Indole amides and related compounds and their uses in the treatment of medical conditions

Abstract

The present invention provides indole amides and related compounds, pharmaceutical compositions, and their use in the treatment of medical conditions.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefit and priority of U.S. provisional application No. 63 / 610,803 filed December 15, 2023, the contents of which are incorporated herein by reference in their entirety.

[0003] Field of invention

[0004] The present invention provides indole amides and related compounds, pharmaceutical compositions, and their use in the treatment of medical conditions. Background Technology

[0005] ATP-binding cassette (ABC) transporters are a large, phylogenetically conserved family of genes with extensive physiological and pathological relevance.[1,2] They are expressed throughout the body and transport various substrates across lipid membranes. ABC transporters are transmembrane ATP-binding proteins that use the energy released during ATP hydrolysis to move substrates from one side of a lipid membrane to another.[2,3]

[0006] At least 21 ABC transporters are the cause of rare monogene disorders, and many more transporters are associated with the predisposition and symptoms of common and complex diseases. These broad (pathogenic)physiological relevances place this class of proteins at the intersection of disease causation and therapeutic potential, clearly demonstrating that they are promising targets for drug discovery. Based on a small number of characterized disorders, including cystic fibrosis (CF), progressive familial intrahepatic cholestasis 2 (PFIC2), and Stargardt disease (STGD), pathogenic ABC transporter missense mutations share mechanistic commonalities, which primarily affect protein folding to lead to endoplasmic reticulum (ER) degradation (trafficking defects) or affect protein function to reduce substrate transport (transport defects). Importantly, small molecule compounds can enable the treatment of disease symptoms that are not directly caused by mutations in ABC transporter genes.

[0007] There is a need for small molecule compounds capable of positively modulating ABC transporter function and thus being usable for the treatment of diseases; such enhancement is predicted to have therapeutic value in modifying the disease or treating disease symptoms. For example, for the treatment of PFIC2, PFIC3, PXE / GACI, STGD, X-ALD, and Alzheimer's disease, modulators capable of addressing mutations in ABCB11, ABCB4, ABCC6, ABCA4, ABCD1, ABCA1, and ABCA7 are required.

[0008] Therefore, there is a need for new therapeutic methods and compounds to treat ABC transporter dysfunction. The present invention addresses the aforementioned need and provides other related advantages.

[0009] The present invention provides indole amides and related compounds, pharmaceutical compositions, and their uses in the treatment of medical conditions. In particular, one aspect of the present invention is a group of indole amide compounds, such as compounds represented by the formula I.

[0010]

[0011] Or provide a pharmaceutically acceptable salt thereof, wherein, in the above formula, the variables are as defined in the detailed description. Further description of an additional set of indole amide compounds is provided in the detailed description. The compound may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0012] Another aspect of the present invention provides a method for treating ABC transporter dysfunction. The method comprises the step of treating the ABC transporter dysfunction further described in the detailed description by administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject requiring treatment for ABC transporter dysfunction. Specific details for implementing the invention

[0013] The present invention provides indole amides and related compounds, pharmaceutical compositions, and their use in the treatment of medical conditions. Unless otherwise specified, the practice of the present invention utilizes the ordinary skills of organic chemistry, pharmacology, molecular biology (including recombination techniques), cell biology, biochemistry, and immunology. These skills are described in the literature, e.g., “Comprehensive Organic Synthesis” (BM Trost & I. Fleming, eds., 1991–1992); “Handbook of experimental immunology” (DM Weir & CC Blackwell, eds.); “Current protocols in molecular biology” (FM Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (JE Coligan et al. These are described in , eds., 1991), each of which is incorporated herein by reference in its entirety.

[0014] Various aspects of the invention are presented in the following sections; however, the aspects of the invention described in one particular section are not limited to any particular section. Additionally, where a variable is not accompanied by a definition, the prior definition of the variable applies.

[0015] definition

[0016] The compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. Unless otherwise specified, these definitions shall apply regardless of whether the terms are used by themselves or in combination with other terms. Accordingly, the definition of 'alkyl' applies not only to 'alkyl' but also to the 'alkyl' portion, such as '-O-alkyl'. For the purposes of the present invention, chemical elements are [Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are confirmed according to Ed.]). Additionally, the general principles of organic chemistry are confirmed according to the literature ["Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999] and the literature ["March's Advanced Organic Chemistry", 5 th It is described in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001], the entire contents of which are incorporated herein by reference.

[0017] As used herein, the terms “aliphatic” or “aliphatic group” mean a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as “aliphatic”) and has a single attachment site to the rest of the molecule. Unless otherwise specified, the aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, ‘aliphatic’ refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has a single attachment site to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0018] As used herein, the terms 'bicyclic ring' or 'bicyclic ring system' refer to any bicyclic ring system, that is, a carbocyclic or heterocyclic having one or more saturated or unsaturated units and one or more atoms common between the two rings of the ring system. Accordingly, this term OrsoIt includes any permissible ring fusion, such as fusion or spirocyclic. As used herein, the term 'heterobicyclic' is a subset of 'bicyclic' in which one or more heteroatoms are required to be present in one or both rings of the bicycle. These heteroatoms may be present at ring junctions, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term 'cross-linked bicyclic' refers to any bicyclic ring system having at least one bridge, i.e., saturated or partially unsaturated carbocyclic or heterocyclic. As defined by IUPAC, a 'bridge' is an unbranched atomic chain or atom or valence bond connecting two bridge heads, and a 'bridge head' is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the cross-linked bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such cross-linked bicyclic groups are widely known in the art and include those presented below, each of which is attached to any substitutable carbon or nitrogen atom in the remainder of the molecule. Unless otherwise specified, the cross-linked bicyclic group is optionally substituted with one or more substituents as presented for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the cross-linked bicyclic group is optionally substituted. An exemplary bicyclic ring comprises the following.

[0019]

[0020] An exemplary cross-linked bicycle includes the following.

[0021]

[0022] The term 'lower alkyl' is C 1-4 It refers to linear or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0023] The term 'lower haloalkyl' refers to C substituted with one or more halogen atoms. 1-4 It refers to a linear or branched alkyl group.

[0024] The term 'heteroatom' refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any quaternary form of basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, e.g., N(3,4-dihydro-2) H -as in pyrrolyl), NH (as in pyrrolidinyl), or NR + It means one or more of (including as in N-substituted pyrrolidinyl).

