47 µmol, 1.0 equivalent) and TEA (19 mg, 188 µmol, 4.0 equivalent) in DCM (5 mL) was cooled to 0ºC, and then Int-13 (21 mg, 47 µmol, 1.0 equivalent) was added. The reaction mixture was stirred for 30 min, diluted with H2O (10 mL), and extracted with DCM (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography using a 40 g C18 column (eluted with a gradient of 35%–95% MeCN (with 0.1% FA) in water) to give compound I-77 (3.9 mg, 9 µmol, 19%) as a white solid. Compound I-77: Retention time: 1.913 min. LC-MS (ESI): m / z 444.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.24 (t, J = 2.1 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.84(s, 1H), 6.99-6.94 (m, 1H), 6.72-6.67 (m, 1H), 2.59 (s, 3H), 2.29 (s, 3H), 2.05 (s, 3H), 1.91-1.81 (m, 1H), 0.79-0.70 (m, 2H), 0.60-0.51 (m, 1H), 0.36-0.24 (m, 1H).

[0323] Method C: Synthesize the following compounds using appropriate reagents: compounds I-74, I-75, I-76, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87 and I-271. Example 4 Method D: Synthesis of Compound I-39

[0324] Step 1: A stirred solution of 2,4,6-trimethylphenol (R-2, 1.36 g, 10.0 mmol, 1.0 equivalent) in THF (20 mL) was cooled to 0ºC, and NaH (480 mg, 12.0 mmol, 1.2 equivalent) was slowly added. The resulting mixture was stirred at room temperature under a N2 atmosphere for 30 min, and then treated with 2,6-dichloro-3-nitropyridine (R-1, 1.92 g, 10.0 mmol, 1.0 equivalent). The mixture was stirred at room temperature for 2 h, and then the reaction was quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The layers were separated, and the aqueous layer was 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-1 as a yellow solid (2.40 g, 8.22 mmol, 82%). LCMS (ESI): m / z = 293 [M+H] + .

[0325] Step 2: At room temperature, Fe powder (280 mg, 5.0 mmol, 5.0 equivalent) and ammonium chloride (268 mg, 5.0 mmol, 5.0 equivalent) were added to a stirred solution of Int-1 (292 mg, 1.0 mmol, 1.0 equivalent) in 10 mL of EtOH and 5 mL of H2O. The resulting mixture was stirred at 80ºC for 5 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness. The residue was diluted with water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 2:1) to give Int-14 as a gray solid (197 mg, 0.75 mmol, 75%). LCMS (ESI): m / z = 263 [M+H] + .

[0326] Step 3: Cool the stirred solution of Int-14 (197 mg, 0.75 mmol, 1.0 equivalent) and TEA (0.3 mL) in DCM (5 mL) to 0ºC and slowly add methanesulfonyl chloride (R-4, 205 mg, 1.8 mmol, 2.5 equivalent). Stir the resulting mixture at room temperature for 20 min. After completion, dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (10 mL x 3). Combine the organic layers and concentrate under reduced pressure. Dissolve the resulting residue with THF (10 mL) and then add an aqueous solution of KOH (1 M, 5 mL) to the solution. Stir the resulting mixture at room temperature for 30 min, then dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers, dry with anhydrous Na2SO4, and concentrate under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 4:1) to give Int-15 as a white solid (207 mg, 0.609 mmol, 81%). LCMS (ESI): m / z = 341 [M+H] + .

[0327] Step 4: Pd(PPh3)4 (35 mg, 0.03 mmol, 0.1 equivalent) was added to a mixture of Int-15 (100 mg, 0.29 mmol, 1 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 52 mg, 0.353 mmol, 1.2 equivalent), and Na2CO3 (94 mg, 0.882 mmol, 3.0 equivalent) in dioxane (5 mL) and water (1 mL). The resulting mixture was stirred overnight at 105ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give compound I-39 (35 mg, 86 µmol, 29%) as a white solid. Compound I-39: Retention time: 1.758 min. LCMS (ESI): m / z = 409.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.95 (d, J= 1.8 Hz, 1H), 8.56 (t, J = 1.9 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.85 (d, J= 8.1 Hz, 1H), 6.98 (s, 2H), 3.21 (s, 3H), 2.29 (s, 3H), 2.04 (s, 6H).

[0328] Using method D, synthesize the following compounds using appropriate reagents: compounds I-2, I-5, I-6, I-7, I-8, I-9, I-10, I-13, I-14, I-29, I-36, I-45, I-275 and I-277. Example 5 Method E: Synthesis of Compound I-47

[0329] Step 1: At room temperature, Cs₂CO₃ (4.0 g, 12.3 mmol, 1.5 equivalent) was added to a stirred solution of 6-chloro-2-(trimethoxy)-3-nitropyridine (Int-1, 2.40 g, 8.22 mmol, 1.0 equivalent) and cyclopropyl(piperazin-1-yl) methyl ketone (R-11, 1.52 g, 9.86 mmol, 1.2 equivalent) in DMF (20 mL). The resulting mixture was stirred at 80ºC for 2 h. After completion, the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-16 as a yellow solid (2.74 g, 6.68 mmol, 81%). LCMS (ESI): m / z = 411 [M+H] + .

[0330] Step 2: Under nitrogen atmosphere, Pd / C (274 mg, 10 wt%) was added to a stirred solution of Int-16 (2.74 g, 6.68 mmol, 1.0 equivalence) in MeOH (20 mL). The suspension was degassed under vacuum and purged several times with H2. The resulting mixture was stirred at room temperature for 2 h. After completion, the suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give Int-17 (2.18 g, 5.74 mmol, 86%) as a brown solid. LCMS(ESI): m / z = 381 [M+H] + .

[0331] Step 3: A stirred solution of Int-17 (100 mg, 0.263 mmol, 1.0 equivalent) and TEA (79.8 mg, 0.789 mmol, 3.0 equivalent) in DCM (5 mL) was cooled to 0ºC, and then methanesulfonyl chloride (R-4, 36.0 mg, 0.316 mmol, 1.2 equivalent) was slowly added. The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 4B) to give compound I-47 (30.4 mg, 66 µmol, 25%) as a white solid. Compound I-47: Retention time: 1.381 min. LCMS (ESI): m / z = 459.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.90 (s,2H), 6.42 (d, J = 8.6 Hz, 1H), 3.67-3.55 (m, 2H), 3.47-3.39 (m, 2H), 3.28-3.11 (m, 4H), 3.02 (s, 3H), 2.25 (s, 3H), 2.01 (s, 6H), 1.98-1.92 (m, 1H), 0.77-0.63 (m, 4H).

[0332] Use Method E to synthesize the following compounds using appropriate amine reagents: Compounds I-11, I-12, I-16, I-17, I-20, I-21, I-26, I-27, I-28, I- 30. I-32, I-33, I-34, I-244, I-254, I-255, I-256, I-257, I-261, I-262, I-273 and I-274. Example 6 Synthesis of amine reagent R-14 required for the synthesis of compound I-27 using method E

[0333] Step 1: Cool the stirred solution of 4-(chlorocarbonyl)piperazine-1-carboxylic acid tert-butyl ester (R-12, 500 mg, 2.01 mmol, 1.0 equivalent) in DCM (30 mL) to 0ºC, and then sequentially use MeNH2. .The mixture was treated with HCl (269 mg, 4.02 mmol, 2.0 equivalent) and TEA (610 mg, 6.03 mmol, 3.0 equivalent). The reaction mixture was stirred for 30 min, then diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give tert-butyl 4-(methylcarbamoyl)piperazine-1-carboxylate (R-13, 500 mg, quantified) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI): m / z = 244 [M+H] + .

[0334] Step 2: Add TFA (10 mL) to a stirred solution of 4-(methylcarbamoyl)piperazine-1-carboxylate (R-13, 500 mg, crude) in DCM (20 mL). Stir the resulting mixture at room temperature for 2 h. After completion, concentrate the reaction mixture under reduced pressure to obtain crude N-methylpiperazine-1-carboxamide (TFA salt) (R-14, 400 mg, quantified) as a yellow oil, which is used directly in the next step (Step 1 of Method E) without further purification. LCMS (ESI): m / z = 144 [M+H] + . Example 7 Method F: Synthesis of compound I-48

[0335] MeI (0.1 mL) was added to a stirred solution of compound I-55 (40 mg, 95 µmol, 1.0 equivalent, prepared by method A) and K₂CO₃ (39 mg, 285 µmol, 3.0 equivalent) in DMF (2 mL). The resulting mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC (method 4B) to give compound I-48 (7.5 mg, 17 µmol, 18%) as a white solid. Compound I-48: Retention time: 2.011 min. LC-MS (ESI) m / z = 432.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 1.8 Hz,1H), 8.61 (d, J = 2.3 Hz, 1H), 8.16 (t, J = 2.1 Hz, 1H), 8.05 (d, J = 7.9 Hz,1H), 7.87 (d, J = 7.9 Hz, 1H), 7.00 (s, 2H), 3.35 (s, 3H), 3.22 (s, 3H), 2.29 (s, 3H), 2.03 (s, 6H).

[0336] The following compounds were synthesized from appropriate starting materials using Method F: Compounds I-52, I-53, I-64, I-69, I-70, I-134, I-135, I-136 , I-139, I-142, I-146, I-148, I-149, I-153, I-154, I-156, I-157, I-166 and I-272. Example 8 Method G: Synthesis of compound I-41

[0337] Step 1: Cool the stirred solution of Int-3 (1.0 g, 2.95 mmol, 1.0 equivalent) in ACN (30 mL) to 0ºC, then use... t BuONO (457 mg, 4.43 mmol, 1.5 equivalence) and CuBr2 (978 mg, 4.43 mmol, 1.5 equivalence) were used. The reaction mixture was stirred at room temperature for 3 h, then diluted with water (50 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 rapid column chromatography via silica gel column (eluting with PE:EtOAc = 3:1 to 2:1) to give Int-18 (652 mg, 1.62 mmol, 55%) as a white solid. LC-MS (ESI) m / z = 403 [M+H] + .

[0338] Step 2: Brettphos Pd G3 (20 mg, 0.02 mmol, 1 equivalent), and Brettphos (18 mg, 0.03 mmol, 0.15 equivalent) were added to a mixture of Int-18 (100 mg, 0.222 mmol, 1 equivalent), oxetane-3-sulfonamide (R-15, 31 mg, 0.222 mmol, 1.0 equivalent), and Cs2CO3 (218.7 mg, 0.667 mmol, 3.0 equivalent) in dioxane (10 mL). The resulting mixture was stirred at 100ºC under a nitrogen atmosphere for 1 h, then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 4C) to give compound I-41 (7.1 mg, 15 µmol, 7%) as a white solid. Compound I-41: Retention time: 1.795 min. LC-MS (ESI) m / z = 460.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.57 (d, J= 2.2 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz,1H), 6.98 (s, 2H), 4.85-4.81 (m, 5H), 2.29 (s, 3H), 2.03 (s, 6H).

[0339] Using method G, the following compounds I-228, I-235, I-236, I-237 and I-267 were synthesized from suitable reagents. Example 9 Method H: Synthesis of compound I-67

[0340] Step 1: At -78ºC, NaHMDS (0.6 mL, 1 M in THF, 2 equivalents) was added to a stirred solution of Int-3 (100 mg, 0.30 mmol, 1 equivalent) in DMF (10 mL). The reaction mixture was stirred for 30 min, then 3-chloropropane-1-sulfonyl chloride (R-16, 63 mg, 0.36 mmol, 1.2 equivalents) was added, and the resulting mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL) and then extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give Int-19 (150 mg, quantified) as a yellow oil, which was used directly for the next step without further purification. LCMS(ESI): m / z = 480 [M+H] + .

[0341] Step 2: Add Cs₂CO₃ (200 mg, 0.62 mmol) to a stirred solution of Int-19 (150 mg, crude) in DMF (10 mL). Stir the resulting mixture overnight at room temperature. After completion, dilute the reaction mixture with H₂O (15 mL) and extract with EtOAc (20 mL x 3). Combine the organic layers, wash with brine (20 mL x 3), dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. Purify the residue by preparative HPLC (Method 4B) to give compound I-67 (15 mg, 0.034 mmol, 11% in both steps) as a white solid. Compound I-67: Retention time: 2.162 min. LC-MS (ESI) m / z = 444.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.60 (s,1H), 8.15 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 6.98(s, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.46 (t, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.03 (s, 6H), 1.32-1.20 (m, 2H).

[0342] The following compounds, I-66 and I-221, were synthesized from suitable reagents using method H. Example 10 Method I: Synthesis of Compound I-42

[0343] To a stirred solution of compound I-55 (100 mg, 0.24 mmol, 1 equivalent), cyclopropylboronic acid (R-8, 41 mg, 0.48 mmol, 2.0 equivalent), and Na₂CO₃ (75 mg, 0.72 mmol, 3.0 equivalent) in DME (10 mL), Cu(OAc)₂ (44 mg, 0.24 mmol, 1.0 equivalent) and 2,2'-dipyridine (37 mg, 0.24 mmol, 1.0 equivalent) were added. The resulting mixture was stirred at 75ºC for 16 h under O₂ conditions. After completion, the reaction mixture was diluted with H₂O (15 mL) and extracted with DCM (20 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 4B) to give compound I-42 (20 mg, 44 µmol, 18%) as a white solid. Compound I-42: Retention time: 2.002 min. LCMS (ESI): m / z = 458.3 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ 8.80 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.16(t, J = 2.1 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 6.99(s, 2H), 3.38-3.34 (m, 1H), 3.28 (s, 3H), 2.29 (s, 3H), 2.02 (s, 6H), 0.87-0.83 (m, 4H). Example 11 Method J: Synthesis of Compound I-100

[0344] Step 1: 2,6-Dichloropyridin-3-amine (R-17, 16.2 g, 100 mmol, 1.0 equivalent) was dissolved in a mixture of concentrated HCl (100 mL) and glacial acetic acid (50 mL). The resulting solution was cooled to 0ºC, and an aqueous solution of NaNO2 (50 mL, 0.28 g / mL, 2.0 equivalent) was slowly added. The reaction mixture was stirred for 30 min, then CuCl2 (13.3 g, 100 mmol, 1.0 equivalent) was added, and SO2 was bubbled through the reaction mixture at 0ºC for 15 min. After completion, the mixture was poured into ice water (150 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (500 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 2:1 to 1:1) to give Int-20 as a yellow solid (10.0 g, 41.3 mmol, 41%).

[0345] Step 2: At 0ºC, add 5 mL of ammonia solution to a stirred solution of Int-20 (500 mg, 2.04 mmol, 1.0 equivalent) in DCM (20 mL). Stir the resulting mixture at room temperature for 30 min. After completion, dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (20 mL x 3). Combine the organic layers, dry to anhydrous Na2SO4, and concentrate under reduced pressure. Purify the residue by rapid column chromatography using silica gel (eluting with PE:EtOAc = 1:2 to 1:1) to give Int-21 (289 mg, 1.28 mmol, 63%) as a white solid. LCMS (ESI): m / z = 227 [M+H] + .

[0346] Step 3: Pd(PPh3)4 (231.1 mg, 0.2 mmol, 0.1 equivalent) was added to a mixture of Int-21 (452 ​​mg, 2.0 mmol, 1.0 equivalent), (5-chloropyridin-3-yl)boronic acid (R-3, 314 mg, 2.0 mmol, 1.0 equivalent), and Na2CO3 (318 mg, 6.0 mmol, 3.0 equivalent) in a mixed solvent of toluene, EtOH, and water (20 mL, 3:3:1). The resulting mixture was stirred at 60ºC for 6 h. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 100:1 to 3:1) to give Int-22 as a white solid (425 mg, 1.40 mmol, 70%). LCMS (ESI): m / z = 304 [M+H] + .