[0025] As used herein, the term 'unsaturated' means that a moiety has one or more unsaturated units.

[0026] The term '2-C' used at this institution 1-8 (or C 1-6 ) Saturated or unsaturated, linear or branched hydrocarbon chains refer to linear or branched dialkylene, alkenylene, and alkynylene chains as defined herein.

[0027] The term 'alkylene' refers to a divalent alkyl group. An 'alkylene chain' is a polymethylene group, i.e., -(CH2) n- and, 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 group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for the substituted aliphatic group.

[0028] The term '-(COalkylene)-' refers to a bond. Therefore, the term '-(C 0-3 Alkylene)-' is a bond (i.e., C0) and -(C 1-3 It contains an alkylene)-group.

[0029] The term 'alkenylene' refers to a divalent alkenyl group. The substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those listed below for the substituted aliphatic group.

[0030] The terms 'halo' and 'halogen' mean F, Cl, Br, or I.

[0031] The term "aryl," used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, at least one ring of the system being aromatic, and each ring of the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In specific embodiments of the present invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc. A group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, is also included within the category of the term "aryl" as used herein. The term "phenylene" refers to a polyvalent phenyl group having a suitable number of open valencies, taking into account the groups attached thereto. For example, when 'phenylene' has two groups attached to it, a divalent phenyl group (e.g., ) and; when 'phenylene' has three groups attached thereto, it is a trivalent phenyl group (e.g., The term 'arylene' refers to a divalent aryl group.

[0032] The terms ‘heteroaryl’ and ‘heteroar-’, used alone or as part of a larger moiety, e.g., ‘heteroaralkyl’ or ‘heteroaralkoxy’, refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to a carbon atom. The term ‘heteroatom’ refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternary form of basic nitrogen. The heteroaryl group comprises, without limitation, thienyl, furanyl, pyrrolyl, imidazoleyl, pyrazolyl, triazoleyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazoleyl, thiazolyl, isothiazoleyl, thiadiazoleyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indoliginyl, furinyl, naphthiridinyl, and pteridinyl. As used herein, the terms 'heteroaryl' and 'heteroar-' also comprise a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclil rings, and unless otherwise specified, the radical or attachment site is on the heteroaromatic ring or one of the rings in which the heteroaromatic ring is fused. Non-limiting examples include indoleyl, isoindoleyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazoleyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H-Includes quinoliginil, carbazoleyl, acrridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group may be mono- or bicyclic. The term 'heteroaryl' may be used interchangeably with the terms 'heteroaryl ring', 'heteroaryl group', or 'heteroaromatic', any of which includes an optionally substituted ring. The term 'heteroaralkyl' refers to an alkyl group substituted by a heteroaryl, and the alkyl and heteroaryl portions are independently and optionally substituted.

[0033] The term 'heteroarylene' refers to a polyvalent heteroaryl group having an appropriate number of open valencies considering the groups attached thereto. For example, 'heteroarylene' is a divalent heteroaryl group when it has two groups attached thereto; and 'heteroarylene' is a trivalent heteroaryl group when it has three groups attached thereto.

[0034] The terms 'heterocycle', 'heterocyclile', 'heterocyclic radical', and 'heterocyclic ring' as used herein 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 as defined above and has one or more, preferably 1 to 4, heteroatoms in addition to a carbon atom. When used with reference to the ring atoms of a heterocycle, the term 'nitrogen' includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen is N(3,4-dihydro-2 H- As in the case of pyrrolyl), NH (as in the case of pyrrolidinyl), or + NR( N- It can be (as in the case of substituted pyrrolidinyl).

[0035] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolaninyl, diazefinyl, oxazefinyl, thiazefinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms 'heterocycle', 'heterocyclile', 'heterocyclile ring', 'heterocyclic group', 'heterocyclic moiety', and 'heterocyclic radical' are used interchangeably herein, and furthermore, the heterocyclile ring comprises one or more aryl, heteroaryl, or alicyclic rings, e.g., indolinyl, 3 H- It includes a group fused to indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be mono- or bicyclic. The term 'heterocyclylalkyl' refers to an alkyl group substituted by a heterocyclyl, and the alkyl and heterocyclyl portions are independently and optionally substituted. The term 'oxo-heterocyclyl' refers to a heterocyclyl substituted by one or more oxo groups. The term 'heterocyclilene' refers to a polyvalent heterocyclyl group having an appropriate number of open valencies considering the groups attached thereto. For example, 'heterocyclilene' is a divalent heterocyclyl group when it has two groups attached thereto; and 'heterocyclilene' is a trivalent heterocyclyl group when it has three groups attached thereto. The term 'oxo-heterocyclilene' refers to a multivalent oxo-heterocyclile group having an appropriate number of open valencies, taking into account the groups attached thereto.

[0036] As used herein, the term 'partially unsaturated' refers to a ring moiety comprising at least one double or triple bond. The term 'partially unsaturated' is intended to encompass rings having polyunsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0037] As described herein, the compounds of the present invention may contain 'optionally substituted' moiety. Generally, the term 'substitution' means that one or more hydrogens of a specified moiety are replaced with suitable substituents, whether or not the term 'optionally' precedes them. Unless otherwise specified, the 'optionally substituted' group may have suitable substituents at each substitutable position of the group, and when more than one position of any given structure is substituted with more than one substituent selected from the specified group, the substituents may be the same or different at all positions. The combinations of substituents conceived by the present invention are preferably those that form stable or chemically feasible compounds. As used herein, the term 'stable' refers to a compound that is substantially unchanged when applied to conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0038] Each optional substituent on the substitutable carbon is a halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 -(CH2) that can be substituted with SR°; R° 0-4 -(CH2) that can be replaced by Ph; R° 0-4 O(CH2) 0-1Ph; R°로 치환될 수 있는 -CH=CHPh; R°로 치환될 수 있는 -(CH2) 0-4 O(CH2) 0-1 -피리딜; -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; -(C1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 It is a monovalent substituent independently selected from linear or branched alkylene)C(O)ON(R°)2.

[0039] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; notwithstanding the above definition, two independent cases of R° are taken together with their intervening atom(s) to form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted with a divalent substituent on the saturated carbon atom of R° selected from =O and =S; each R° is a halogen, -(CH2) 0-2 R ● , -(HalloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(HalloR ● ), -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) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ●3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● It is selectively substituted with a monovalent substituent independently selected from.

[0040] Each R ● C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Independently selected from a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur, and each R ● It is unsubstituted, or if a halo precedes it, it is substituted with only one or more halogens; optional substituents on the saturated carbon are =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 A divalent substituent independently selected from S-, or a divalent substituent bonded to an adjacent substitutable carbon of the 'selectively substituted' group, is -O(CR * 2) 2-3 O- and, R * Each independent case of hydrogen, C 1-6 It is selected from an aliphatic or unsubstituted 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] R * Ga C 1-6 When aliphatic, R * is a halogen, -R ●, -(HalloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2 is optionally substituted, and each R ● C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Independently selected from a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur, and each R ● When unsubstituted or preceded by a halo, it is substituted with only one or more halogens.

[0042] The selective substituent on the substitutable nitrogen is independently -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † and; each R † is independently hydrogen, C 1-6 It is an aliphatic, unsubstituted -OPh, or unsubstituted 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R †Two independent cases of are taken together with their intervening atoms(s) to form an unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † Ga C 1-6 When aliphatic, R † is a halogen, -R ● , -(HalloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2 is optionally substituted, and each R ● C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Independently selected from a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur, and each R ● When unsubstituted or preceded by a halo, it is substituted with only one or more halogens.

[0043] As used herein, the term "pharmaceuticalally acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and correspond to a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are widely known in the art. For example, SM Berge et alPharmaceutically acceptable salts are described in detail in the literature [J. Pharmaceutical Sciences, 1977, 66, 1-19] by reference herein. 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-added salts are salts of amino groups formed using inorganic acids, such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, Includes pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salt, etc.

[0044] In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are, for example, [P. Stahl] in the literature. et al. , Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al. , Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould. I nternational J. of Pharmaceutics (1986) 33 201-217; Anderson et al. , The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book This is discussed in [Food & Drug Administration, Washington, DC on their website]. The disclosures thereof are incorporated herein by reference.

[0045] Salts derived from appropriate bases are alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 It includes alkyl)tetraphosphates. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, when appropriate.

[0046] Unless otherwise specified, the structures described herein also include structures of all isomer forms (e.g., enantiomers, diastereomers, and geometric (or morphological)); for example, R and S stereoconfigurations for each asymmetric center, Z and E double bond isomers, and Z and E morphological isomers. Thus, not only single stereochemical isomers of the compounds but also enantiomers, diastereomers, and geometric (or morphological) mixtures are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention comprises compounds that differ only in the presence of one or more isotope-enriched atoms. For example, the substitution of hydrogen by deuterium or tritium or 13 C- or 14 Compounds having the present structure, comprising the substitution of carbon by C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0047] A mixture of diastereomers can be separated into their individual diastereomers by methods known to those skilled in the art, such as chromatography and / or fractional crystallization, based on their physicochemical differences. The enantiomers can be separated by a suitable optically active compound ( for example , react with a chiral auxiliary, e.g., chiral alcohol or moscher acid chloride) to convert a mixture of enantiomers into a mixture of diastereomers, separate the diastereomers, and convert the individual diastereomers into their corresponding pure enantiomers ( for exampleIt can be separated by hydrolysis. Alternatively, a specific enantiomer of the compound of the present invention may be prepared by asymmetric synthesis. Additionally, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), a diastereomer salt is formed using a suitable optically active acid or base, and then the formed diastereomer is decomposed by fractional crystallization or chromatographic means known in the art, followed by the subsequent recovery of the pure enantiomer.

[0048] The individual stereoisomers of the compounds of the present invention may, for example, have substantially no other isomers, or may, for example, be mixed with all other or other selected stereoisomers as a racemic mixture. The chiral center(s) of the compounds of the present invention are IUPAC As defined by the 1974 recommendations S or R It may have a stereochemical configuration. Additionally, the compound described herein is a rotationally hindered isomer ( for example All forms of such rotation-impaired isomers are considered part of the present invention as long as they exist as substituted biaryls.

[0049] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both its chemical structure and chemical name, and there is ambiguity between the structure and the name, the structure takes precedence. Additionally, it should be noted that in the text, reaction schemes, examples, and tables of this application, any carbon with an unsatisfied valence, as well as heteroatoms, are assumed to have a sufficient number of hydrogen atoms to satisfy the valence.

[0050] As used herein, singular terms mean 'one or more' and include the plural unless contextually inappropriate.

[0051] The term 'alkyl' refers herein to each C1-C 12 Alkyl, C1-C10 It refers to saturated linear or branched hydrocarbons such as linear or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, referred to as alkyl, 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, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0052] The term 'cycloalkyl' refers to a monovalent saturated cyclic, bicyclic, or cross-linked cyclic (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, referred herein as 'C3 to C6 cycloalkyl' derived, for example, from cycloalkanes. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term 'cycloalkylene' refers to a divalent cycloalkyl group.

[0053] 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.

[0054] The term 'hydroxyalkyl' refers to an alkyl group substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, etc.

[0055] The terms 'alkenyl' and 'alkynyl' refer to unsaturated aliphatic groups recognized in the art that are similar in length to the alkyl described above and are substitutable, each containing at least one double or triple bond.

[0056] The terms 'alkyxyl' or 'alkoxy' refer to the alkyl groups defined above that are recognized in the art and have oxygen radicals attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert - Includes butoxy, etc. The term 'haloalkoxyl' refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc.

[0057] The term 'oxo' is recognized in the industry and refers to an '=O' substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0058] sign ' ' indicates the attachment point.

[0059] Where any substituent or variable occurs more than once in any component or compound of the present invention, unless otherwise specified, its definition in each case is independent of its definition in all other cases.

[0060] One or more compounds of the present invention may exist in a non-solvent form as well as in a solvent form having a pharmaceutically acceptable solvent such as water, ethanol, etc., and the present invention is intended to encompass both the solvent and nonsolvent forms. 'Solvent' refers to a physical association of a compound of the present invention and one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvent may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. 'Solvent' encompasses both solution-phase solvents and isolable solvents. Non-limiting examples of suitable solvents include ethanolates, methanolates, etc. 'Hydrate' is a solvent in which the solvent molecule is H2O.

[0061] As used herein, the terms 'subject' and 'patient' are used interchangeably and refer to an organism treated by the method of the present invention. Such an organism is preferably a mammal ( for example It includes, but is not limited to, murine, monkey, horse, cow, pig, dog, cat, etc., and most preferably includes humans.