[0347] Step 4: At room temperature, Cs₂CO₃ (161 mg, 0.495 mmol, 1.5 equivalent) was added to a stirred solution of Int-22 (100 mg, 0.33 mmol, 1.0 equivalent) and 2,4,6-trimethylphenol (R-2, 54 mg, 0.396 mmol, 1.2 equivalent) in DMA (15 mL). The resulting mixture was stirred at 120ºC for 3 h. After completion, the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 5:1 to 3:1) to give compound I-100 (21 mg, 52 µmol, 16%) as a white solid. Compound I-100: Retention time: 1.594 min. LCMS (ESI): m / z = 404.1 [M+H] + ; 1H NMR (400 MHz, CD3OD-d4) δ 8.85 (d, J = 1.9 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.41 (d, J =7.9 Hz, 1H), 8.19 (t, J = 2.1 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 6.98 (s, 2H), 2.33 (s, 3H), 2.11 (s, 6H).

[0348] The following compounds, I-88, I-94, I-95, I-96, I-97, I-98, I-99, I-101 and I-102, were synthesized from suitable reagents using method J. Example 12 Synthesis of dichloropyridine reagent R-20 required for the synthesis of compound I-95 using method J.

[0349] Step 1: Add (Boc)₂O (654 mg, 3.0 mmol, 1.5 equivalence) and TEA (405 mg, 4.0 mmol, 2.0 equivalence) to a stirred solution of Int-21 (452 ​​mg, 2.0 mmol, 1.0 equivalence) in DCM (20 mL). Stir the resulting mixture at room temperature for 30 min. After completion, dilute the reaction mixture with H₂O (10 mL) and extract with EtOAc (20 mL x 3). Combine the organic layers, dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. Purify the residue by rapid column chromatography using silica gel (eluting with PE:EtOAc = 5:1 to 4:1) to give R-18 (528 mg, 1.62 mmol, 81%) as a white solid. LCMS (ESI): m / z = 327 [M+H] + .

[0350] Step 2: CH3I (275 mg, 1.94 mmol, 1.2 equivalent) and Cs2CO3 (792 mg, 2.43 mmol, 1.5 equivalent) were added to a stirred solution of R-18 (528 mg, 1.62 mmol, 1.0 equivalent) in DCM (20 mL). The resulting mixture was stirred at room temperature for 30 min. After stirring, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (25 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 10:1 to 5:1) to give R-19 (435 mg, 1.28 mmol, 79%) as a white solid. LCMS (ESI): m / z = 341 [M+H] + .

[0351] Step 3: Add concentrated HCl (5 mL) to a stirred solution of R-19 (435 mg, 1.28 mmol, 1 equivalent) in THF (5 mL). Stir the resulting mixture at room temperature for 1 h. After completion, dilute the reaction mixture with H2O (30 mL) and carefully neutralize with NaHCO3 (aqueous solution) until the pH is adjusted to pH = 8-9. Extract the resulting mixture with EtOAc (30 mL x 3), dry the combined organic layers with anhydrous Na2SO4 and concentrate under reduced pressure. Purify the residue by rapid column chromatography using silica gel (eluting with PE:EtOAc = 4:1 to 3:1) to give R-20 (252 mg, 1.05 mmol, 82%) LCMS (ESI): m / z = 241 [M+H). + . Example 13 Synthesis of dichloropyridine reagent R-21 required for the synthesis of compound I-97 by method J

[0352] CH3I (625 mg, 4.4 mmol, 2.2 equivalence) and Cs2CO3 (1.95 g, 6.0 mmol, 3.0 equivalence) were added to a stirred solution of Int-21 (452 ​​mg, 2.0 mmol, 1.0 equivalence) in DCM (20 mL). The resulting mixture was stirred at room temperature for 30 min. After stirring, the mixture was diluted with H2O (10 mL) 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 rapid column chromatography on silica gel (eluting with PE:EtOAc = 4:1 to 3:1) to give R-21 (411 mg, 1.62 mmol, 81%) as a white solid. LCMS (ESI): m / z = 255 [M+H] + . Example 14 Method K: Synthesis of compounds I-61 and I-59

[0353] Step 1: At 25ºC, 2,4,6-trimethylphenol (R-2, 1.5 g, 11.0 mmol, 1.0 equivalent) and t-BuOK (4.93 g, 44.0 mmol, 4.0 equivalent) were slowly added to a stirred solution of 5-bromo-3-fluoro-2-nitropyridine (R-22, 2.43 g, 11.0 mmol, 1.0 equivalent) in THF (30 mL). The resulting mixture was stirred at 25ºC under a nitrogen atmosphere for 1 h. After completion, the reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL). The layers were separated, and the aqueous layer was 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-23 (3.4 g, 10.1 mmol, 92%) as a yellow solid. LCMS (ESI): m / z = 337 [M+H] + .

[0354] Step 2: Pd(dppf)Cl2 (717 mg, 0.98 mmol, 0.1 equivalent) was added to a mixture of Int-23 (3.3 g, 9.82 mmol, 1.0 equivalent), (5-chloropyridin-3-yl)boronic acid (R-3, 2.31 g, 14.7 mmol, 1.5 equivalent) and K2CO3 (5.41 g, 39.3 mmol, 4.0 equivalent) in dioxane (50 mL) and water (10 mL). The resulting mixture was stirred at 100ºC under a nitrogen atmosphere for 1 h. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-24 (2.9 g, 7.84 mmol, 80%) as a white oil. LCMS (ESI): m / z = 370 [M+H] + .

[0355] Step 3: At room temperature, Fe powder (4.23 g, 75.7 mmol, 10.0 equivalent) and ammonium chloride (4.05 g, 75.7 mmol, 10.0 equivalent) were added to a stirred solution of Int-24 (2.8 g, 7.57 mmol, 1.0 equivalent) in 30 mL of EtOH and 10 mL of H2O. The resulting mixture was stirred at 80ºC for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness. The residue was diluted with water (10 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 3:1 to 2:1) to give Int-25 (2 g, 5.89 mmol, 78%) as a yellow solid. LCMS (ESI): m / z = 340 [M+H] + .

[0356] Step 4: 1-Methylpyrazole-4-sulfonyl chloride (R-23, 319 mg, 1.77 mmol, 2.0 equivalent) and DMAP (5 mg, 0.044 mmol, 0.05 equivalent) were added to a stirred solution of Int-25 (300 mg, 0.88 mmol, 1.0 equivalent) in pyridine (3 mL). The resulting mixture was stirred at 120ºC for 15 h. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 3:1 to 2:1) to give compound I-61 (24 mg, 0.050 mmol, 5%) as a white solid. Compound I-61: Retention time: 1.686 min. LCMS (ESI): m / z = 484 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.87(s, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.40 (s, 1H),8.27 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 6.98 (s, 2H), 6.73 (s, 1H), 3.88 (s, 3H), 2.26 (s, 3H), 2.03 (s, 6H).

[0357] Step 5: Cs₂CO₃ (81 mg, 0.25 mmol, 3.0 equivalent) and iodomethane (17 mg, 0.12 mmol, 1.5 equivalent) were added to a solution of compound I-61 (40 mg, 0.083 mmol, 1.0 equivalent) in DMF (1 mL). The resulting mixture was stirred at 25ºC for 1 h. After completion, the reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 4B) to give compound I-59 (7.3 mg, 0.015 mmol, 18%) as a white solid. Compound I-59: Retention time: 1.848 min. LCMS (ESI): m / z = 498.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ 8.69 (d, J = 1.9 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.46 (d,J = 2.1 Hz, 1H), 8.40 (s, 1H), 8.17 (t, J = 2.1 Hz, 1H), 7.84 (s, 1H), 7.02(s, 2H), 6.96 (d, J = 2.1 Hz, 1H), 3.93 (s, 3H), 3.15 (s, 3H), 2.28 (s, 3H), 2.07 (s, 6H). Example 15 Method L: Synthesis of Compound I-93

[0358] Step 1: At room temperature, Cs₂CO₃ (3.91 g, 12.0 mmol, 1.2 equivalent) was added to a stirred solution of 2,4-dichloro-5-iodopyrimidine (R-24, 2.74 g, 10.0 mmol, 1.0 equivalent) in DMF (30 mL). The resulting mixture was stirred at 80ºC for 5 h. After completion, the reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined and washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 10:1 to 5:1) to give Int-26 as a white solid (2.92 g, 7.82 mmol, 78%). LCMS (ESI): m / z = 375 [M+H] + .

[0359] Step 2: Pd2(dba)3 (714.3 mg, 0.78 mmol, 1 equivalent), XantPhos (677.0 mg, 1.17 mmol, 0.15 equivalent), and DIEA (302.4 mg, 2.34 mmol, 3.0 equivalent) were added to a mixture of Int-26 (2.92 g, 7.82 mmol, 1 equivalent) and phenylmethanethiol (970 mg, 7.82 mmol, 1.0 equivalent) in toluene (20 mL). The resulting mixture was stirred overnight at 80ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 5:1 to 4:1) to give Int-27 as a white solid (2.09 g, 5.65 mmol, 72%). LCMS (ESI): m / z = 371 [M+H] + .

[0360] Step 3: Pd(dppf)Cl2 (417 mg, 0.57 mmol, 0.1 equivalent) was added to a stirred solution of Int-27 (2.09 g, 5.65 mmol, 1.0 equivalent), (5-chloropyridin-3-yl)boronic acid (R-3, 1.06 g, 6.78 mmol, 1.2 equivalent), and K2CO3 (2.34 mg, 16.95 mmol, 3.0 equivalent) in dioxane (20 mL) and water (4 mL). The resulting mixture was stirred overnight at 80ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-28 as a white solid (1.73 g, 3.86 mmol, 68%). LCMS (ESI): m / z = 448 [M+H] + .

[0361] Step 4: The solution of Int-28 (100 mg, 0.224 mmol, 1 equivalent) in ACN (5 mL) was cooled to 0ºC and then treated with an aqueous solution of acetic acid (0.13 mL, 50%, 5 equivalent) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (R-9, 87 mg, 0.447 mmol, 2 equivalent). The reaction mixture was stirred for 30 min, and then NH3•H2O (2 mL) was added, followed by TEA (2 mL). The resulting mixture was stirred overnight at 80ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 4B) to give compound I-93 (21.9 mg, 0.05 mmol, 23%) as a white solid. Compound I-93: Retention time: 1.662. LCMS (ESI): m / z = 439.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.30 (t, J = 2.1 Hz, 1H), 8.05 (s,2H), 7.28 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 2.07 (s, 3H).

[0362] Using method L, the following compounds, I-89 and I-90, were synthesized from suitable starting materials. Example 16 Method M: Synthesis of compound I-104

[0363] Step 1: A stirred solution of Int-3 (1.0 g, 2.95 mmol, 1.0 equivalent) in HCl / H2O (30 mL, 1 M) was cooled to 0ºC and treated with an aqueous solution of NaNO2 (306 mg, 4.43 mmol, 1.5 equivalent). The resulting mixture was stirred at 0ºC for 1 h, and then KI (735 mg, 4.43 mmol, 1.5 equivalent) was added at 0ºC. The reaction mixture was stirred at 0ºC for another 1 h, then diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel column (eluting with PE:EtOAc = 3:1 to 2:1) to give Int-29 (500 mg, 1.11 mmol, 38%) as a white solid. LC-MS (ESI) m / z = 451 [M+H] + .

[0364] Step 2: Add K₂CO₃ (61 mg, 0.44 mmol, 2.0 equivalence), sodium methanesulfinate (R-25, 45 mg, 0.444 mmol, 2.0 equivalence), CuI (4 mg, 0.022 mmol, 0.1 equivalence), and L-proline (5 mg, 0.044 mmol, 0.2 equivalence) to a stirred mixture of Int-29 (100 mg, 0.22 mmol, 2.0 equivalence) in DMSO (10 mL). Stir the resulting mixture at 120ºC for 3 h. After completion, dilute the reaction mixture with H₂O (20 mL) and extract with EtOAc (20 mL x 3). Combine the organic layers and wash with brine (20 mL x 3), dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 5:1 to 4:1) to give compound I-104 (60 mg, 0.15 mmol, 67%) as a white solid. Compound I-104: Retention time: 1.897. LCMS (ESI): m / z = 403.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.8Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.25 (t, J = 2.1Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.02 (s, 2H), 3.51 (s, 3H), 2.30 (s, 3H), 2.05 (s, 6H). Example 17 Method N: Synthesis of compound I-103

[0365] Step 1: Add sodium (methylthioalkyl) (39 mg, 0.557 mmol, 1.5 equivalence), Xantphos (64 mg, 0.111 mmol, 0.3 equivalence), Pd2(dba)3 (68 mg, 0.074 mmol, 0.20 equivalence), and DIEA (288 mg, 2.23 mmol, 6.0 equivalence) to a stirred mixture of Int-18 (150 mg, 0.372 mmol, 1.0 equivalence) and dioxane (20 mL) to the mixture in dioxane (20 mL). Stir the resulting mixture at 100ºC for 1.5 h. Then dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers, wash with brine (15 mL x 3), dry to anhydrous Na2SO4, and concentrate under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 3:1 to 2:1) to give Int-30 as a white solid (80 mg, 0.216 mmol, 58%). LC-MS (ESI) m / z = 371 [M+H] + .

[0366] Step 2: Add (diacetoxyiodine)benzene (R-26, 236 mg, 0.728 mmol, 3.0 equivalent) and ammonium carbamate (76 mg, 0.971 mmol, 4.0 equivalent) to a stirred mixture of Int-30 (90 mg, 0.243 mmol, 1.0 equivalent) in MeOH (10 mL). Stir the resulting mixture at 100ºC for 1 h. After completion, dilute the reaction mixture with H2O (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers, wash with brine (15 mL x 3), dry to anhydrous Na2SO4, and concentrate under reduced pressure. Purify the residue on silica gel by rapid column chromatography (eluting with PE:EtOAc = 3:1 to 1:1) to give compound I-103 (30 mg, 0.075 mmol, 30%) as a white solid. Compound I-103: Retention time: 1.644 min. LC-MS (ESI) m / z = 402.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ8.83 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.23 ​​(t, J = 2.1 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.01 (s, 2H), 4.74 (s,1H), 3.38 (s, 3H), 2.30 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H). Example 18 Method O: Synthesis of compound I-23

[0367] Step 1: At room temperature, Cs₂CO₃ (6.68 g, 20.5 mmol, 1.5 equivalent) was added to a stirred solution of Int-1 (4.0 g, 13.7 mmol, 1.0 equivalent) and piperazine-1-carboxylate tert-butyl ester (R-27, 3.05 g, 16.4 mmol, 1.2 equivalent) in DMF (12 mL). The resulting mixture was stirred at 80ºC for 2 h. After completion, the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-31 (5.8 g, 13.1 mmol, 96%) as a white solid. LCMS (ESI): m / z = 443 [M+H] + .

[0368] Step 2: Under nitrogen atmosphere at room temperature, Pd / C (274 mg, 10 wt%) was added to a stirred solution of Int-31 (4.1 g, 9.27 mmol, 1.0 equivalent) in MeOH (20 mL). The suspension was degassed under vacuum and purged several times with H2. The resulting mixture was stirred at room temperature for 2 h. After completion, the suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give Int-32 (3.6 g, quantified) as a brown solid. LCMS(ESI): m / z = 413 [M+H] + .

[0369] Step 3: Cool the stirred solution of Int-32 (2.8 g, 6.79 mmol, 1.0 equivalent) and TEA (0.3 mL) in DCM (30 mL) to 0ºC and slowly add methanesulfonyl chloride (R-4, 1.94 g, 17.0 mmol, 2.5 equivalent). Stir the resulting mixture at room temperature for 20 min. After completion, dilute the reaction mixture with H2O (20 mL) and extract with EtOAc (30 mL x 3). Combine the organic layers, dry to anhydrous Na2SO4, and concentrate under reduced pressure. Dissolve the residue in THF (10 mL), and then add an aqueous solution of KOH (1 M, 10 mL) to the solution. Stir the resulting mixture at room temperature for 30 min. After completion, dilute the reaction mixture with H2O (20 mL) and extract with EtOAc (25 mL x 3). Combine the organic layers, dry to anhydrous Na2SO4, and concentrate under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 4:1) to give Int-33 as a white solid (2.0 g, 4.076 mmol, 60%). LCMS (ESI): m / z = 491 [M+H] + .