[0062] term 'IC' 50 ' refers to the concentration of a compound recognized in the industry and required to achieve 50% inhibition of the target.

[0063] term 'EC' 50 ' refers to the concentration of a compound required to achieve a reaction with a maximum target effect of 50% relative to the baseline, which is recognized in the industry.

[0064] Term 'E max ' refers to the concentration of a compound recognized in the industry and required to achieve the maximum target effect.

[0065] The term 'effective dose' as used herein refers to a beneficial or desired result ( for exampleIt refers to an amount of compound sufficient to achieve the result of treatment, improvement, inhibition, or prevention. The effective amount may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific formulation or route of administration. As used herein, the term 'treating' refers to any effect, for example It includes reducing, decreasing, controlling, improving, or eliminating pathological conditions, diseases, disabilities, etc., thereby causing improvement in them or improvement in their symptoms.

[0066] As used herein, the term 'pharmaceutical composition' refers to a combination of an active agent and an inactive or active carrier, and this refers to a composition In vivo or In vitro It is made particularly suitable for diagnostic or therapeutic purposes.

[0067] As used herein, the term 'pharmaceuticalally acceptable carrier' refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsion ( for example It refers to oil / water or water / oil emulsions) and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for instance, the literature [Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ].

[0068] For therapeutic use, the salts of the compounds of the present invention are considered pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0069] In addition, when a compound of the chemical formula contains both a basic moiety (e.g., pyridine or imidazole, to the other hand) and an acidic moiety (e.g., carboxylic acid, to the other hand), an amphoteric ion ('salt') may be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable ( in other words It is a salt that is non-toxic and physiologically acceptable. Such a salt of the compound of the present invention may be formed, for example, by reacting the compound of the present invention with a certain amount of an acid or base equal to an equivalent amount in a medium, such as a medium in which the salt precipitates or in an aqueous medium, and then freeze-drying.

[0070] Throughout the description, where a composition is described as having, including, or comprising a specific component, or where a process and method are described as having, including, or comprising a specific step, additionally, it is considered that there exist a composition of the present invention that is essentially composed of or composed of the mentioned component, and a process and method according to the present invention that is essentially composed of or composed of the mentioned processing step.

[0071] Generally, compositions specifying percentages are based on weight unless otherwise specified.

[0072] I. Indole amide compounds

[0073] One aspect of the present invention provides an indole amide compound. The compound may be used in the pharmaceutical compositions and therapeutic methods described herein. An exemplary compound is described in the following section along with an exemplary procedure for preparing the compound. One aspect of the present invention is a compound represented by Formula I.

[0074]

[0075] or providing a pharmaceutically acceptable salt thereof; in the above formula,

[0076] A 1 is a bicyclic device selected from the following, and

[0077]

[0078] or

[0079] X 1 is one of the following,

[0080] (i) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 oxazolyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Imidazolyl substituted with;

[0081] (ii) -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )]m -(t R 7 isochromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 77,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7Benzo[d]oxazole-2-(3H)-one substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted with;

[0082] (iii) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 pyridinyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrimidinyl substituted with;

[0083] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with

[0084] (v) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R6 )] m -(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-O'Neill substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazole[4,5-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1-H-pyrazolo[4,3-b]pyridinyl substituted with -N(R4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dehydro-1H-indenyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 indolin-2-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazo[4,5-c]pyridine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[4,3-c]pyridine substituted with;

[0085] (vi) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 imidazo[2,1-b]thiazolyl substituted with;

[0086] (vii) -N(R 4 )-[C(R 5 )(R 6)] m -(p R 7 3,4-dehydro-1 substituted with H -Benzo[ c ][1,2]thiazinyl 2,2-dioxide), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[b]thiophene 1,1-dioxide substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted with;

[0087] (viii) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Quinazolin-4(3H)-O'Neill), substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydroquinoline-2(1H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,4-dehydroisoquinoline-3(2H)-o'nyl substituted with -N(R4 )-[C(R 5 )(R 6 )] m -(p R 7 isoquinoline-1-(2H)-O'Nill substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2,3,4-tetrahydroisoquinoline substituted with); or

[0088] (ix) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Bicyclo[1.1.1]fentanyl substituted with;

[0089] R 1 C 1-4 It is alkyl or hydrogen;

[0090] R 2 In each case, independently hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 Representing a cycloalkyl group, each ring has q R 2B Replaced with;

[0091] R 2B C independently in each case 1-3 Representing an alkyl or halo;

[0092] R 3 is hydrogen; fluoro; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B Replaced with;

[0093] R 4 is hydrogen, C 1-4 Alkyl, -C(O)(C 1-4 alkyl), or -S(O)2(C 1-4 alkyl) and;

[0094] R 5 and R 6 In each case, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, -C 1-3 Alkylene-N(R 8 )2, -(R 8 C substituted with 1-6 Aliphatic), or -(CH2) 0-3 -O-(CH2) 0-3 -CH3 or; R 5 and R 6 They take together to form a C3-5 saturated carbocyclic ring;

[0095] R 7 C independently in each case 1-6 Alkyl, halo, cyano, hydroxyl, -C(O)N(R 8 )2, -N(R 8 )C(O)-R 8 , -C(O)-R 8 , -(R 8 C substituted with 1-6 Aliphatic), C 1-6 Alkoxyl, C 3-6 Cycloalkyl, -S(O)2N(R 8 )2, -S(O)2R8 , -N(R 8 )S(O)2R 8 , C 1-3 Alkylene-C(O)N(R 8 )2, -S(O)(NH)R 8 , C 3-6 Cycloalkyl, -C(O)N(R 8 )(C 3-6 cycloalkyl), -C(O)OC 1-3 Alkyl, C 1-3 Haloalkyl, -NH(R 8 ), -C(NH)NH(R 8 ) , -O-( C 3-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from cycloalkyl), or nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring has s R 7B Replaced with;

[0096] R 7B C independently in each case 1-3 Alkyl, halo, hydroxyl, or C 3-6 Representing a cycloalkyl group;

[0097] R 8 In each case, hydrogen independently; C 1-6 Aliphatic, hydroxyl, -NH2, -S(O)2CH3, C 3-6 Cycloalkyl, cyano, phenyl, C 1-4 Haloalkyl, C 1-6 Representing a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from alkoxy, nitrogen, oxygen, and sulfur, or a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0098] R 9 Silver is hydrogen, chloro, fluoro, or C 1-3 It is alkyl;

[0099] m is 0, 1, 2, or 3, and;

[0100] n is 1, 2, or 3, and;

[0101] p is 0, 1, 2, or 3, and;

[0102] q and s are independently 0, 1, 2, or 3;

[0103] t is 0, 1, 2, or 3, and;

[0104] u is 1 or 2.

[0105] The definition of the variable in the above chemical formula I encompasses multiple chemical groups. The present application considers, for example, i) where the definition of the variable is a single chemical group selected from the chemical groups presented above, ii) where the definition of the variable is a set of two or more chemical groups selected from the chemical groups presented above, and iii) where the compound is defined by a combination of the variables defined by (i) or (ii).

[0106] In certain embodiments, the compound is a compound of chemical formula I.

[0107] Generally, as described above, A 1 It is a bicyclic machine selected from the following.

[0108]

[0109] or

[0110] In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver this c. In a specific embodiment, A 1silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver or is. In a specific embodiment, A 1 silver or is. In a specific embodiment, A 1 silver or is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 It is selected from the group of compounds indicated in Table 1 below.

[0111] Generally, as described above, X 1 is one of the following.

[0112] (i) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4)-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 oxazolyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Imidazolyl substituted with;

[0113] (ii) -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 isochromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]oxazole-2-(3H)-one substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted with;

[0114] (iii) -N(R 4 )-[C(R 5 )(R6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 pyridinyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrimidinyl substituted with;

[0115] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with

[0116] (v) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-O'Neill substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )]m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with, -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazole[4,5-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1-H-pyrazolo[4,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dehydro-1H-indenyl substituted with -N(R 4)-[C(R 5 )(R 6 )] m -(p R 7 indolin-2-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazo[4,5-c]pyridine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[4,3-c]pyridine substituted with;

[0117] (vi) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 imidazo[2,1-b]thiazolyl substituted with;

[0118] (vii) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dehydro-1 substituted with H -Benzo[ c ][1,2]thiazinyl 2,2-dioxide), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 73,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[b]thiophene 1,1-dioxide substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted with;

[0119] (viii) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Quinazolin-4(3H)-O'Neill), substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydroquinoline-2(1H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,4-dehydroisoquinoline-3(2H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoquinoline-1-(2H)-O'Nill substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2,3,4-tetrahydroisoquinoline substituted with); or

[0120] (ix) -N(R 4 )-[C(R 5 )(R 6 )]m -(p R 7 Bicyclo[1.1.1]fentanyl substituted with).

[0121] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 oxazolyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is imidazolyl substituted with

[0122] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 isochromanyl substituted with), -N(R4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with -N(R 4 )-[C(R 5 )(R6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]oxazole-2-(3H)-one substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R7 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted with

[0123] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 pyridinyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrimidinyl substituted with

[0124] In a specific embodiment, X 1 silver or and each of these is p R 7 It is substituted by a phenyl group substituted with .

[0125] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m-(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-O'Neill substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazole[4,5-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1-H-pyrazolo[4,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5)(R 6 )] m -(p R 7 1H-pyrazolo[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dehydro-1H-indenyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 indolin-2-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazo[4,5-c]pyridine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1H-pyrazolo[4,3-c]pyridine substituted with

[0126] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is an imidazo[2,1-b]thiazolyl substituted with

[0127] In a specific embodiment, X 1 is -N(R 4 )-[C(R5 )(R 6 )] m -(p R 7 3,4-dehydro-1H substituted with -Benzo[ c ][1,2]thiazinyl 2,2-dioxide), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[b]thiophene 1,1-dioxide substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted with

[0128] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Quinazolin-4(3H)-O'Neill), substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydroquinoline-2(1H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R7 1,4-dehydroisoquinoline-3(2H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoquinoline-1-(2H)-O'Nill substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,2,3,4-tetrahydroisoquinoline substituted with

[0129] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 It is a thiazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is thiadiazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,3,4-oxadiazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrazole substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is oxazolyl substituted with. In certain embodiments, X 1 is -N(R4 )-[C(R 5 )(R 6 )] m -(p R 7 It is imidazolyl substituted with

[0130] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 It is a chromanyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 It is isochromanyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrobenzofuranyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrofuro[3,2-c]pyridinyl substituted with. In certain embodiments, X1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R7 It is 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrofuro[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrofuro[2,3-c]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrofuro[2,3-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is a benzo[d]oxazole-2(3H)-one substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted with

[0131] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 It is a phenyl substituted with . In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is a pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrimidinyl substituted with

[0132] In a specific embodiment, X 1 is p R 7 phenyl substituted with is. In certain embodiments, X 1 is p R 7 phenyl substituted with is. In certain embodiments, X 1 is p R 7 phenyl substituted with am.

[0133] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R6 )] m -(p R 7 It is benzo[d]imidazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is indazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is isoindolin-1-o'neil substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,2-dihydro-3H-indazole-3-onyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with. In certain embodiments, X 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with

[0134] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R7 It is an imidazo[2,1-b]thiazolyl substituted with

[0135] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dehydro-1 substituted with H -Benzo[ c It is ][1,2]thiazinyl 2,2-dioxide). In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is benzo[b]thiophene 1,1-dioxide substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted with

[0136] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R7 It is quinazoline-4(3H)-o'neil substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydroquinoline-2(1H)-o'nyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,4-dihydroisoquinoline-3(2H)-o'nyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is isoquinoline-1(2H)-o'nyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,2,3,4-tetrahydroisoquinoline substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is a bicyclo[1.1.1]fentanyl substituted with

[0137] In a specific embodiment, X 1 It is selected from the group of compounds indicated in Table 1 below.

[0138] Generally, as described above, R 1 C 1-4 It is alkyl or hydrogen. In certain embodiments, R 1 C 1-4 It is an alkyl. In certain embodiments, R 1is hydrogen. In certain embodiments, R 1 C 1-2 It is an alkyl. In certain embodiments, R 1 is -CH3. In certain embodiments, R 1 It is selected from the group of compounds indicated in Table 1 below.