[0370] Step 4: Add TFA (10 mL) to the stirred solution of Int-33 (2.0 g, 4.076 mmol, 1.0 equivalent) in DCM (20 mL). Stir the resulting mixture at room temperature for 2 h. After completion, concentrate the reaction mixture under reduced pressure to obtain Int-34 (1.2 g, quantitative) as a yellow oily TFA salt, which was used directly in the next step without further purification. LCMS (ESI): m / z = 391 [M+H] + .

[0371] Step 5: To a stirred solution of oxetane-3-carboxylic acid (R-28, 16 mg, 0.15 mmol, 1.1 equivalence) and HATU (49 mg, 0.13 mmol, 1.0 equivalence) in DMF (3 mL), TEA (1 mL) and Int-34 TFA salt (50 mg, 0.13 mmol, 1.0 equivalence) were added. The mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was purified by preparative HPLC (Method 10A) to give compound I-23 (20 mg, 0.042 mmol, 33%). Compound I-23: Retention time: 1.418 min. LCMS (ESI): m / z = 475.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s,1H), 7.50 (d, J = 8.5 Hz, 1H), 6.90 (s, 2H), 6.41 (d, J = 8.6 Hz, 1H), 4.69-4.57 (m, 4H), 4.15-4.08 (m, 1H), 3.45-3.38 (m, 2H), 3.24-3.06 (m, 6H), 3.01 (s, 3H), 2.25 (s, 3H), 1.99 (s, 6H). Example 19 Method P: Synthesis of compound I-92

[0372] Step 1: Add 1-methylpiperazin-2-one (R-29, 228 mg, 2.0 mmol, 1.0 equivalent) and Cs₂CO₃ (782 mg, 2.4 mmol, 1.2 equivalent) to a stirred solution of R-20 (480 mg, 2.0 mmol, 1.0 equivalent) in DMA (20 mL). Stir the resulting mixture at 80ºC for 3 h. After completion, dilute the reaction mixture with H₂O (30 mL) and extract with EtOAc (30 mL x 3). Combine the organic layers, dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. Purify the residue by rapid column chromatography using silica gel (eluting with PE:EtOAc = 4:1 to 2:1) to give Int-35 (363 mg, 1.14 mmol, 57%) as a white solid. LCMS (ESI): m / z = 319 [M+H] + .

[0373] Step 2: Cs₂CO₃ (156 mg, 0.48 mmol, 3.0 equivalence) and 2,4,6-trimethylphenol (R-2, 33 mg, 0.24 mmol, 1.5 equivalence) were added to a solution of Int-35 (50 mg, 0.16 mmol, 1.0 equivalence) in DMF (5 mL). The resulting mixture was stirred at 100ºC for 16 h. After completion, the reaction mixture was purified by preparative HPLC (Method 4B) to give compound I-92 (10 mg, 0.024 mmol, 15%) as a white solid. Compound I-92: Retention time: 1.186 min. LCMS (ESI): m / z = 419.5 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.6 Hz,1H), 6.87 (s, 2H), 6.18 (d, J = 8.6 Hz, 1H), 4.85 (d, J = 5.8 Hz, 1H), 3.96(s, 2H), 3.56 (t, J = 5.4 Hz, 2H), 3.27 (t, J = 5.4 Hz, 2H), 2.98 (s, 3H), 2.70 (d, J = 4.4 Hz, 3H), 2.30 (s, 3H), 2.07 (s, 6H).

[0374] Method P: Synthesize the following compound using appropriate reagents: Compound I-73. Example 20 Method Q: Synthesis of Compound I-5

[0375] Step 1: At 0ºC, NaH (480 mg, 12.0 mmol, 1.2 equivalent) was slowly added to a stirred solution of 2,4,6-trimethylpyridin-3-ol (R-30, 1.38 g, 10.0 mmol, 1.0 equivalent) in THF (50 mL). The resulting mixture was stirred at room temperature under a N2 atmosphere for 30 min. 2,6-Dichloro-3-nitropyridine (R-1, 1.92 g, 10.0 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 2 h. After completion, the reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-36 (2.34 g, 8 mmol, 80%) as a yellow solid. LCMS (ESI): m / z = 294 [M+H] + .

[0376] Step 2: At room temperature, Fe powder (280 mg, 5.0 mmol, 5 equivalents) and ammonium chloride (268 mg, 5.0 mmol, 5 equivalents) were added to a stirred solution of Int-36 (294 mg, 1.0 mmol, 1.0 equivalents) in 10 mL of EtOH and 5 mL of H2O. The resulting mixture was stirred at 80ºC for 5 h. After completion, the reaction mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness. The residue was diluted with water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 2:1) to give Int-37 (210.4 mg, 0.8 mmol, 80%) as a gray solid. LCMS (ESI): m / z = 264 [M+H] + .

[0377] Step 3: At 0ºC, methanesulfonyl chloride (228 mg, 2.0 mmol, 2.5 equivalent) was slowly added to a stirred solution of Int-37 (210.4 mg, 0.8 mmol, 1.0 equivalent) and TEA (0.3 mL) in DCM (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and concentrated under reduced pressure.

[0378] The residue was dissolved in THF (10 mL) and KOH aqueous solution (1 M, 5 mL) was added. The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 4:1) to give Int-38 as a white solid (218 mg, 0.636 mmol, 80%). LCMS (ESI): m / z = 342 [M+H] + .

[0379] Step 4: Pd(PPh3)4 (35 mg, 0.03 mmol, 0.1 equivalent) was added to a mixture of Int-38 (100 mg, 0.293 mmol, 1 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 52 mg, 0.351 mmol, 1.2 equivalent), and Na2CO3 (93.2 mg, 0.879 mmol, 3.0 equivalent) in dioxane (5 mL) and water (1 mL). The resulting mixture was stirred overnight at 105ºC under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound I-5 (8 mg, 0.019 mmol, 7%) as a white solid.

[0380] Compound I-5: Retention time: 1.829 min; LCMS (ESI): m / z = 410.2 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ 8.98 (d, J = 2.2 Hz, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.52(t, J = 2.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 3.14 (s, 3H), 2.43 (s, 3H), 2.22 (s, 3H), 2.07 (s, 3H).

[0381] The following compounds were synthesized from the appropriate alcohol, boronic acid / borate, and sulfonyl chloride reagent using Method Q: Compounds I-172, I-186, I-187, I-188, I-211, I-226, I-227, I-231, I-232, I-23 8. I-239, I-241, I-242, I-243, I-246, I-247, I-250, I-259, I-260, I-266, I-269, I-270, I-276, I-282 and I-284. Example 21 Method R: Synthesis of compound I-4

[0382] Step 1: K₂CO₃ (1.38 g, 9.96 mmol, 4.0 equivalence), cyclopropylboranediol (320 mg, 3.73 mmol, 1.5 equivalence), and Pd(dppf)Cl₂ (91 mg, 0.12 mmol, 0.05 equivalence) were added to a stirred solution of R-31 (500 mg, 2.49 mmol, 1.0 equivalence) in dioxane (30 mL) and H₂O (10 mL). The resulting mixture was stirred at 120ºC under N₂ for 24 h. After completion, the reaction mixture was decanted into water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give Int-39 as a white solid (200 mg, 1.23 mmol, 49%). LC-MS (ESI) m / z = 163 [M+H] + .

[0383] Step 2: Sodium nitrite (170 mg, 2.47 mmol, 2.0 equivalent) was slowly added to a stirred solution of Int-39 (200 mg, 1.23 mmol, 1.0 equivalent) in H₂SO₄ / H₂O (2 mL / 10 mL) at 0ºC. After addition, the resulting mixture was stirred at 0ºC for 30 min. Afterward, the reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ (15 mL) and then extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give Int-40 (150 mg, 0.92 mmol, 75%) as a white solid. LC-MS (ESI) m / z = 164 [M+H] + .

[0384] Step 3: At 0ºC, NaH (61 mg x 60 wt%, 1.53 mmol, 2.5 equivalence) was slowly added to a stirred solution of Int-40 (100 mg, 0.61 mmol, 1.0 equivalence) in THF (10 mL). The resulting mixture was stirred at 0ºC for 30 min. Then, 2,6-dichloro-3-nitropyridine (R-1, 351 mg, 1.83 mmol, 3.0 equivalence) was added and the resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was decanted into water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-41 as a white solid (50 mg, 0.16 mmol, 26%). LC-MS (ESI) m / z = 320 [M+H] + .

[0385] Step 4: Add NH4Cl (201 mg, 3.75 mmol, 10.0 equivalent) and Fe (210 mg, 3.75 mmol, 10.0 equivalent) to a solution of Int-41 (120 mg, 0.38 mmol, 1.0 equivalent) in EtOH (9 mL) and H2O (3 mL). Stir the resulting mixture at 80ºC under N2 for 1 h. After completion, filter the reaction mixture through a diatomaceous earth pad and wash the filter cake with MeOH (20 mL). Concentrate the combined filtrates to dryness. Dilute the residue with water (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers and wash with brine (15 mL), dry to anhydrous Na2SO4, and concentrate under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-42 as a white solid (70 mg, 0.24 mmol, 64%). LC-MS (ESI) m / z = 290 [M+H] + .

[0386] Step 5: MsCl (17.75 mg, 0.16 mmol, 1.0 equivalent) was added to a solution of Int-42 (45 mg, 0.16 mmol, 1.0 equivalent) and TEA (47 mg, 0.47 mmol, 3.0 equivalent) in DCM (4 mL) at 25ºC. The resulting mixture was stirred at 25ºC for 1 h. After completion, the reaction mixture was diluted with water (10 mL) and then extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give Int-43 (50 mg, 0.11 mmol, 70%) as a yellow oil. LC-MS (ESI) m / z = 446 [M+H] + .

[0387] Step 6: At room temperature, KOH (30 mg, 0.54 mmol, 6.0 equivalence) was added to a stirred mixture of Int-43 (40 mg, 90 µmol, 1.0 equivalence) in THF (3 mL) and H2O (1 mL). The resulting mixture was stirred at 50ºC for 2 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1 to 3:1) to give Int-44 (30 mg, 82 µmol, 91%) as a white solid. LC-MS (ESI) m / z = 368 [M+H] + .

[0388] Step 7: Add Na₂CO₃ (35 mg, 0.33 mmol, 4.0 equivalence), (5-cyanopyridin-3-yl)boronic acid (18 mg, 123 µmol, 1.5 equivalence), and Pd(PPh₃)₄ (9 mg, 8 µmol, 0.1 equivalence) to a solution of Int-44 (30 mg, 8 µmol, 1.0 equivalence) in dioxane (3 mL) and H₂O (1 mL). Stir the reaction mixture at 60ºC under N₂ for 16 h. After completion, decant the reaction mixture into water (10 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers and wash with brine (15 mL), dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. The residue was purified by reversed-phase chromatography using a 40 g C18 column (eluted with a gradient of 5%–50% MeCN (with 0.1% FA) in water) to give compound I-4 (4.6 mg, 10 µmol, 12%) as a yellow solid.

[0389] Compound I-4: Retention time: 0.55 min; LC-MS (ESI) m / z = 436.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 7.63 (s, 2H), 7.05 (s, 1H), 2.16 (s, 3H), 2.04 (s, 3H), 1.36-1.33 (m, 1H), 1.23 (s, 3H), 0.91- 0.86 (m, 4H).

[0390] The following compounds, I-120, I-127, I-147, I-208, I-213, I-229, I-264 and I-268, were synthesized from suitable reagents using method R. Example 22 Method S: Synthesis of compound I-167

[0391] Step 1: NBS (2.7 g, 15.3 mmol, 2.5 equivalents) was slowly added to a stirred solution of 2-(trifluoromethyl)pyrimidin-5-ol (R-32, 1.0 g, 6.1 mmol, 1.0 equivalent) in MeCN (30 mL). After stirring at room temperature for 2 h, the reaction was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 5:1) to give Int-45 (897.5 mg, 2.8 mmol, 46%) as a white solid. LCMS (ESI): m / z = 321 [M+H] + .

[0392] Step 2: A mixture of Int-45 (897.5 mg, 2.8 mmol, 1 equivalent), methylboronic acid (838.0 mg, 14.0 mmol, 5.0 equivalent), cataCXium A Pd G3 (203.9 mg, 0.28 mmol, 0.1 equivalent), and K2CO3 (1.55 g, 11.2 mmol, 4.0 equivalent) in dioxane (20 mL) and water (4 mL) was stirred overnight at 80ºC under N2 atmosphere. After completion, the mixture was diluted with H2O (70 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 4:1) to give Int-46 (371 mg, 1.9 mmol, 68%) as a yellow solid. LCMS (ESI): m / z = 193[M+H] + .

[0393] Step 3: Under a nitrogen atmosphere at 0ºC, NaH (91.2 mg, 2.3 mmol, 1.2 equivalents) was slowly added to a stirred solution of Int-46 (371 mg, 1.9 mmol, 1.0 equivalents) in THF (10 mL). After stirring for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 401.2 mg, 2.1 mmol, 1.1 equivalents) was added to the mixture at 0ºC. After stirring at room temperature for 2 h, the reaction was quenched with a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 0 to 5:1) to give Int-47 as a yellow solid (469.5 mg, 1.35 mmol, 71%). LCMS (ESI): m / z = 349 [M+H] + .

[0394] Step 4: A mixture of Int-47 (469.5 mg, 1.35 mmol, 1.0 equivalent), Fe powder (378.0 mg, 6.75 mmol, 5 equivalent), and NH4Cl (722.1 mg, 13.5 mmol, 10 equivalent) in EtOH (20 mL) and H2O (5 mL) was stirred at 80ºC for 2 h. After completion, the mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL x 3). The combined filtrates were concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 2:1 to 1:1) to give Int-48 as a white solid (304.9 mg, 0.96 mmol, 71%). LCMS (ESI): m / z = 319 [M+H] + .

[0395] Step 5: At 0ºC, an aqueous solution of NaNO2 (2.0 M, 1 mL, 2.0 equivalent) was slowly added to a stirred solution of Int-48 (304.9 mg, 0.96 mmol, 1.0 equivalent) in concentrated HCl (40 mL) and glacial acetic acid (20 mL). After stirring for 30 min, CuCl2 (129.1 mg, 0.96 mmol, 1.0 equivalent) was added to the mixture, and SO2 was bubbled into the reaction mixture at 0ºC for 15 min. After completion, the mixture was poured into ice water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with saturated NaHCO3 aqueous solution (80 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 2:1 to 1:1) to give Int-49 as a yellow solid (163.6 mg, 0.41 mmol, 43%). LCMS (ESI): m / z = 402 [M+H] + .

[0396] Step 6: At 0ºC, methylamine hydrochloride (55.4 mg, 0.82 mmol, 2.0 equivalent) and TEA (0.5 mL) were added to a stirred solution of Int-49 (163.6 mg, 0.41 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 30 min, the mixture was diluted with H2O (10 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 rapid column chromatography via silica gel (eluting with PE:EtOAc = 1:1 to 1:3) to give Int-50 (109.1 mg, 0.276 mmol, 67%) as a white solid. LCMS (ESI): m / z = 397 [M+H] + .

[0397] Step 7: A mixture of Int-50 (109.1 mg, 0.276 mmol, 1.0 equivalent), (5-chloropyridin-3-yl)boronic acid (R-10, 45.0 mg, 0.304 mmol, 1.1 equivalent), Pd(PPh3)4 (34.7 mg, 0.03 mmol, 0.11 equivalent), and Na2CO3 (86.4 mg, 0.828 mmol, 3.0 equivalent) in dioxane (10 mL) and water (2 mL) was stirred at 90ºC under a nitrogen atmosphere for 6 h. After completion, the reaction mixture was diluted with H2O (20 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 preparative HPLC (column: WelchXBridge C18 250 X 21 mm, gradient: 30%-95% MeCN in H2O [with 0.1% FA]) to give compound I-167 (23.2 mg, 0.05 mmol, 18%).

[0398] Compound I-167: Retention time: 1.527 min; LCMS (ESI): m / z = 465 [M+H] + ; 1 H NMR(400 MHz, DMSO) δ 9.13 – 9.05 (m, 2H), 8.64 (d, J = 1.8 Hz, 1H), 8.52 – 8.44(m, 1H), 8.20 – 8.12 (m, 1H), 8.02 (d, J = 0.5 Hz, 1H), 2.63 (s, 3H), 2.44 (d, J = 5.1 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -68.31 (s).