[0139] Generally, as described above, R 2 In each case, independently hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 Representing a cycloalkyl group, each ring has q R 2B It is replaced by. In certain embodiments, R 2 represents a halo independently in each case. In certain embodiments, R 2 C independently in each case 1-4 Represents an alkyl group. In certain embodiments, R 2 -S(O)2R independently in each case 8 It represents. In certain embodiments, R 2 C independently in each case 1-4 Represents an alkoxyl. In certain embodiments, R 2 C independently in each case 1-4 It represents a haloalkyl. In certain embodiments, R 2 represents a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case, and said ring has q R 2BIt is replaced by. In certain embodiments, R 2 is a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case; or C 3-5 Representing a cycloalkyl group, the ring has q R 2B It is replaced by. In certain embodiments, R 2 In each case, independently hydrogen, halo, or C 1-4 It represents an alkyl group.

[0140] In certain embodiments, R 2 is hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B It is replaced by. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is a halo. In certain embodiments, R 2 is C 1-4 It is an alkyl. In certain embodiments, R 2 -S(O)2R 8 is. In certain embodiments, R 2 is cyano. In certain embodiments, R 2 is C 1-4 It is an alkoxyl. In certain embodiments, R 2 is a hydroxyl. In certain embodiments, R 2 is C 1-4 It is a haloalkyl. In certain embodiments, R 2is a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring has q R 2B It is replaced by. In certain embodiments, R 2 is a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and the ring has q R 2B It is replaced by. In certain embodiments, R 2 is hydrogen, halo, or C 1-4 It is an alkyl. In certain embodiments, R 2 It is selected from the group of compounds indicated in Table 1 below.

[0141] Generally, as described above, R 2B C independently in each case 1-3 Represents an alkyl or halo. In certain embodiments, R 2B C independently in each case 1-3 Represents an alkyl group. In certain embodiments, R 2B represents a halo independently in each case. In certain embodiments, R 2B It is selected from the group of compounds indicated in Table 1 below.

[0142] Generally, as described above, R 3 is hydrogen; fluoro; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5It is cycloalkyl, and each ring has q R 2B It is replaced by. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a fluoro. In certain embodiments, R 3 is C 1-4 It is an alkyl. In certain embodiments, R 3 -S(O)2R 8 is. In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 1-4 It is an alkoxyl. In certain embodiments, R 3 is a hydroxyl. In certain embodiments, R 3 is C 1-4 It is a haloalkyl. In certain embodiments, R 3 is a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring has q R 2B It is replaced by. In certain embodiments, R 3 is a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring has q R 2B It is replaced by. In certain embodiments, R 3 is q R 2B C substituted with 3-5 It is a cycloalkyl. In certain embodiments, R 3 It is selected from the group of compounds indicated in Table 1 below.

[0143] Generally, as described above, R 4 is hydrogen, C 1-4 Alkyl, -C(O)(C 1-4 alkyl), or -S(O)2(C 1-4 It is an alkyl). In certain embodiments, R 4 is hydrogen or C 1-4 It is an alkyl. In certain embodiments, R 4is hydrogen. In certain embodiments, R 4 is C 1-4 It is an alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is ethyl. In certain embodiments, R 4 is -C(O)(C 1-4 It is an alkyl). In certain embodiments, R 4 is -S(O)2(C 1-4 It is an alkyl). In certain embodiments, R 4 It is selected from the group of compounds indicated in Table 1 below.

[0144] Generally, as described above, R 5 and R 6 In each case, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, -C 1-3 Alkylene-N(R 8 )2, -(R 8 C substituted with 1-6 Aliphatic), or -(CH2) 0-3 -O-(CH2) 0-3 -CH3 or; R 5 and R 6 is taken together C 3-5 It forms a saturated carbocyclic ring. In certain embodiments, R 5 and R 6 In each case, independently hydrogen or C 1-4 Represents an alkyl group. In certain embodiments, R 5 and R 6 are each hydrogen. In certain embodiments, R 5 is hydrogen, and R 6 is -CH3. In certain embodiments, R 5 and R 6 C independently in each case 1-4 Represents an alkyl group. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 6C independently in each case 3-5 It represents a cycloalkyl group. In certain embodiments, R 6 C independently in each case 1-4 It represents a hydroxyalkyl group. In certain embodiments, R 6 -C independently in each case 1-3 Alkylene-N(R 8 Represents )2. In certain embodiments, R 6 -(R 8 C substituted with 1-6 It represents an aliphatic. In certain embodiments, R 6 -(CH2) independently in each case 0-3 -O-(CH2) 0-3 - Represents CH3. In certain embodiments, R 5 and R 6 is together C 3-5 It forms a saturated carbocyclic ring. In certain embodiments, R 5 is selected from the group of compounds listed in Table 1 below. In certain embodiments, R 6 It is selected from the group of compounds indicated in Table 1 below.

[0145] Generally, as described above, R 7 C independently in each case 1-6 Alkyl, halo, cyano, hydroxyl, -C(O)N(R 8 )2, -N(R 8 )C(O)-R 8 , -C(O)-R 8 , -(R 8 C substituted with 1-3 Aliphatic), C 1-6 Alkoxyl, C 3-6 Cycloalkyl, -S(O)2N(R 8 )2, -S(O)2R 8 , -N(R 8 )S(O)2R 8 , C 1-3 Alkylene-C(O)N(R 8 )2, -S(O)(NH)R8 , C 3-6 Cycloalkyl, -C(O)N(R 8 )(C 3-6 cycloalkyl), -C(O)OC 1-3 Alkyl, C 1-3 Haloalkyl, -NH(R 8 ), -C(NH)NH(R 8 ) , -O-( C 3-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from cycloalkyl), or nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring has s R 7B It is replaced by. In certain embodiments, R 7 C independently in each case 1-6 Represents an alkyl group. In certain embodiments, R 7 represents a halo independently in each case. In certain embodiments, R 7 represents cyano independently in each case. In certain embodiments, R 7 -C(O)N(R) independently in each case 8 Represents )2. In certain embodiments, R 7 -S(O)(NH)R independently in each case 8 It represents. In certain embodiments, R 7 C independently in each case 1-3 Alkylene-C(O)N(R 8 Represents )2. In certain embodiments, R 7 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7 -N(R 8 )C(O)-R 8 It represents. In certain embodiments, R 7 -C(O)-R independently in each case 8 It represents. In certain embodiments, R 7-(R 8 C substituted with 1-3 It represents an aliphatic. In certain embodiments, R 7 C independently in each case 1-6 Represents an alkoxyl. In certain embodiments, R 7 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7 -C(O)N(R) independently in each case 8 )(C 3-6 Representing cycloalkyl), each cycloalkyl has s R 7B It is replaced by. In certain embodiments, R 7 -C(O)OC independently in each case 1-3 Represents an alkyl group. In certain embodiments, R 7 C independently in each case 1-3 It represents a haloalkyl. In certain embodiments, R 7 -NH(R 8 Represents ). In certain embodiments, R 7 -C(NH)NH(R) independently in each case 8 Represents ). In certain embodiments, R 7 -O-(C 3-6 Representing cycloalkyl), each cycloalkyl has s R 7B It is replaced by. In certain embodiments, R 7 -S(O)2N(R) independently in each case 8 Represents )2. In certain embodiments, R 7 -S(O)2R independently in each case 8 It represents. In certain embodiments, R 7 -N(R 8 )S(O)2R 8 It represents. In certain embodiments, R 7...in each case, represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said heteroaromatic ring comprises s R 7B It is replaced by. In certain embodiments, R 7 -C(O)-R 8 or -C(O)N(R 8 )2. In certain embodiments, R 7 -C(O)N(R 8 )2. In certain embodiments, R 7 is a hydroxyl. In certain embodiments, R 7 is -C(O)NH2. In certain embodiments, R 7 In each case, it independently represents cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo. In certain embodiments, R 7 It is selected from the group of compounds indicated in Table 1 below.