[0399] Method S: Use appropriate reagents to synthesize the following compounds: compounds I-133, I-168, I-258, I-265, I-280, I-281, I-285, I-292, I-309, I-310 and I-315. Example 23 Method T: Synthesis of compound I-220

[0400] Step 1: A mixture of Int-38 (100 mg, 0.29 mmol, 1.0 equivalent), (5-(methoxycarbonyl)pyridin-3-yl)boronic acid (R-33, 58.33 mg, 0.322 mmol, 1.1 equivalent), cataCXium A Pd G3 (21.33 mg, 0.03 mmol, 0.1 equivalent), and K2CO3 (121.3 mg, 0.879 mmol, 3.0 equivalent) in dioxane (10 mL) and water (2 mL) was stirred at 100ºC for 6 h under N2 atmosphere. After completion, the reaction mixture was diluted with 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 rapid column chromatography over silica gel (eluting with PE:EtOAc = 1:1 to 1:3) to give Int-51 as a white solid (104.3 mg, 0.24 mmol, 83%). LCMS (ESI): m / z = 443 [M+H] + .

[0401] Step 2: At 0ºC under a N2 atmosphere, a THF solution of MeMgBr (1 M, 0.84 mL, 0.84 mmol, 3.5 equivalences) was slowly added to a stirred solution of Int-51 (104.3 mg, 0.24 mmol, 1 equivalent) in THF (20 mL). After stirring at room temperature for 2 h, the reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (12 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 1:1 to 1:4) to give compound I-220 (11.2 mg, 0.025 mmol, 10.7%).

[0402] Compound I-220: Retention time: 0.421 min; LCMS (ESI): m / z = 443.2 [M+H] + . 1H NMR(400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.73 (dd, J = 14.8, 2.1 Hz, 2H), 8.21 (t,J = 2.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 3.23 (s, 3H), 2.64 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.43 (s, 6H). Example 24 Method U: Synthesis of compound I-212

[0403] Step 1: Under a nitrogen atmosphere at -78ºC, DIBAL-H (0.5 mL, 1.5 M, 0.75 mmol, 4.2 equivalences) was added dropwise to a stirred mixture of Int-51 (80 mg, 0.18 mmol, 1 equivalent) in THF (1 mL). After stirring at -20ºC for 2 h, an aqueous solution of sodium potassium tartrate tetrahydrate (30 mL) was added. The mixture was then stirred at room temperature for another 30 min and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 1:1) to give Int-52 (66.3 mg, 0.16 mmol, 87%) as a yellow solid. LCMS (ESI): m / z = 415 [M+H] + .

[0404] Step 2: Add MnO2 (139 mg, 1.6 mmol, 10 equivalents) to a stirred solution of Int-52 (65 mg, 0.16 mmol, 1 equivalent) in THF (2 mL). After stirring overnight at 70ºC, cool the reaction mixture to room temperature and filter through a diatomaceous earth pad, washing the filter cake with DCM (20 mL x 3). Concentrate the combined filtrates under reduced pressure to give Int-53 (30 mg, crude) as a white solid, which is used directly in the next step. LCMS (ESI): m / z = 413 [M+H] + .

[0405] Step 3: Under a N2 atmosphere at 0ºC, dimethyl (1-diazo-2-oxopropyl)phosphonate (27.95 mg, 0.15 mmol) and K2CO3 (25.13 mg, 0.18 mmol) were slowly added to a stirred mixture of Int-53 (30 mg, crude) in MeOH (2 mL). After stirring at room temperature for 1 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 30%-95% MeCN in H2O [with 0.1% TFA]) to give compound I-212 as a white solid (5 mg, 0.012 mmol, 7.7% in both steps).

[0406] Compound I-212: Retention time: 1.178 min; LCMS (ESI): m / z = 409.2 [M+H] + . 1 H NMR(400 MHz, DMSO) δ 9.88 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 1.9Hz, 1H), 8.11 (t, J = 2.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1Hz, 1H), 7.10 (s, 1H), 4.48 (s, 1H), 3.18 (s, 3H), 2.44 (s, 3H), 2.23 (s,3H), 2.07 (s, 3H). Example 25 Method V: Synthesis of Compound I-161

[0407] Step 1: NBS (4.1 g, 23 mmol, 2.5 equivalents) was slowly added to a stirred solution of 4-methylpyridin-3-ol (R-34, 1.0 g, 9.2 mmol, 1.0 equivalent) in MeCN (50 mL). After stirring at room temperature for 2 h, the reaction was diluted with H2O (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 1:3) to give Int-54 (1.25 g, 4.7 mmol, 51.3%) as a white solid. LCMS (ESI): m / z = 266 [M+H] + .

[0408] Step 2: Under a nitrogen atmosphere at 0ºC, NaH (282 mg, 7.05 mmol, 1.5 equivalent) was slowly added to a stirred solution of Int-54 (1.25 g, 4.7 mmol, 1 equivalent) in THF (50 mL). After stirring for 30 min, MOMCl (454 mg, 5.6 mmol, 1.2 equivalent) was added to the mixture, and the mixture was stirred again at room temperature for 2 h. After completion, the mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1) to give Int-55 (1.1 g, 3.6 mmol, 76.6%) as a white solid. LCMS (ESI): m / z = 310 [M+H] + .

[0409] Step 3: A mixture of Int-55 (1.1 g, 3.6 mmol, 1 equivalent), cyclopropylboronic acid (1.5 g, 18.0 mmol, 5.0 equivalent), cataCXium A Pd G3 (524.4 mg, 0.72 mmol, 0.2 equivalent), and K2CO3 (2.0 g, 14.4 mmol, 4.0 equivalent) in dioxane (50 mL) and water (10 mL) was stirred overnight at 80ºC under a nitrogen atmosphere. After completion, the mixture was diluted with H2O (70 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1) to give Int-56 as a white solid (298.4 mg, 1.28 mmol, 35.6%). LCMS (ESI): m / z = 234 [M+H] + .

[0410] Steps 4 and 5: TFA (8 mL) was added to a stirred solution of Int-56 (298.4 mg, 1.28 mmol, 1.0 equivalent) in DCM (20 mL). After stirring for 30 min at room temperature, the mixture was concentrated under reduced pressure to remove the solvent and TFA. Crude Int-57 was dissolved in anhydrous THF (20 mL), and NaH (128 mg, 3.2 mmol, 2.5 equivalent) was slowly added to the resulting mixture at 0ºC under N2 atmosphere. After stirring for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 290 mg, 1.5 mmol, 1.2 equivalent) was added to the mixture. The resulting mixture was stirred for another 2 h at room temperature. After completion, the reaction was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 3:1) to give Int-58 as a yellow solid (296.4 mg, 0.86 mmol, 67.1%). LCMS (ESI): m / z = 346 [M+H] + .

[0411] Step 6: A mixture of Int-58 (296.4 mg, 0.86 mmol, 1.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 148 mg, 1.0 mmol, 1.2 equivalent), Pd(PPh3)4 (104 mg, 0.09 mmol, 0.1 equivalent), and Na2CO3 (273.5 mg, 2.58 mmol, 3.0 equivalent) in dioxane (40 mL) and water (8 mL) was stirred at 80ºC for 4 h under a N2 atmosphere. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (40 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 1:4) to give Int-59 as a yellow solid (263 mg, 0.64 mmol, 74%). LCMS (ESI): m / z = 414 [M+H] + .

[0412] Step 7: The mixture of Int-59 (263 mg, 0.64 mmol, 1.0 equivalent), Fe powder (179.2 mg, 3.2 mmol, 5 equivalent), and NH4Cl (342.4 mg, 6.4 mmol, 10 equivalent) in EtOH (50 mL) and H2O (25 mL) was stirred at 80ºC for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH. The combined filtrates were concentrated, and the residue was ground with H2O and filtered to give Int-60 (210 mg, crude) as a brown solid, which was used directly in the next step. LCMS (ESI): m / z = 384 [M+H] + .

[0413] Steps 8 and 9: At 0ºC, MsCl (0.5 mL) and TEA (1 mL) were slowly added to a stirred solution of Int-60 (100 mg, crude) in DCM (20 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure. Crude Int-61 was dissolved with THF (20 mL), and then an aqueous solution of NaOH (4 M, 2 mL) was added to the mixture. After stirring at room temperature for 30 min, the mixture was neutralized with HCl (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XB-C18 5 μm x 21.2 x 250 mm, gradient: 15%-95% MeCN (with 0.1% TFA) in H2O) to give compound I-161 as a white solid (18.4 mg, 0.04 mmol, 2 steps 15.4%).

[0414] Compound I-161: Retention time: 3.861 min; LCMS (ESI): m / z = 462.1 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ (ppm)10.02 (s, 1H), 9.06 (d, J = 2.2 Hz, 1H), 8.97 (d, J= 1.9 Hz, 1H), 8.55 (t, J = 2.1 Hz, 1H), 8.00 – 7.86 (m, 2H), 7.05 (s, 1H), 3.23 (s, 3H), 2.10 – 1.99 (m, 5H), 0.97 – 0.64 (m, 8H).

[0415] Method V: The following compounds, I-162 and I-171, are synthesized using appropriate alcohols, boric acids / borates, and sulfonyl chlorides. Example 26 Method W: Synthesis of compound I-137

[0416] Step 1: SeO2 (18.4 g, 164.4 mmol, 2.5 equivalents) was slowly added to a stirred solution of 2,4-dimethyl-5-nitropyridine (R-35, 10.0 g, 65.8 mmol, 1.0 equivalent) in dioxane (100 mL). After stirring at 120ºC for 5 h, the reaction was diluted with H2O (150 mL) and extracted with EtOAc (120 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 10:1) to give Int-62 (4.5 g, 27.1 mmol, 41.2%) as a yellow solid. LCMS (ESI): m / z = 167 [M+H] + .

[0417] Step 2: PTSA (464.9 mg, 2.7 mmol, 0.1 equivalent) was slowly added to a stirred solution of Int-62 (4.5 g, 27.1 mmol, 1.0 equivalent) and ethylene glycol (16.8 g, 271 mmol, 10.0 equivalent) in toluene (100 mL). After stirring at 100ºC for 5 h, the reaction was diluted with H2O (160 mL) and extracted with EtOAc (120 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 10:1) to give Int-63 (5.1 g, 24.2 mmol, 89.3%) as a yellow solid. LCMS (ESI): m / z = 211 [M+H] + .

[0418] Step 3: Pd / C (250 mg) was added to a mixture of Int-63 (5.1 g, 24.2 mmol, 1.0 equivalent) in MeOH (30 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. After completion, the mixture was filtered, the filter cake was washed with MeOH (20 mL x 3), and the combined filtrates were concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluting with PE:EtOAc = 0 to 3:1) to give Int-64 (3.6 g, 20.2 mmol, 83.6%) as a white solid. LCMS (ESI): m / z = 211 [M+H] + .

[0419] Steps 4 and 5: At 0ºC, concentrated sulfuric acid (20 mL) and an aqueous solution of NaNO2 (2 M, 15 mL, 30 mmol, 1.5 equivalent) were slowly added to a stirred solution of Int-64 (3.6 g, 20.2 mmol, 1.0 equivalent) in water (100 mL). After stirring at 80ºC for 6 h, the mixture was poured into ice water (150 mL) and neutralized with an aqueous solution of NaOH (4 M). After completion, the resulting mixture was extracted with EtOAc (100 mL x 3) and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Crude Int-65 was dissolved in anhydrous THF (100 mL), and then NaH (1.2 g, 30 mmol, 1.5 equivalent) was slowly added to the resulting mixture at 0ºC under a N2 atmosphere. After stirring for 30 min, MOMCl (1.95 g, 24.2 mmol, 1.2 equivalents) was added to the mixture. After stirring at room temperature for 2 h, the mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1) to give Int-66 as a white solid (1.5 g, 8.3 mmol, 41.4% in both steps). LCMS (ESI): m / z = 182 [M+H] + .

[0420] Step 6: At 0ºC, DAST (5.4 g, 33.2 mmol, 4.0 equivalent) was added to a stirred solution of Int-66 (1.5 g, 8.3 mmol, 1.0 equivalent) in DCM (50 mL). After stirring at room temperature for 30 min, the reaction mixture was diluted with H2O (100 mL) and extracted with DCM (80 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 4:1) to give Int-67 (1.2 g, 5.8 mmol, 69.5%) as a white solid. LCMS (ESI): m / z = 204 [M+H] + .

[0421] Step 7: Add TFA (5 mL) to a stirred solution of Int-67 (1.2 g, 5.8 mmol, 1.0 equivalent) in DCM (20 mL). After stirring at room temperature for 30 min, concentrate the mixture under reduced pressure to remove the solvent. Purify the residue by rapid column chromatography over silica gel (eluting with EtOAc) to give Int-68 (763.4 mg, 4.8 mmol, 82.8%) as a white solid. LCMS (ESI): m / z = 160 [M+H] + .

[0422] Steps 8 and 9: NBS (1.0 g, 5.8 mmol, 1.2 equivalence) was added to a stirred solution of Int-68 (763.4 mg, 4.8 mmol, 1.0 equivalence) in DMF (30 mL). After stirring at room temperature for 2 h, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Crude Int-69 was dissolved in anhydrous THF (40 mL), and NaH (230 mg, 7.2 mmol, 1.5 equivalence) was slowly added to the resulting mixture at 0ºC under N2 atmosphere. After stirring for 30 min, MOMCl (580 mg, 7.2 mmol, 1.5 equivalence) was added to the mixture. After stirring at room temperature for 2 h, the mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 4:1) to give Int-70 as a white solid (955.4 mg, 3.4 mmol, 70.3% in both steps). LCMS (ESI): m / z = 282 [M+H] + .

[0423] Step 10: A mixture of Int-70 (955.4 mg, 3.4 mmol, 1.0 equivalent), cyclopropylboronic acid (584 mg, 6.8 mmol, 2.0 equivalent), cataCXium A Pd G3 (255 mg, 0.35 mmol, 0.1 equivalent), and K2CO3 (1.4 g, 10.2 mmol, 3.0 equivalent) in dioxane (30 mL) and H2O (6 mL) was stirred at 100ºC under N2 atmosphere for 3 h. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 4:1) to give Int-71 (681 mg, 2.8 mmol, 82.3%) as a white solid. LCMS (ESI): m / z = 244 [M+H] + .

[0424] Steps 11 and 12: TFA (8 mL) was added to a stirred solution of Int-71 (681 mg, 2.8 mmol, 1.0 equivalent) in DCM (20 mL). After stirring for 30 min at room temperature, the mixture was concentrated under reduced pressure to remove the solvent and TFA. Crude Int-72 was dissolved in anhydrous THF (40 mL), and NaH (280 mg, 7.0 mmol, 2.5 equivalent) was slowly added to the resulting mixture at 0ºC under N2 atmosphere. After stirring for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 656.2 mg, 3.4 mmol, 1.2 equivalent) was added to the mixture. The resulting mixture was stirred for another 2 h at room temperature. After completion, the reaction was quenched with a saturated aqueous solution of NH4Cl (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 2:1) to give Int-73 as a yellow solid (609 mg, 1.7 mmol, 61.3% in both steps). LCMS (ESI): m / z = 356 [M+H] + .

[0425] Step 13: A mixture of Int-73 (609 mg, 1.7 mmol, 1.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 296 mg, 2.0 mmol, 1.2 equivalent), Pd(PPh3)4 (196.5 mg, 0.17 mmol, 0.1 equivalent), and Na2CO3 (530.6 mg, 5.1 mmol, 3.0 equivalent) in dioxane (40 mL) and water (10 mL) was stirred at 80ºC for 4 h under a nitrogen atmosphere. 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 1:5) to give Int-74 (517.8 mg, 1.2 mmol, 72%) as a yellow solid. LCMS (ESI): m / z = 424 [M+H] + .

[0426] Step 14: The mixture of Int-74 (517.8 g, 1.2 mmol, 1.0 equivalent), Fe powder (336 mg, 6.0 mmol, 5 equivalent), and NH4Cl (642 mg, 12 mmol, 10 equivalent) in EtOH (50 mL) and H2O (20 mL) was stirred at 80ºC for 3 h. After completion, the mixture was filtered through a diatomaceous earth mat, the filter cake was washed with MeOH, the combined filtrates were concentrated, and the residue was ground with H2O and filtered to obtain Int-75 (480 mg, crude product) as a brown solid, which was used directly in the next step. LCMS (ESI): m / z = 394 [M+H] + .

[0427] Steps 15 and 16: At 0ºC, MsCl (1 mL) and TEA (2 mL) were slowly added to a stirred solution of Int-75 (120 mg, crude) in DCM (10 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure. Crude Int-76 was dissolved with THF (10 mL), and then an aqueous solution of NaOH (4 M, 1 mL) was added to the mixture. After stirring at room temperature for 30 min, the mixture was neutralized with HCl (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 40%-95% MeCN in H2O (with 0.1% NH4HCO3)) to give compound I-137 as a white solid (19.3 mg, 0.041 mmol, 13.7% in three steps).

[0428] Compound I-137: Retention time: 1.538 min; LCMS (ESI): m / z = 472.1 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ (ppm)10.10 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.96 (d, J= 1.8 Hz, 1H), 8.56 (t, J = 1.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.93 (d, J= 8.1 Hz, 1H), 7.51 (s, 1H), 6.87 (t, J = 55.1 Hz, 1H), 3.25 (s, 3H), 2.20(s, 3H), 2.18 – 2.12 (m, 1H), 1.01 – 0.87 (m, 2H), 0.86 – 0.68 (m, 2H); 19 FNMR (376 MHz, DMSO-d6) δ (ppm) -114.46 (d, J = 12.7 Hz).

[0429] Method of use: The following compound I-179 is synthesized by means of appropriate alcohol, boric acid / borate and sulfonyl chloride. Example 27Method X: Synthesis of Compound I-200

[0430] Step 1: NBS (2.7 g, 15.3 mmol, 2.5 equivalents) was slowly added to a stirred solution of 2-(trifluoromethyl)pyrimidin-5-ol (R-36, 1.0 g, 6.1 mmol, 1.0 equivalent) in MeCN (30 mL). After stirring at room temperature for 2 h, the reaction was diluted with H2O (70 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 1:1) to give Int-77 (897.5 mg, 2.8 mmol, 45.9%) as a white solid. LCMS (ESI): m / z = 321 [M+H] + .

[0431] Step 2: A mixture of Int-77 (897.5 mg, 2.8 mmol, 1.0 equivalent), methylboronic acid (838.0 mg, 14.0 mmol, 5.0 equivalent), cataCXium A Pd G3 (203.9 mg, 0.28 mmol, 0.1 equivalent), and K2CO3 (1.55 g, 11.2 mmol, 4.0 equivalent) in dioxane (30 mL) and water (6 mL) was stirred overnight at 80ºC under a N2 atmosphere. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 1:1) to give Int-78 (371 mg, 1.9 mmol, 67.9%) as a yellow solid. LCMS (ESI): m / z = 193 [M+H] + .

[0432] Step 3: Under a nitrogen atmosphere at 0ºC, NaH (92 mg, 2.3 mmol, 1.2 equivalents) was slowly added to a stirred solution of Int-78 (371 mg, 1.9 mmol, 1.0 equivalents) in THF (10 mL). After stirring at 0ºC for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 405.3 mg, 2.1 mmol, 1.1 equivalents) was added to the mixture at 0ºC. After stirring at room temperature for 2 h, the reaction was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 0 to 5:1) to give Int-79 as a yellow solid (469.5 mg, 1.35 mmol, 71%). LCMS (ESI): m / z = 349 [M+H] + .

[0433] Step 4: A mixture of Int-79 (142.7 mg, 0.41 mmol, 1.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 72.5 mg, 0.49 mmol, 1.2 equivalent), Pd(PPh3)4 (46.2 mg, 0.04 mmol, 0.1 equivalent), and Na2CO3 (128 mg, 1.23 mmol, 3.0 equivalent) in dioxane (20 mL) and water (4 mL) was stirred at 80ºC for 2 h under a nitrogen atmosphere. After completion, the reaction mixture was diluted with 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 rapid column chromatography over silica gel (eluting with EA) to give Int-80 as a yellow solid (116.5 mg, 0.28 mmol, 68.3%). LCMS (ESI): m / z = 417 [M+H] + .

[0434] Step 5: The mixture of Int-80 (116.5 mg, 0.28 mmol, 1.0 equivalent), Fe powder (78 mg, 1.4 mmol, 5 equivalent), and NH4Cl (150 mg, 2.8 mmol, 10 equivalent) in EtOH (20 mL) and H2O (10 mL) was stirred at 80ºC for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH. The combined filtrates were concentrated, the residue was ground with H2O, and then filtered to give Int-81 (80 mg, crude product) as a brown solid. LCMS (ESI): m / z = 387 [M+H] + .

[0435] Steps 6 and 7: At 0ºC, MsCl (0.5 mL) and TEA (1 mL) were slowly added to a stirred solution of Int-81 (80 mg, crude) in DCM (10 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure. Crude Int-82 was dissolved in THF (10 mL), and then an aqueous solution of NaOH (4 M, 1 mL) was added to the resulting mixture. After stirring at room temperature for 30 min, the mixture was neutralized with HCl (1 M) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 30%-95% MeCN (with 0.1% TFA) in H2O) to give compound I-200 as a white solid (14.7 mg, 0.032 mmol, 11.3% in three steps).

[0436] Compound I-200: Retention time: 1.358 min; LCMS (ESI): m / z = 465.1 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.03 (d, J = 1.9 Hz, 1H), 8.98 (d,J = 1.4 Hz, 1H), 8.52 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz,1H), 3.26 (s, 3H), 2.43 (s, 6H); 19F NMR (376 MHz, DMSO-d6) δ (ppm) -68.29(s).

[0437] Method X involves synthesizing the following compounds using appropriate alcohols, boric acid / borates, and sulfonyl chlorides: compounds I-131, I-138, I-145, I-151, and I-205. Example 28 Method Y: Synthesis of compound I-155

[0438] Step 1: NBS (1.96 g, 11.0 mmol, 1.1 equivalent) was added to a stirred solution of 6-(trifluoromethyl)pyridine-3-amine (R-37, 1.6 g, 10.0 mmol, 1.0 equivalent) in MeCN (50 mL). After stirring at room temperature for 2 h, the mixture was diluted with H2O (90 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 rapid column chromatography via silica gel (eluted with PE:EtOAc = 10:1) to give Int-83 (2.0 g, 8.3 mmol, 83.0%) as a colorless oil. LCMS (ESI): m / z = 241 [M+H] + .

[0439] Step 2: A mixture of Int-83 (2.0 g, 8.3 mmol, 1.0 equivalent), MeB(OH)2 (2.0 g, 16.6 mmol, 2.0 equivalent), cataCXium A Pd G3 (604.5 mg, 0.83 mmol, 0.1 equivalent), and K2CO3 (3.4 g, 24.9 mmol, 3.0 equivalent) in dioxane (50 mL) and H2O (10 mL) was stirred at 100ºC under a N2 atmosphere for 3 h. After completion, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 5:1) to give Int-84 as a yellow solid (1.15 g, 6.56 mmol, 79.0%). LCMS (ESI): m / z = 177 [M+H] + .

[0440] Step 3: NBS (1.4 g, 7.9 mmol, 1.2 equivalent) was added to a stirred solution of Int-84 (1.15 g, 6.56 mmol, 1.0 equivalent) in MeCN (30 mL). After stirring at room temperature for 2 h, 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 rapid column chromatography via silica gel (eluted with PE:EtOAc = 5:1) to give Int-85 (1.4 g, 5.58 mmol, 85%) as a yellow solid. LCMS (ESI): m / z = 255 [M+H] + .

[0441] Step 4: A mixture of Int-85 (1.4 g, 5.58 mmol, 1.0 equivalent), cyclopropylboronic acid (955.3 g, 11.2 mmol, 2.0 equivalent), cataCXium A Pd G3 (407.8 mg, 0.56 mmol, 0.1 equivalent), and K2CO3 (2.3 g, 16.7 mmol, 3.0 equivalent) in dioxane (50 mL) and H2O (10 mL) was stirred at 100ºC under a N2 atmosphere for 3 h. After completion, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 4:1) to give Int-86 as a yellow solid (990 mg, 4.58 mmol, 82.1%). LCMS (ESI): m / z = 217 [M+H] + .

[0442] Steps 5 and 6: At 0ºC, concentrated sulfuric acid (10 mL) and an aqueous solution of NaNO2 (1 M, 7 mL, 7 mmol, 1.5 equivalent) were slowly added to a stirred solution of Int-86 (990 mg, 4.58 mmol, 1.0 equivalent) in water (50 mL). After stirring at room temperature for 6 h, the mixture was poured into ice water (50 mL) and neutralized with an aqueous solution of NaOH (4 M). After completion, the resulting mixture was extracted with EtOAc (30 mL x 3), and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue Int-87 was dissolved in anhydrous THF (20 mL), and then NaH (275 mg, 6.9 mmol, 1.5 equivalent) was slowly added to the resulting mixture at 0ºC under a N2 atmosphere. After stirring at 0ºC for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 1.06 g, 5.5 mmol, 1.2 equivalents) was added to the mixture. After stirring at room temperature for 2 h, the mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 1:5) to give Int-88 as a yellow solid (717.6 mg, 1.92 mmol, 42% in both steps). LCMS (ESI): m / z = 374 [M+H] + .

[0443] Step 7: A mixture of Int-88 (717.6 mg, 1.92 mmol, 1.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 341 mg, 2.3 mmol, 1.2 equivalent), Pd(PPh3)4 (231 mg, 0.2 mmol, 0.1 equivalent), and Na2CO3 (610.6 mg, 5.76 mmol, 3.0 equivalent) in dioxane (100 mL) and water (20 mL) was stirred at 80ºC for 4 h under a nitrogen atmosphere. 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 on silica gel by rapid column chromatography (eluting with PE:EtOAc = 1:9) to give Int-89 as a yellow solid (643.7 mg, 1.46 mmol, 76%). LCMS (ESI): m / z = 442 [M+H] + .

[0444] Step 8: The mixture of Int-89 (643.7 mg, 1.46 mmol, 1.0 equivalent), Fe powder (408.8 mg, 7.3 mmol, 5 equivalent), and NH4Cl (781 mg, 14.6 mmol, 10 equivalent) in EtOH (50 mL) and H2O (20 mL) was stirred at 80ºC for 3 h. After completion, the mixture was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH (20 mL x 3). The combined filtrates were concentrated under reduced pressure to give Int-90 (621 mg, crude product) as a brown solid, which was used directly in the next step. LCMS (ESI): m / z = 412 [M+H] + .

[0445] Steps 9 and 10: At 0ºC, MsCl (85 mg, 0.74 mmol / L) and TEA (2 mL) were slowly added to a stirred solution of Int-90 (621 mg, crude) in DCM (20 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure. The crude residue Int-91 was dissolved in dioxane (10 mL) and an aqueous solution of NaOH (4 M, 1 mL) was added to the mixture. After stirring at room temperature for 30 min, the mixture was neutralized with HCl (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 1:4) to give compound I-155 as a white solid (136 mg, 0.28 mmol, 19.2% in three steps). LCMS (ESI): m / z = 490 [M+H] + .

[0446] Compound I-155: Retention time: 1.558 min; LCMS (ESI): m / z = 490 [M+H] + ; 1H NMR(400 MHz, DMSO) δ 10.13 (s, 1H), 9.01 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 1.9Hz, 1H), 8.53 (t, J = 2.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1Hz, 1H), 7.35 (s, 1H), 3.26 (s, 3H), 2.36 (s, 3H), 2.08 – 1.99 (m, 1H), 0.93(t, J = 7.1 Hz, 4H).

[0447] Method Y uses appropriate amines, boric acid / borates, and sulfonyl chlorides to synthesize the following compounds: compounds I-140, I-141, I-152, I-158, I-163, I-184, I-198, I-217, I-218, I-219, I-225, and I-240. Example 29 Method Z: Synthesis of compound I-175

[0448] Step 1: A mixture of formamide (R-38, 50 g, 1.1 mol, 2.0 equivalent) and 3-chloropentane-2,4-dione (R-39, 74.4 g, 550 mmol, 1.0 equivalent) in formic acid (30 mL) was stirred at 120ºC for 16 h. After completion, the reaction mixture was poured into ice water (500 mL), neutralized with an aqueous solution of NaOH (4 M), and extracted with EtOAc (120 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 0 to 5:1) to give Int-92 (10.3 g, 82.4 mmol, 15%) as a brown oil. LCMS (ESI): m / z = 126 [M+H] + .

[0449] Step 2: The stirred mixture of Int-92 (10.3 g, 82.4 mmol, 1.0 equivalent) in NH4OH (50 mL) was stirred at 180ºC for 8 h. After completion, the mixture was cooled to room temperature and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluting with PE:EtOAc = 100:1 to 1:100) to give Int-93 (7.1 g, 57.2 mmol, 69.5%) as a yellow solid. LCMS (ESI): m / z = 125 [M+H] + .

[0450] Step 3: NBS (6.5 g, 36.5 mmol, 1.2 equivalents) was slowly added to a stirred solution of Int-93 (3.8 g, 30.4 mmol, 1.0 equivalent) in MeCN (20 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 0 to 2:1) to give Int-94 (2.0 g, 9.9 mmol, 32.6%) as a brown solid. LCMS (ESI): m / z = 203 [M+H] + .

[0451] Step 4: Under a nitrogen atmosphere at 0ºC, NaH (237.6 mg, 5.94 mmol, 1.2 equivalents) was added to a stirred solution of Int-94 (1 g, 4.95 mmol, 1.0 equivalents) in THF (10 mL). After stirring for 30 min, MOMCl (597.8 mg, 7.43 mmol, 1.5 equivalents) was slowly added to the mixture. The resulting mixture was stirred at room temperature for 1 h, and the reaction was then quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 0 to 5:1) to give Int-95 (876 mg, 3.56 mmol, 72%) as a yellow solid. LCMS (ESI): m / z = 247 [M+H] + .

[0452] Step 5: A mixture of Int-95 (476 mg, 1.93 mmol, 1.0 equivalent), potassium ethylenetrifluoroborate (R-40, 388.9 mg, 2.90 mmol, 1.5 equivalent), Pd(dppf)Cl2 (141.4 mg, 0.19 mmol, 0.1 equivalent), and K2CO3 (801.1 mg, 5.80 mmol, 3.0 equivalent) in dioxane (50 mL) and water (10 mL) was stirred overnight at 90ºC under a nitrogen atmosphere. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 4:1) to give Int-96 as a white solid (321 mg, 1.65 mmol, 85.5%). LCMS (ESI): m / z = 195 [M+H] + .

[0453] Step 6: At -78ºC, O3 was bubbled through a stirred solution of Int-96 (321 mg, 1.65 mmol, 1.0 equivalence) in a mixed solvent of DCM (6 mL) and MeOH (2 mL) for 30 min. Then, N2 was bubbled through the mixture for another 1 h to remove residual O3. After completion, the mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography using silica gel (eluted with PE: EtOAc = 3:1) to give Int-97 (220 mg, 1.12 mmol, 67.8%) as a white solid. LCMS (ESI): m / z = 197 [M+H] + .

[0454] Step 7: At 0ºC, DAST (722.8 mg, 4.5 mmol, 4.0 equivalent) was added to a stirred solution of Int-97 (220 mg, 1.12 mmol, 1.0 equivalent) in DCM (5 mL). After stirring at room temperature for 30 min, the reaction mixture was diluted with H2O (40 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluted with PE:EtOAc = 10:1 to 3:1) to give Int-98 (151 mg, 0.69 mmol, 61.7%) as a white solid. LCMS (ESI): m / z = 219 [M+H] + .