[0146] Generally, as described above, R 7B C independently in each case 1-3 Alkyl, halo, hydroxyl, or C 3-6 It represents a cycloalkyl group. In certain embodiments, R 7B C independently in each case 1-3 Represents an alkyl group. In certain embodiments, R 7B represents a halo independently in each case. In certain embodiments, R 7B represents a hydroxyl independently in each case. In certain embodiments, R 7B C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7B It is selected from the group of compounds indicated in Table 1 below.

[0147] Generally, as described above, R 8In each case, hydrogen independently; C 1-6 Aliphatic, hydroxyl, -NH2, -S(O)2CH3, C 3-6 Cycloalkyl, cyano, phenyl, C 1-4 Haloalkyl, C 1-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from alkoxy, nitrogen, oxygen, and sulfur, or a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 C independently in each case 1-6 It represents an aliphatic. In certain embodiments, R 8 is a hydroxyl. In certain embodiments, R 8 is -NH2. In certain embodiments, R 8 is -S(O)2CH3. In certain embodiments, R 8 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 8 It is cyano. In certain embodiments, R 8 C independently in each case 1-6 It represents an alkoxyl. In certain embodiments, R 8 is phenyl. In certain embodiments, R 8 C independently in each case 1-4 It represents a haloalkyl. In certain embodiments, R 8 represents a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case. In certain embodiments, R 8represents a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case. In certain embodiments, R 8 It is selected from the group of compounds indicated in Table 1 below.

[0148] As generally described above, R 9 Silver is hydrogen, chloro, fluoro, or C 1-3 It is an alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is a fluoro. In certain embodiments, R 9 C 1-3 It is an alkyl. In certain embodiments, R 9 is chloro. In certain embodiments, R 9 It is selected from the group of compounds indicated in Table 1 below.

[0149] Generally, as defined above, m is 0, 1, or 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0150] Generally, as described above, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0151] Generally, as described above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 2 or 3. In certain embodiments, p is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0152] Generally, as described above, q and s are independently 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0153] Generally, as described above, t is 0, 1, 2, or 3. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 1, 2, or 3. In certain embodiments, t is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0154] Generally, as described above, u is 1 or 2. In certain embodiments, u is 1. In certain embodiments, u is 2. In certain embodiments, u is 3. In certain embodiments, u is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0155] In certain embodiments, the compound of Formula I additionally has the following formula Ia or Ib or is defined as a pharmaceutically acceptable salt thereof.

[0156]

[0157] In certain embodiments, the compound of formula I additionally has formula Ic , Id , or Ie or is defined as a pharmaceutically acceptable salt thereof.

[0158]

[0159] In certain embodiments, the compound of formula I additionally has formula If or Ig or is defined as a pharmaceutically acceptable salt thereof.

[0160]

[0161] In certain embodiments, the compound of formula I additionally has formula Ih or Ii or is defined as a pharmaceutically acceptable salt thereof.

[0162]

[0163] In certain embodiments, the compound of formula I additionally has formula Ij, Ik, Il, Im, In, or Io or is defined as a pharmaceutically acceptable salt thereof.

[0164]

[0165] In certain embodiments, the compound of formula I additionally has formula Ip, Iq, or Ir or is defined as a pharmaceutically acceptable salt thereof.

[0166]

[0167] In certain embodiments, the compound of formula I additionally has formula Is , It , Iu , or Ivor is defined as a pharmaceutically acceptable salt thereof.

[0168]

[0169] In certain embodiments, the compound of formula I additionally has formula Iw or Ix or is defined as a pharmaceutically acceptable salt thereof.

[0170]

[0171] In certain embodiments, the compound of formula I additionally has formula Iy, Iz, or Iaa or is defined as a pharmaceutically acceptable salt thereof.

[0172]

[0173] In certain embodiments, the compound of formula I additionally has formula Iab , Iac , or Iad or is defined as a pharmaceutically acceptable salt thereof.

[0174]

[0175] In certain embodiments, the compound of formula I additionally has formula Iae or defined as a pharmaceutically acceptable salt thereof,

[0176]

[0177] In the above formula, ring B 1 is one of the following.

[0178] (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0179] (ii) t R7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0180] (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0181] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0182] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 76,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0183] In certain embodiments, the compound of formula I additionally has formula Iaf or defined as a pharmaceutically acceptable salt thereof,

[0184]

[0185] In the above formula, ring B 1 is one of the following.

[0186] (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0187] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0188] (iii) t R 7 Phenyl substituted with p Rs7 Pyridinyl substituted with;

[0189] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0190] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0191] In certain embodiments, the compound of formula I additionally has formula Iaf or defined as a pharmaceutically acceptable salt thereof,

[0192]

[0193] In the above formula, ring B 1 is one of the following,

[0194] (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0195] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 73,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0196] (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0197] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0198] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with,

[0199] t is 1, 2, or 3. Generally, as described above, ring B 1 is one of the following.