[0455] Step 8: Add HCl / dioxane (5 mL) to a stirred solution of Int-98 (151 mg, 0.69 mmol, 1.0 equivalent) in dioxane (5 mL). After stirring at room temperature for 30 min, concentrate the mixture under reduced pressure to give Int-99 (150 mg, crude) as a white solid. LCMS (ESI): m / z = 175 [M+H] + .

[0456] Steps 9 to 13: Perform the procedure similar to that used in Method Y (Steps 6-10) to provide compound I-175, which is purified by rapid column chromatography over silica gel (eluted with PE: EtOAc = 1:100) to give compound I-175 as a white solid (3.0 mg, 0.0065 mmol, 50.2%).

[0457] Compound I-175: Retention time: 1.288 min; LCMS (ESI): m / z = 456 [M+H] + ; 1 H NMR(400 MHz, DMSO) δ 10.07 (s, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 2.3Hz, 1H), 8.09 (t, J = 2.0 Hz, 1H), 7.98 (dd, J = 21.5, 8.1 Hz, 2H), 6.99 (t,J = 54.2 Hz, 1H), 3.24 (s, 3H), 2.39 (s, 6H); 19 F NMR (376 MHz, DMSO) δ -117.42 (s).

[0458] Method Z uses appropriate alcohols, boric acid / borates, and sulfonyl chlorides to synthesize the following compounds: compounds I-144 and I-173. Example 30 Method ZA: Synthesis of compound I-204

[0459] Step 1: NBS (28.9 g, 163.4 mmol, 2.5 equivalents) was slowly added to a stirred solution of methyl 5-hydroxypyridinecarboxylate (R-41, 10 g, 65.4 mmol, 1.0 equivalent) in DMF (100 mL). After stirring at room temperature for 1 h, the reaction was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 1:99) to give Int-104 (17.1 g, 55.4 mmol, 84.7%) as a yellow solid. LCMS (ESI): m / z = 310 [M+H] + .

[0460] Step 2: A mixture of Int-104 (2.0 g, 6.5 mmol, 1.0 equivalent), methylboric acid (1.9 g, 32.4 mmol, 5.0 equivalent), cataCXium A Pd G3 (469.95 mg, 0.65 mmol, 0.1 equivalent), and K2CO3 (2.7 g, 19.4 mmol, 3.0 equivalent) in dioxane (60 mL) and water (10 mL) was stirred overnight at 100ºC under a N2 atmosphere. Afterward, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Int-105 (824 mg, crude) as a yellow solid. LCMS (ESI): m / z = 182 [M+H] + .

[0461] Step 3: Under a nitrogen atmosphere at 0ºC, NaH (218.5 mg, 5.46 mmol) was slowly added to a stirred solution of Int-105 (824 mg, crude) in THF (5 mL). After stirring for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 961.5 mg, 5.0 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for another 1 h. After completion, the reaction was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 0 to 5:1) to give Int-106 (302 mg, 0.89 mmol, 13.8% in both steps) as a yellow solid. LCMS (ESI): m / z = 338 [M+H] + .

[0462] Step 4: Under a N2 atmosphere at 0ºC, a THF solution of DIBAL-H (1M, 2.7 mL, 2.7 mmol, 3.0 equivalent) was added to a stirred solution of Int-106 (302 mg, 0.89 mmol, 1.0 equivalent) in THF (50 mL). After stirring at room temperature for 2 h, an aqueous solution of sodium potassium tartrate tetrahydrate (50 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 10:1 to 2:1) to give Int-107 (178 mg, 0.57 mmol, 64.2%) as a white solid. LCMS (ESI): m / z = 310 [M+H] + .

[0463] Step 5: Add MnO2 (251 mg, 2.88 mmol, 5.0 equivalent) to a stirred solution of Int-107 (178 mg, 0.57 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 30 min, filter the reaction mixture through a diatomaceous earth pad and wash the filter cake with DCM (20 mL x 3). Concentrate the combined filtrates under reduced pressure to give Int-108 (152 mg, 0.49 mmol, 85.9%) as a white solid. LCMS (ESI): m / z = 308 [M+H] + .

[0464] Step 6: At 0ºC, DAST (318.8 mg, 1.98 mmol, 4.0 equivalent) was added to a stirred solution of Int-108 (152 mg, 0.49 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 30 min, the reaction mixture was diluted with H2O (40 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluted with PE:EtOAc = 10:1 to 3:1) to give Int-109 (93 mg, 0.28 mmol, 57.1%) as a white solid. LCMS (ESI): m / z = 330 [M+H] + .

[0465] Steps 7 to 10: Performed using a similar procedure to that used in Method Y (Steps 7-10) to provide compound I-204, which was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 30%-95% MeCN in H2O [with 0.1% TFA]) to give compound I-204 as a white solid (14.1 mg, 0.032 mmol, 75.4%).

[0466] Compound I-204: Retention time: 1.359 min; LCMS (ESI): m / z = 446.4 [M+H] + ; 1 H NMR(400 MHz, DMSO) δ 10.16 (s, 1H), 8.73 (d, J = 4.7 Hz, 1H), 8.24 (s, 1H), 8.04(s, 2H), 7.83 (d, J = 2.9 Hz, 1H), 7.64 (s, 1H), 6.96 (t, J = 55.0 Hz, 1H), 3.27 (s, 3H), 2.34 (s, 3H), 2.20 (s, 3H); 19 F NMR (376 MHz, DMSO) δ -114.42(d).

[0467] Method ZA uses appropriate alcohols, boric acid / borates and sulfonyl chlorides to synthesize the following compounds: compounds I-197, I-199, I-202, I-203 and I-230. Example 31 Method ZB: Synthesis of Compound I-196

[0468] Step 1: 3,5-Dibromopyridine (R-43, 1.0 g, 4.3 mmol, 1.0 equivalent), 3-methoxyazacyclobutane hydrochloride (584.5 mg, 4.73 mmol, 1.1 equivalent), Pd2(dba)3 (366.3 mg, 0.4 mmol, 0.1 equivalent), XantPhos (372 mg, 0.65 mmol, 0.15 equivalent), and NaO were added. t A mixture of Bu (1.2 g, 13 mmol, 3 equivalents) in dioxane (40 mL) was stirred at 80ºC for 2 h under a N2 atmosphere. Afterward, the mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 5:1) to give Int-113 (822.1 mg, 3.4 mmol, 79.0%) as a colorless oil. LCMS (ESI): m / z = 243 [M+H] + .

[0469] Steps 2 and 3: Under a nitrogen atmosphere at -78ºC, add to a stirred solution of Int-113 (822.1 mg, 3.4 mmol, 1.0 equivalent) in anhydrous THF (20 mL). nA THF solution of BuLi (2.5 M, 1.6 mL, 4.0 mmol, 1.2 equivalents) was added. After stirring for 30 min, B(OMe)3 (530 mg, 5.1 mmol, 1.5 equivalents) was added to the mixture, and the resulting mixture was stirred for another 30 min at room temperature. After completion, the reaction was quenched with MeOH (5 mL) and concentrated under reduced pressure to provide crude Int-114. The crude residue Int-114 was dissolved in dioxane (20 mL) and H2O (4 mL), and then Int-36 (996 mg, 3.4 mmol, 1.0 equivalents), Pd(PPh3)4 (392 mg, 0.34 mmol, 0.1 equivalents), and K2CO3 (1.38 g, 10 mmol, 3 equivalents) were added to the resulting solution. After stirring at 100ºC for 3 h under N2 atmosphere, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 2:1) to give Int-115 as a yellow solid (343.5 mg, 0.82 mmol, 21% in both steps). LCMS (ESI): m / z = 422 [M+H] + .

[0470] Step 4: A mixture of Int-115 (343.5 mg, 0.82 mmol, 1.0 equivalent), Fe powder (230 mg, 4.1 mmol, 5 equivalent), and NH4Cl (438.7 mg, 8.2 mmol, 10 equivalent) in EtOH (10 mL) and H2O (5 mL) was stirred at 80ºC for 2 h. After completion, the mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (20 mL x 3). The filtrates were combined and concentrated under reduced pressure to give Int-116 (250 mg, crude) as a brown solid. LCMS (ESI): m / z = 392 [M+H] + .

[0471] Steps 5 and 6: At 0ºC, MsCl (0.5 mL) and TEA (1 mL) were slowly added to a stirred solution of Int-116 (100 mg, crude) in DCM (5 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were concentrated under reduced pressure. The crude residue Int-117 was dissolved in dioxane (10 mL), and then an aqueous solution of NaOH (4 M, 1 mL) was added to the resulting mixture. After stirring at room temperature for 30 min, the mixture was neutralized by TFA (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C8250 x 20 mm, gradient: 30%-95% MeCN in aqueous solution of NH4HCO3 (10 mM)) to give compound I-196 as a white solid (12.1 mg, 0.026 mmol, 7.9% in three steps).

[0472] Compound I-196: Retention time: 0.885 min; LCMS (ESI): m / z = 470.1 [M+H] + ; 1 H NMR(400 MHz, DMSO) δ 9.83 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 6.98 – 6.94 (m, 1H), 4.39 – 4.30 (m, 1H), 4.06 – 3.98 (m, 2H), 3.58 (dd, J =8.3, 4.1 Hz, 2H), 3.25 (s, 3H), 3.15 (s, 3H), 2.43 (s, 3H), 2.21 (s, 3H), 2.06 (s, 3H).

[0473] Method ZB synthesizes the following compounds using appropriate amines, boric acid / borates, and sulfonyl chlorides: compounds I-185, I-190, I-194, I-195, I-201, I-263, and I-278. Example 32 Method ZC: Synthesis of compound I-326

[0474] Step 1: A mixture of 5-bromo-6-methoxynicotinonitrile (R-44, 1.0 g, 4.7 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane-2,2'-dioxane-45, 1.4 g, 5.6 mmol, 1.2 equivalent), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.1 equivalent), and KOAc (1.4 g, 14.1 mmol, 3.0 equivalent) in dioxane (50 mL) was stirred at 100ºC under N2 atmosphere for 3 h. After completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 4:1) to give Int-118 as a white solid (892.5 mg, 3.4 mmol, 72.3%). LCMS (ESI): m / z = 261 [M+H] + .

[0475] Step 2: CataCXium A Pd G3 (73 mg, 0.1 mmol, 0.1 equivalent) was added to a mixture of Int-38 (340 mg, 1.0 mmol, 1 equivalent), Int-118 (260 mg, 1.0 mmol, 1.0 equivalent), and K2CO3 (415 mg, 3.0 mmol, 3.0 equivalent) in dioxane (50 mL) and water (10 mL). The resulting mixture was stirred overnight at 100ºC under a N2 atmosphere. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 1:1) to give Int-119 (250 mg, 0.57 mmol, 57%) as a white solid. LCMS(ESI): m / z = 440 [M+H] + .

[0476] Step 3: Add BBr3 (2 mL) to a stirred solution of Int-119 (100 mg, 0.23 mmol) in DCM (20 mL). After stirring at room temperature for 2 h, quench the mixture with MeOH (20 mL) and concentrate under reduced pressure to remove the solvent. Dilute the residue with H2O (20 mL) and extract with EtOAc (30 mL x 3). Dry the combined organic phases over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the residue on silica gel by rapid column chromatography (eluting with DCM:MeOH = 5:1) to give Int-120 (44 mg, 0.1 mmol, 42%) as a white solid. LCMS (ESI): m / z = 444 [M+H] + .

[0477] Step 4: Add Burgess reagent (120 mg, 0.5 mmol, 5 equivalents) to a stirred solution of Int-120 (44 mg, 0.1 mmol, 1 equivalent) in DCE (10 mL). After stirring at 60ºC for 2 h, dilute the residue with H2O (20 mL) and extract with EtOAc (30 mL x 3). Dry the combined organic phases over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the residue by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 15%-95% MeCN (with 0.1% FA) in H2O) to give compound I-326 (8.5 mg, 0.02 mmol, 20%) as a white solid.

[0478] Compound I-326: Retention time: 0.439 min; LC-MS (ESI) m / z = 426.1 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 9.92 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 8.2Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.50 (s, 1H), 3.21 (s, 4H), 2.58 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H).

[0479] Method ZC synthesizes the following compounds: compounds I-307 and I-324, using appropriate aryl halides, boric acid / borates, and sulfonyl chlorides. Example 33 Method ZD: Synthesis of Compound I-170

[0480] Step 1: NCS (2.56 g, 19.2 mmol, 1.2 equivalence) was slowly added to a stirred solution of 4,6-dimethylpyrimidin-5-ol (R-46, 2.0 g, 16.1 mmol, 1.0 equivalence) in MeCN (60 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluting with PE:EtOAc = 0 to 2:1) to give Int-121 (1.68 g, 10.6 mmol, 66.0%) as a white solid. LCMS (ESI): m / z = 159 [M+H] + .

[0481] Step 2: Under a nitrogen atmosphere at 0ºC, NaH (80 mg, 60% dispersed in mineral oil, 2.0 mmol, 1.2 equivalent) was added to a stirred solution of Int-121 (1.68 g, 10.6 mmol, 1.0 equivalent) in THF (60 mL). After stirring for 30 min, MOMCl (1.27 g, 16 mmol, 1.5 equivalent) was slowly added. The resulting mixture was stirred at room temperature for 1 h, then the reaction was quenched with ice-cold H2O (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography via silica gel (eluted with PE:EtOAc = 0 to 6:1) to give Int-122 (1.86 g, 9.2 mmol, 86.9%) as a yellow solid. LCMS (ESI): m / z = 203[M+H] + .

[0482] Step 3: A mixture of Int-122 (80 mg, 0.4 mmol, 1 equivalent), 3,3-difluorozacriane hydrochloride (R-47, 103.6 mg, 0.8 mmol, 2 equivalents), and Cs₂CO₃ (391 mg, 1.2 mmol, 3 equivalents) in DMF (5 mL) was stirred at 100ºC for 16 h. After completion, the resulting solution was diluted with H₂O (70 mL) and extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (eluted with PE:EtOAc = 5:1) to give Int-123 (40 mg, 0.15 mmol, 39%) as a white solid. LCMS (ESI): m / z = 260 [M+H] + .

[0483] Step 4: Add TFA (0.5 mL) to the solution of Int-123 (20 mg, 0.08 mmol) in DCM (2 mL). After stirring at room temperature for 1 h, concentrate the mixture under vacuum to obtain Int-124 (30 mg, crude product) as a yellow oil, which is used directly in the next step. LCMS (ESI): m / z = 216 [M+H] + .

[0484] Step 5: Under a nitrogen atmosphere at 0ºC, NaH (10 mg, 60% dispersed in mineral oil, 0.21 mmol, 1.5 equivalent) was slowly added to a stirred solution of Int-124 (30 mg, 0.14 mmol, 1.0 equivalent) in THF (5 mL). After stirring at 0ºC for 30 min, 2,6-dichloro-3-nitropyridine (R-1, 30.0 mg, 0.16 mmol, 1.1 equivalent) was added to the mixture at 0ºC. After stirring at room temperature for 2 h, the reaction was quenched with ice water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 4:1) to give Int-125 (20 mg, 0.054 mmol, 38.5%) as a yellow solid. LCMS (ESI): m / z = 372 [M+H] + .

[0485] Step 6: A mixture of Int-125 (20.0 mg, 0.05 mmol, 1.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 9.0 mg, 0.06 mmol, 1.2 equivalent), Pd(PPh3)4 (6.0 mg, 0.005 mmol, 0.1 equivalent), and K2CO3 (21 mg, 0.15 mmol, 3.0 equivalent) in dioxane (20 mL) and water (4 mL) was stirred at 100ºC for 4 h under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (20 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 rapid column chromatography over silica gel (eluting with EA) to give Int-126 (30 mg, 80% purity, 0.05 mmol, 99%) as a yellow solid. LCMS (ESI): m / z = 440 [M+H] + .

[0486] Step 7: The mixture of Int-126 (24 mg, 0.05 mmol, 1.0 equivalent), Fe powder (14 mg, 0.25 mmol, 5 equivalent), and NH4Cl (27 mg, 0.5 mmol, 10 equivalent) in EtOH (30 mL) and H2O (15 mL) was stirred at 80ºC for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH. The combined filtrates were concentrated, the residue was ground with H2O, and then filtered to give Int-127 (30 mg, crude) as a brown solid. LCMS (ESI): m / z = 410 [M+H] + .

[0487] Steps 8 and 9: At 0ºC, MsCl (0.5 mL) and TEA (1 mL) were slowly added to a stirred solution of Int-127 (30 mg, crude) in DCM (10 mL). After stirring at room temperature for 10 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure to provide Int-128. Crude Int-128 (35 mg) was dissolved in THF (10 mL), and an aqueous solution of NaOH (4 M, 1 mL) was added to the resulting mixture. After stirring at room temperature for 30 min, the mixture was neutralized with HCl (1 M) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WelchXBridge C18 250 x 21 mm, gradient: 20%-95% MeCN (with 0.1% TFA) in H2O) to give compound I-170 as a white solid (8.5 mg, 0.017 mmol, 34.9% in 3 steps).

[0488] Compound I-170: Retention time: 1.522 min; LCMS (ESI): m / z = 488.1 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ (ppm) 9.96 (br, 1H), 9.06 (d, J = 2.2 Hz, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.60 (t, J = 2.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.90 (d,J = 8.1 Hz, 1H), 4.48 (t, J = 12.5 Hz, 4H), 3.20 (s, 3H), 2.18 (s, 6H); 19 FNMR (377 MHz, DMSO-d6) δ (ppm) -99.06 (s).

[0489] Method of use: ZD synthesizes the following compounds using appropriate alcohols, amines, boric acids / borates and sulfonyl chlorides: compounds I-159, I-160 and I-169. Example 34 Method ZE: Synthesis of Compound I-174

[0490] Step 1: Add 3-iodooxetine (R-48, 90 mg, 0.40 mmol, 1 equivalent), NiBr2 (Dtpdy) (20 mg, 0.04 mmol, 0.1 equivalent), 4CzIPN (64 mg, 0.08 mmol, 0.2 equivalent), and TEA (0.16 mL, 1.20 mmol, 3 equivalent) to a stirred solution of Int-95 (100 mg, 0.40 mmol, 0.1 equivalent) in dioxane (3 mL). The resulting mixture was stirred at 25ºC for 2 h under blue light (455 nm) irradiation. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 0 to 1:1) to give Int-129 (30 mg, 0.13 mmol, 33%) as a yellow oil. (ESI): m / z = 225 [M+H] + .

[0491] Step 2: Add TFA (0.5 mL) to the stirred solution of Int-129 (30 mg, 0.13 mmol) in DCM (2 mL). After stirring at room temperature for 1 h, concentrate the solution under reduced pressure to obtain Int-130 (30 mg, crude product), a yellow oil, which is used directly in the next step. LCMS (ESI): m / z = 181 [M+H] + .

[0492] Steps 3 to 7: Performed using a similar procedure to that used in Method ZD (Steps 5-9) to provide compound I-174, which was purified by preparative HPLC (column: Welch XBridge C18 250 x 21 mm, gradient: 20%-95% MeCN (with 0.1% TFA) in H2O) to give compound I-174 (2.0 mg, 0.0044 mmol) as a white solid.

[0493] Compound I-174: Retention time: 0.944 min; LCMS (ESI): m / z = 453.3 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 2.2 Hz, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.40 (s, 1H), 7.80 (s, 2H), 4.95 – 4.85 (m, 4H), 4.53 – 4.42 (m, 1H), 2.99 (s, 3H), 2.30 (s, 6H).

[0494] Method of use: ZE synthesizes the following compound I-143 using appropriate alcohols, amines, boric acids / borates and sulfonyl chlorides. Example 35 Method ZF: Synthesis of compound I-165

[0495] Step 1: A solution of 1-cyclopropylbutane-1,3-dione in acetonitrile (R-49, 58 mmol, 5 M, 11.6 mL, 1 equivalent) was added to a stirred solution of tert-butylammonium bromide (13.9 g, 90 mmol, 1.5 equivalent) and TMSCl (9 mL, 180 mmol, 3.0 equivalent) in anhydrous acetonitrile (50 mL), followed by dropwise addition of anhydrous DMSO (14 mL). After stirring at 0ºC for 1.5 h, the mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 9:1) to give Int-135 (5.76 g, 36 mmol, 62.2%) as a colorless oil. LCMS (ESI): m / z = 161 [M+H] + .

[0496] Step 2: A mixture of Int-135 (5.0 g, 31.3 mol, 1.0 equivalent) and NH4OAc (7.2 g, 93.8 mol, 3.0 equivalent) in AcOH (40 mL) was stirred at 120ºC for 16 h. After cooling to room temperature, the mixture was diluted with H2O (200 mL), neutralized with an aqueous solution of NaOH (4 M), and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 0 to 5:1) to give Int-136 (2.2 g, 13.3 mmol, 43%) as a brown oil. LCMS (ESI): m / z = 166 [M+H] + .

[0497] Step 3: The mixture of Int-136 (2.2 g, 13.3 mmol, 1.0 equivalent) in NH4OH (20 mL) was stirred at 180ºC for 8 h. After completion, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 100:1 to 1:100) to give Int-137 (1.3 g, 7.9 mmol, 59.6%) as a yellow solid. LCMS (ESI): m / z = 165 [M+H] + .

[0498] Steps 4 to 8: Performed using a similar procedure to that used in Method ZD (Steps 5-9) to provide compound I-165, which was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 10%-95% MeCN (with 0.1% FA) in H2O) to give compound I-165 (5.2 mg, 0.012 mmol) as a white solid.

[0499] Compound I-165: Retention time: 1.159 min; LCMS (ESI): m / z = 437 [M+H] + ; 1HNMR(400 MHz, DMSO) δ 10.09 (s, 1H), 9.06 (d, J = 2.2 Hz, 1H), 8.99 (d, J = 1.9Hz, 1H), 8.60 (t, J = 2.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1Hz, 1H), 3.25 (s, 3H), 2.54 (s, 3H), 2.25 (s, 3H), 2.10 (ddd, J = 13.1, 8.1,4.8 Hz, 1H), 0.97 (d, J = 30.8 Hz, 4H).

[0500] Method of use: ZF synthesized the following compounds using appropriate reagents (including boric acid / borates and sulfonyl chlorides): compounds I-150, I-164, I-181, I-183, I-191, I-192, I-193, I-234, I-235 and I-236. Example 36 Method ZG: Synthesis of compound I-177

[0501] Step 1: At 0ºC, concentrated sulfuric acid (4 mL) and an aqueous solution of NaNO2 (3.3 mL, 2.0 M, 6.6 mmol, 2.0 equivalent) were slowly added to a stirred solution of R-50 (400 mg, 3.28 mmol, 1.0 equivalent) in H2O (20 mL). After stirring for 30 min, the mixture was poured into ice water (50 mL) and neutralized with an aqueous solution of NaOH (1 M). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluted with PE:EtOAc = 2:1 to 1:1) to give Int-142 (221 mg, 1.8 mmol, 54.8%) as a yellow solid. LCMS (ESI): m / z = 124 [M+H] + .

[0502] Step 2: NBS (384.5 mg, 2.16 mmol, 1.2 equivalence) was slowly added to a stirred solution of Int-142 (221 mg, 1.8 mmol, 1.0 equivalence) in MeCN (10 mL). After stirring at room temperature for 30 min, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 10:1 to 4:1) to give Int-143 (230 mg, 1.14 mmol, 63.6%) as a white solid. LCMS (ESI): m / z = 202 [M+H] + .

[0503] Step 3: Under a nitrogen atmosphere at 0ºC, NaH (57.5 mg, 1.37 mmol, 1.2 equivalents) was slowly added to a stirred solution of Int-143 (230 mg, 1.14 mmol, 1.0 equivalents) in 10 mL of THF. After stirring at 0ºC for 30 min, chloro(methoxy)methane (100.3 mg, 1.25 mmol, 1.1 equivalents) was added dropwise to the mixture. After stirring at room temperature for 2 h, the reaction was quenched with a saturated aqueous solution of NH4Cl (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 5:1) to give Int-144 (255 mg, 1.04 mmol, 91%) as a white solid. LCMS(ESI): m / z = 246 [M+H] + .

[0504] Step 4: Add Int-144 (100 mg, 0.69 mmol, 1.0 equivalent), azacyclobutane hydrochloride (71.1 mg, 0.76 mmol, 1.1 equivalent), RuPhos Pd G3 (56 mg, 0.07 mmol, 0.1 equivalent), and NaO tA mixture of Bu (198.9 mg, 2.07 mmol, 3.0 equivalent) in dioxane (20 mL) was stirred at 100ºC for 6 h under a N2 atmosphere. Afterward, the reaction mixture was diluted with H2O (40 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 rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 2:1) to give Int-145 (55.5 mg, 0.25 mmol, 36%) as a white solid. LCMS (ESI): m / z = 223 [M+H] + .

[0505] Step 5: Add TFA (1 mL) to the stirred solution of Int-145 (55.5 mg, 0.25 mmol, 1.0 equivalent) in DCM (5 mL). After stirring at room temperature for 20 min, concentrate the reaction mixture under reduced pressure to obtain Int-146 (50 mg, crude) as a white solid, which is used directly in the next step. LCMS (ESI): m / z = 215 [M+H] + .

[0506] Steps 6 to 10: Perform the same procedure as used in Method ZD (Steps 5-9) to provide compound I-177, which was purified by preparative HPLC (column: YMC-Actus Triart C8 250 x 20 mm, gradient: 30%-95% MeCN in aqueous solution of NH4HCO3 (10 mM)) to give compound I-177 (4.2 mg, 0.0093 mmol) as a white solid.

[0507] Compound I-177: Retention time: 2.665 min; LCMS (ESI): m / z = 451 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.05 (d, J = 2.2Hz, 1H), 8.97 (d, J = 1.9 Hz, 1H), 8.57 (t, J = 2.1 Hz, 1H), 7.94 – 7.83 (m,2H), 6.18 (s, 1H), 3.92 (t, J = 7.3 Hz, 4H), 3.19 (s, 3H), 2.33 – 2.27 (m,2H), 2.11 (s, 3H), 2.01 (s, 3H).

[0508] Method of use: ZG synthesizes the following compound I-180 using appropriate amines, boric acid / borate and sulfonyl chloride. Example 37 Method ZH: Synthesis of compound I-176

[0509] Step 1: At 0ºC, POCl3 (819.6 mg, 5.28 mmol, 3 equivalents) was slowly added to a stirred solution of 4,6-dimethyl-3-nitropyridine-2-ol (R-51, 300 mg, 1.76 mmol, 1.0 equivalent) in DMF (10 mL). After stirring at 90ºC for 3 h, the reaction mixture was quenched with H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 5:1 to 2:1) to give Int-150 (272 mg, 1.46 mmol, 83%) as a white solid. LCMS (ESI): m / z = 187 [M+H] + .

[0510] Step 2: Under a nitrogen atmosphere at 0ºC, NaH (30 mg, 0.75 mmol, 1.2 equivalent) was slowly added to a stirred solution of cyclopropanol (34 mg, 0.59 mmol, 1 equivalent) in THF (10 mL). After stirring for 30 min, Int-150 (100 mg, 0.54 mmol, 0.9 equivalent) was added to the mixture, and the mixture was stirred at room temperature for another 2 h. After completion, the reaction was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 5:1 to 2:1) to give Int-151 (91 mg, 0.44 mmol, 81%) as a white solid. LCMS (ESI): m / z = 209 [M+H] + .

[0511] Step 3: Add Pd / C (94 mg) to a stirred solution of Int-151 (91 mg, 0.44 mmol) in MeOH (10 mL). Stir the resulting mixture overnight at room temperature under H2 atmosphere. After completion, filter the mixture and wash the resulting filter cake with MeOH (10 mL x 3). Concentrate the combined organic phases under reduced pressure. Purify the residue on silica gel by rapid column chromatography (eluting with PE:EtOAc = 0 to 3:1) to give Int-152 (74 mg, 0.41 mmol, 93.2%) as a white solid. LCMS (ESI): m / z = 179 [M+H] + .

[0512] Steps 4 to 9: Perform the same procedure as in Method Y (Steps 5-10) to provide compound I-176, which was purified by preparative HPLC (column: YMC-Actus Triart C8 250 x 20 mm, gradient: 30%-95% MeCN in aqueous solution of NH4HCO3 (10 mM)) to give compound I-176 (5.1 mg, 0.011 mmol) as a white solid.

[0513] Compound I-176: Retention time: 1.425 min; LCMS (ESI): m / z = 452 [M+H] + ; 1H NMR(400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.98 (d, J = 1.9Hz, 1H), 8.59 (t, J = 2.1 Hz, 1H), 7.94 – 7.86 (m, 2H), 6.90 (s, 1H), 4.24(tt, J = 6.1, 3.0 Hz, 1H), 3.14 (s, 3H), 2.42 (s, 3H), 2.15 (s, 3H), 0.59 –0.52 (m, 2H), 0.23 – 0.15 (m, 2H).

[0514] Method of use: ZH synthesizes the following compound I-209 using appropriate alcohols, boric acid / borates and sulfonyl chlorides. Example 38 Method ZI: Synthesis of Compound I-222

[0515] Step 1: Ac₂O (70 mL) was added to a stirred solution of 2-hydroxy-4,6-dimethylnicotinonitrile (R-52, 14.8 g, 100 mmol) in HNO₃ (200 mL). After stirring at room temperature for 10 h, a mixed solvent of PE and EtOAc (1:1, 200 mL) was added to the mixture to obtain a suspension. The mixture was filtered, and the filter cake was washed with PE (50 mL x 3) and dried under vacuum to give Int-158 (9.2 g, 47.7 mmol, 47.7%) as a white solid. LCMS (ESI): m / z = 194 [M+H] + .

[0516] Step 2: Sulfuric acid (35 mL) was slowly added to a stirred solution of Int-158 (7 g, 36.3 mmol, 1.0 equivalent) in water (200 mL). The resulting mixture was stirred at 180ºC under a N2 atmosphere for 2 h. After completion, the reaction mixture was cooled to room temperature and extracted with EtOAc (100 mL x 5). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 1:5) to give Int-159 (4.0 g, 23.8 mmol, 65.6%) as a yellow solid. LCMS (ESI): m / z = 169 [M+H] + .

[0517] Step 3: DMF (1 mL) was slowly added to a stirred solution of Int-159 (2.4 g, 14.3 mmol, 1.0 equivalent) in POCl3 (30 mL). After stirring at 110ºC for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (150 mL) and the resulting solution was extracted with EtOAc (100 mL x 3). The combined organic phases were then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 1:1) to give Int-160 (1.2 g, 6.45 mmol, 45.1%) as a white solid. LCMS (ESI): m / z = 187 [M+H] + .

[0518] Step 4: NaOMe (513 mg, 9.5 mmol, 5 equivalents) was slowly added to a stirred solution of Int-160 (350 mg, 1.9 mmol, 1.0 equivalent) in MeOH (10 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 5:1) to give Int-161 (300 mg, 1.65 mmol, 86.8%) as a white solid. LCMS (ESI): m / z = 183 [M+H] + .

[0519] Step 5: The mixture of Int-161 (300 mg, 1.65 mmol) and Pd / C (80 mg) in MeOH (20 mL) was stirred at room temperature for 2 h under H2 atmosphere. After completion, the reaction mixture was filtered through a diatomaceous earth pad and the filter cake was washed with MeOH (30 mL x 3). The combined filtrates were concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with PE:EtOAc = 0 to 1:10) to give Int-162 (240 mg, 1.58 mmol, 95.6%) as a white solid. LCMS (ESI): m / z = 153 [M+H] + .

[0520] Step 6: At 0ºC, HBF4 (7 mL) and an aqueous solution of NaNO2 (1.25 mL, 2 M, 2.5 mmol, 1.6 equivalent) were slowly added to a stirred solution of Int-162 (240 mg, 1.58 mmol, 1 equivalent) in water (7 mL). After stirring at room temperature for 1 h, the mixture was stirred at 100ºC for 5 h. After completion, the mixture was poured into ice water (50 mL), neutralized with an aqueous solution of NaOH (4 M), and extracted with EtOAc (50 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (eluting with EtOAc) to give Int-163 (91 mg, 0.59 mmol, 37.6%) as a white solid. LCMS (ESI): m / z = 154 [M+H] + .

[0521] Steps 7 to 11: Performed using a similar procedure to that used in Method Y (Steps 6-10) to provide compound I-222, which was purified by preparative HPLC (column: Welch Xbridge XB 5 μm 21.2 x 250 mm, gradient: 25%-95% MeCN (with 0.1% TFA) in H2O) to give compound I-222 (12.1 mg, 0.028 mmol) as a white solid.

[0522] Compound I-222: Retention time: 1.317 min; LCMS (ESI): m / z = 426.4 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 1.9Hz, 1H), 8.57 (t, J = 2.2 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.1Hz, 1H), 6.69 (s, 1H), 3.85 (s, 3H), 3.22 (s, 3H), 2.21 (s, 3H), 2.07 (s,3H).

[0523] Method of use: ZI synthesizes the following compounds I-132 and I-178 using appropriate alcohols, boric acid / borates and sulfonyl chlorides. Example 39 Method ZJ: Synthesis of Compound I-182

[0524] Step 1: A mixture of 2-bromo-3-methyl-5-nitropyridine (R-53, 200 mg, 0.92 mmol, 1.0 equivalent), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (R-54, 350 mg, 1.84 mmol, 2.0 equivalent), and CuI (350 mg, 1.84 mmol, 2.0 equivalent) in DMF (6 mL) was stirred at 100ºC for 2 h under N2 atmosphere. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography over silica gel (eluting with PE:EtOAc = 5:1) to give Int-168 as a white solid (100 mg, 0.49 mmol, 53.3%). LCMS (ESI): m / z = 207 [M+H] + .

[0525] Step 2: A mixture of Int-168 (100 mg, 0.49 mmol, 1.0 equivalent), NH4Cl (262 mg, 4.9 mmol, 10.0 equivalent), and Fe (271 mg, 4.9 mmol, 10.0 equivalent) in EtOH (30 mL) and H2O (10 mL) was stirred at 80ºC for 1 h. After completion, the reaction mixture was filtered through a Celite® pad, and the filter cake was washed with MeOH (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography using silica gel (eluted with PE:EtOAc = 4:1 to 3:1) to give Int-169 (60 mg, 0.34 mmol, 69.4%) as a white solid. LCMS (ESI): m / z = 177 [M+H] + .

[0526] Steps 3 to 10: Performed using a similar procedure to that used in Method Y (Steps 3-10) to provide compound I-182, which was purified by preparative HPLC (column: YMC-Actus Triart C18 250 x 20 mm x 5 μm, gradient: 10%-95% MeCN (with 0.1% FA) in H2O) to give compound I-182 (3.1 mg, 0.0065 mmol) as a white solid.

[0527] Compound I-182: Retention time: 1.457 min; LCMS (ESI): m / z = 464 [M+H] + ; 1 H NMR(400 MHz, DMSO) δ 10.02 (s, 1H), 9.12 (d, J = 2.1 Hz, 1H), 9.00 (d, J = 1.9Hz, 1H), 8.60 (t, J = 2.1 Hz, 1H), 8.00 (q, J = 8.1 Hz, 2H), 7.87 (s, 1H), 3.22 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H). Example 40 Method ZK: Synthesis of Compound I-251

[0528] Step 1: Add Na₂CO₃ (68 mg, 0.63 mmol, 4.0 equivalent), (5-cyanopyridin-3-yl)boronic acid (R-10, 36 mg, 0.24 mmol, 1.5 equivalent), and Pd(PPh₃)₄ (18 mg, 16 µmol, 0.1 equivalent) to a solution of Int-41 (50 mg, 0.1 mmol, 1.0 equivalent) in toluene (6 mL), EtOH (6 mL), and H₂O (2 mL). Stir the reaction mixture at 100ºC under N₂ for 2 h. After stirring, pour the reaction mixture into water (30 mL) and extract with EtOAc (15 mL x 3). Combine the organic layers and wash with brine (20 mL), dry to anhydrous Na₂SO₄, and concentrate under reduced pressure. The residue was purified on silica gel by rapid column chromatography (eluting with PE:EtOAc = 3:1 to 2:1) to give Int-177 (50 mg, 0.13 mmol, 79%) as a white solid. LC-MS (ESI) m / z = 388 [M+H] + .

[0529] Step 2: A mixture of Int-177 (50 mg, 0.13 mmol, 1.0 equivalent), Fe powder (36 mg, 0.65 mmol, 5 equivalent), and NH4Cl (70 mg, 1.3 mmol, 10 equivalent) in EtOH (20 mL) and H2O (10 mL) was stirred at 80ºC for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH. The combined filtrates were concentrated, the residue was ground with H2O, and then filtered to give Int-178 (44.2 mg, crude) as a brown solid. LCMS (ESI): m / z = 358 [M+H] + .

[0530] Step 3: At 0ºC, slowly add Int-178 (380 mg, 1.06 mmol, 1.0 equivalent) to a stirred solu...

Claims

1. A compound represented by formula I: Or its pharmaceutically acceptable salt, wherein: Ring A 1 It is (i) a 6-membered heteroarylene having one or two heteroatoms selected from nitrogen; (ii) a phenylene; or (iii) a 5- to 7-membered saturated or partially unsaturated monocyclic oxy-heterocyclic group having one to two heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic oxo-heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic group containing 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 Replacement; or ring B 1 It is k R 3 Substituted phenyl; Ring C 1 It is a phenylene oxide, a 5- or 6-membered heteroarylene or pyridinyl-N-oxide containing one or two heteroatoms selected from nitrogen, oxygen and sulfur; R 1 is -N(R 9 )-SO2-R 6 , -SO2-N(R 9 )-R 6 , -SO2-N(R 7 )2, -S(NR 9 )(O)-R 6 , -N=S(O)(R 9 )2, -S(O2)-R 6 or ; R 2 Each time it appears, it independently represents the hydroxyl group and C. 1-3 Alkyl, Halogenated, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, C 3-4 cycloalkyl, -OR 11 A 3-5 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl group and heterocyclic group is separated by q R 12 Replacement; or two adjacent Rs 2 Together with the atoms to which they are attached, they form 3-6 membered rings with 0, 1, or 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur; R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 2-3 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl, (C 0-2 (alkylene)-C 1-6 Alkoxy, C 1-3 Hydroxyalkyl, -CON(R) 4 )2、-C(O)-R 5 -C(O)-OR 5 -S(O)2-R 5 -N(R) 4 )-C(O)-R 5 -S(NR) 4 (O)-R 5 C 1-6 Halogenated alkoxy groups, C 3-4 Cycloalkyl groups, or 3-6 membered heterocyclic groups having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl group and heterocyclic group is divided by r R groups. 13 replace; R 4 Each time it appears, it independently represents hydrogen and C. 1-4 Alkyl or cyclopropyl; R 5 and R 6 Each occurrence of C is represented independently. 1-4 Alkyl, C 3-5 cycloalkyl, -(C 0-2 alkylene)-phenyl, -(C 0-2 Alkylene)-(a 3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or -(C 0-2 Alkylene group (5-10-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein the cycloalkyl, phenyl, heterocyclic and heteroaryl groups are separated by m R 8 Substitution, and wherein each alkylene group is replaced by n R groups. 8 replace; R 7 It is hydrogen, or two R atoms attached to the same nitrogen atom. 7 The groups, together with the nitrogen to which they are attached, form a 3- to 6-membered saturated monocycle having 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen atom. R 8 C is represented independently each time it appears. 1-4 Alkyl, Halogenated, C 1-3 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, cyano, or cyclopropyl; R 9 Each time it appears, it independently represents hydrogen and C. 1-3 Alkyl or cyclopropyl; R 10 It is C 1-3 Alkyl, C 1-3 Haloalkyl, halogroup, hydroxyl or cyclopropyl; R 11 It is C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyclopropyl, or 3- to 5-membered saturated heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 It is C 1-3 Alkyl, halogroup, cyano, or -SO2-(C 1-3 alkyl); R 13 It is a halogenated group, C 1-3 Alkyl or C 1-3 Alkoxy; h is 0, 1, or 2; j is 0, 1, or 2; k is 1 or 2; m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 1, 2, 3 or 4; q is 0, 1, or 2; and r is 0, 1, or 2.

2. The compound according to claim 1, wherein the compound is a compound of formula I.

3. The compound according to claim 1 or 2, wherein the ring C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen and sulfur.

4. The compound according to claim 1 or 2, wherein the ring C 1 It is a pyridyl group.

5. The compound according to claim 1 or 2, wherein the ring C 1 It is a pyrimidinyl group.

6. The compound according to any one of claims 1-5, wherein p is 3.

7. The compound according to any one of claims 1-5, wherein p is 4.

8. The compound according to claim 1, wherein the compound is a compound of formula IA or a pharmaceutically acceptable salt thereof: 。 9. The compound of claim 1, wherein the compound is a compound of formula IB, IC, or ID, or a pharmaceutically acceptable salt thereof: 。 10. The compound according to any one of claims 1-9, wherein ring A 1 It is a 6-membered monocyclic heteroaromatic ring containing one or two heteroatoms selected from nitrogen.

11. The compound according to any one of claims 1-9, wherein ring A 1 It is a pyridyl group.

12. The compound according to any one of claims 1-9, wherein ring A 1 It is a pyrimidinyl group.

13. The compound according to any one of claims 1-12, wherein R 1 It is -N(R) 9 )-SO2-R 6 .

14. The compound according to any one of claims 1-12, wherein R 1 It is -SO2-N(R) 9 )-R 6 .

15. The compound according to any one of claims 1-12, wherein R 1 It is -SO2-N(R) 7 )2.

16. The compound according to any one of claims 1-12, wherein R 1 It is -S(NR) 9 (O)-R 6 .

17. The compound according to any one of claims 1-12, wherein R 1 It is -S(O2)-R 6 .

18. The compound according to any one of claims 1-17, wherein h is 0.

19. The compound according to any one of claims 1-17, wherein h is 1.

20. The compound of claim 1, wherein the compound is a compound of formula IE or a pharmaceutically acceptable salt thereof: 。 21. The compound of claim 1, wherein the compound is a compound of formula IF or a pharmaceutically acceptable salt thereof: 。 22. The compound of claim 1, wherein the compound is a compound of the formula IG, IH, IJ, IK or IL or a pharmaceutically acceptable salt thereof: 。 23. The compound of claim 1, wherein the compound is a compound of the formula IM, IN, IO, IP, or IQ, or a pharmaceutically acceptable salt thereof: 。 24. The compound according to any one of claims 20-23, wherein the ring C 1 It is a 6-membered heteroaryl group containing one or two heteroatoms selected from nitrogen, oxygen and sulfur.

25. The compound according to any one of claims 20-23, wherein the ring C 1 It is either pyridyl or pyrimidinyl.

26. The compound according to any one of claims 20-23, wherein the ring C 1 It is a pyridyl group.

27. The compound according to any one of claims 20-23, wherein the ring C 1 It is a pyrimidinyl group.

28. The compound according to any one of claims 1-27, wherein ring B 1 It is a 5-6 membered monocyclic heteroaryl group having 1-3 independent heteroatoms selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is divided by j R 3 replace.

29. The compound according to any one of claims 1-27, wherein ring B 1 It is a 3-7 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bridged or spirocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is divided by j R 3 replace.

30. The compound according to any one of claims 1-27, wherein ring B 1 It is pyridyl, pyrazolyl, imidazolyl, piperazinyl, 2,5,-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl or azacyclobutyl, wherein each ring is divided by j R 3 replace.

31. The compound according to any one of claims 1-27, wherein ring B 1 It was by j R 3 Substituted pyridinyl group.

32. The compound according to any one of claims 1-27, wherein ring B 1 It is k R 3 Substituted phenyl groups.

33. The compound of claim 1, wherein the compound is a compound of formula IW or a pharmaceutically acceptable salt thereof: 。 34. The compound of claim 1, wherein the compound is a compound of formula IX or a pharmaceutically acceptable salt thereof: 。 35. The compound according to any one of claims 1-34, wherein j is 1.

36. The compound according to any one of claims 1-34, wherein j is 2.

37. The compound according to any one of claims 1-34, wherein p is 1.

38. The compound according to any one of claims 1-34, wherein p is 2.

39. The compound according to any one of claims 1-34, wherein p is 3.

40. The compound of claim 1, wherein the compound is a compound of formula IY or a pharmaceutically acceptable salt thereof: 。 41. The compound according to claim 1, wherein the compound is a compound of formula IZ or a pharmaceutically acceptable salt thereof: 。 42. The compound according to any one of claims 1-41, wherein R 3 Each time it appears, it independently represents the halogen group, cyano group, and C group. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl or C 1-6 Alkyl group.

43. The compound according to any one of claims 1-41, wherein R 3 It is a cyano group.

44. The compound according to any one of claims 1-43, wherein R 2 C is represented independently each time it appears. 1-3 Alkyl, C 1-3 Haloalkyl, -O-(C 1-4 (halogenated alkyl) or C 3-4 Cycloalkyl.

45. The compound according to any one of claims 1-43, wherein R 2 Each time it appears, it independently represents methyl, cyclopropyl, -CHF2, -O-cyclopropyl, -CF3, or -O-CF3.

46. ​​The compound according to any one of claims 1-43, wherein R 2 It is a methyl group.

47. The compound according to any one of claims 1-46, wherein R 6 C is represented independently each time it appears. 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, phenyl, heterocyclic and heteroaryl group is surrounded by m R 8 replace.

48. The compound according to any one of claims 1-46, wherein R 6 C is represented independently each time it appears. 1-4 Alkyl or C 3-5 Cycloalkyl.

49. The compound according to any one of claims 1-46, wherein R 6 It is a methyl group.

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

51. The compound of claim 50, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

52. A pharmaceutical composition comprising a compound according to any one of claims 1-51 and a pharmaceutically acceptable carrier.

53. A method for treating a disorder associated with ABC transporter dysfunction, the method comprising administering a therapeutically effective amount of the compound according to any one of claims 1-51 to a subject in need to treat the disorder.

54. The method of claim 53, wherein the impairment associated with ABC transporter dysfunction is characterized by impairment of one or more transporters selected from the group consisting 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.

55. A method for treating or preventing a disorder, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-51 to treat or prevent the disorder, wherein the disorder is selected from Tangier disease, pulmonary surfactant metabolic dysfunction type 3, autosomal recessive congenital ichthyosis 4A (ARCI), naked lymphocyte syndrome type I, naked lymphocyte syndrome type I due to TAP2 deficiency, hereditary generalized pigmentary disorder type 3, X-linked sideroblastic anemia with ataxia, Durbin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis disorder type 5, methylmalonic aciduria and homocystinuria type cblJ, sitosterolemia, Staggart disease, PFIC3, P FIC2, elastic pseudoxanthoma, X-linked adrenoleukodystrophy (ALD), cholestasis, hyperbilirubinemia, intrahepatic cholestasis of pregnancy, biliary atresia, Arager's syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD / NASH, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hill's-Sprolon disease, brain-hepatorenal syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile generalized arterial calcification, calcification defense, autosomal recessive cone-rod dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, hypophospholipid-associated cholelithiasis, chronic kidney disease, progeria (Hargee-Gilles syndrome), hemodialysis, end-stage renal disease, aortic stenosis, peripheral artery disease, or ischemic stroke.

56. The method of claim 55, wherein the barrier is selected from calcification defense, elastic pseudoxanthoma, infantile generalized arterial calcification, chronic kidney disease, progeria (Harge's progeria syndrome), hemodialysis, end-stage renal disease, aortic stenosis, peripheral artery disease, or ischemic stroke.

57. The method of claim 56, wherein the compound is the compound of claim 51.

58. A method for modulating the function of an ABC transporter in a subject, the method comprising administering an effective amount of the compound according to claim 1 to the subject, thereby modulating the function of the ABC transporter in the subject.

59. The method of claim 58, wherein the ABC transporter is selected from one or more of the following: 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.

60. The method according to any one of claims 53-59, wherein the subject is a human.

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