[0200] (i) t R 7A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0201] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0202] (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0203] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0204] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; p R 7Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0205] In a specific embodiment, ring B 1 is (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0206] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0207] (iii) t R7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0208] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0209] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 It is 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0210] In a specific embodiment, ring B 1 is t R 7 It is a thiazole substituted with. In certain embodiments, ring B 1 is p R 7 It is a thiadiazole substituted with. In certain embodiments, ring B 1 is p R 7 2,3-dihydrobenzofuranyl substituted with; or ring B 1 is t R 7 It is a thiazole substituted with. In certain embodiments, ring B 1 is p R 7 It is 1,3,4-oxadiazoleyl substituted with. In certain embodiments, ring B 1 is p R 7 It is a pyrazole substituted with. In certain embodiments, ring B 1 is p R 7 It is oxazolyl substituted with. In certain embodiments, ring B 1 is p R 7It is an imidazole substituted with. In certain embodiments, ring B 1 is t R 7 It is a chromanyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydrobenzofuranyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydrofuro[3,2-c]pyridine substituted with. In certain embodiments, ring B 1 is p R 7 It is 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with. In certain embodiments, ring B 1 is t R 7 Phenyl substituted with p Rs 7 It is a pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 It is pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is a benzo[d]imidazole substituted with. In certain embodiments, ring B 1 is p R 7 It is indazolyl substituted with. In certain embodiments, ring B 1 is p R 7 It is isoindolin-1-o'nyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 1,2-dihydro-3H-indazole-3-onyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0211] In a specific embodiment, ring B 1 is t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; or t R 7 It is a thiazole substituted with. In certain embodiments, ring B 1 is t R 7 Phenyl substituted with p Rs 7 It is a pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; or p R 7 It is isoindolin-1-o'nyl substituted with. In certain embodiments, ring B 1 is p R 7 Pyrrolo[3,2-b]pyridinyl substituted with or p R 7 It is isoindolin-1-O'Neill substituted with.

[0212] In a specific embodiment, ring B 1 It is selected from the group of compounds indicated in Table 1 below.

[0213] In certain embodiments, the compound of formula I additionally has formula Iag or is defined as a pharmaceutically acceptable salt thereof.

[0214]

[0215] In certain embodiments, the compound of formula I additionally has formula Iah or is defined as a pharmaceutically acceptable salt thereof.

[0216]

[0217] In certain embodiments, the compound of formula I additionally has formula Iai or is defined as a pharmaceutically acceptable salt thereof.

[0218]

[0219] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is am.

[0220] II. Additional indole amide compounds

[0221] One aspect of the present invention provides an indole amide compound. The compound may be used in the pharmaceutical compositions and therapeutic methods described herein. An exemplary compound is described in the following section along with an exemplary procedure for preparing the compound. One aspect of the present invention is a compound represented by Formula II.

[0222]

[0223] or providing a pharmaceutically acceptable salt thereof; in the above formula,

[0224] A 1 is a bicyclic heteroaryl selected from the following and

[0225]

[0226] or

[0227] X 1 is one of the following,

[0228] (i) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7oxazolyl substituted with y), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Imidazolyl substituted with;

[0229] (ii) -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5)(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0230] (iii) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyridinyl substituted with;

[0231] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0232] (v) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7isoindolin-1-O'Neill substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with); or p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with;

[0233] R 1 C 1-4 It is alkyl;

[0234] R 2 is hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B Replaced with;

[0235] R 2B C independently in each case 1-3 Representing an alkyl or halo;

[0236] R 3 is hydrogen; fluoro; C 1-4Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B Replaced with;

[0237] R 4 is hydrogen, C 1-4 Alkyl, -C(O)(C 1-4 alkyl), or -S(O)2(C 1-4 alkyl) and;

[0238] R 5 and R 6 In each case, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, -C 1-3 Alkylene-N(R 8 )2, -(R 8 C substituted with 1-6 Aliphatic), or -(CH2) 0-3 -O-(CH2) 0-3 -CH3 or; R 5 and R 6 They take together to form a C3-5 saturated carbocyclic ring;

[0239] R 7 C independently in each case 1-6 Alkyl, halo, cyano, -C(O)N(R 8 )2, -N(R 8 )C(O)-R 8 , -C(O)-R 8 , -(R 8 C substituted with 1-6 Aliphatic), C 1-6 Alkoxyl, C 3-6Cycloalkyl, -S(O)2N(R 8 )2, -S(O)2R 8 , -N(R 8 )S(O)2R 8 , C 1-3 Alkylene-C(O)N(R 8 )2, -S(O)(NH)R 8 , C 3-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from cycloalkyl, or nitrogen, oxygen, and sulfur, wherein each ring has s R 7B Replaced with;

[0240] R 7B C independently in each case 1-3 Alkyl, halo, hydroxyl, or C 3-6 Representing a cycloalkyl group;

[0241] R 8 In each case, independently hydrogen, C 1-6 Aliphatic, hydroxyl, -NH2, -S(O)2CH3, C 3-6 Cycloalkyl, cyano, phenyl, C 1-4 Representing a 5- to 6-membered saturated monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from haloalkyl, nitrogen, oxygen, and sulfur, or a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0242] R 9 Silver is hydrogen, chloro, fluoro, or C 1-3 It is alkyl;

[0243] m is 0, 1, 2, or 3, and;

[0244] n is 1, 2, or 3, and;

[0245] p is 0, 1, 2, or 3, and;

[0246] q and s are independently 0, 1, 2, or 3;

[0247] t is 1, 2, or 3.

[0248] The definition of the variable in the above chemical formula II encompasses multiple chemical groups. The present application considers, for example, i) where the definition of the variable is a single chemical group selected from the chemical groups presented above, ii) where the definition of the variable is a set of two or more chemical groups selected from the chemical groups presented above, and iii) where the compound is defined by a combination of the variables defined by (i) or (ii).

[0249] In a specific embodiment, the compound is a compound of chemical formula II.

[0250] Generally, as described above, A 1 is a bicyclic heteroaryl selected from the following.

[0251]

[0252] or

[0253] In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A1 silver is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 silver , or is. In a specific embodiment, A 1 silver or is. In a specific embodiment, A 1 silver or is. In a specific embodiment, A 1 silver is. In a specific embodiment, A 1 It is selected from the group of compounds indicated in Table 1 below.

[0254] Generally, as described above, X 1 is one of the following.

[0255] (i) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with ), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 oxazolyl substituted with), or -N(R4 )-[C(R 5 )(R 6 )] m -(p R 7 Imidazolyl substituted with;

[0256] (ii) -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )]m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with

[0257] (iii) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyridinyl substituted with;

[0258] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0259] (v) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-O'Neill substituted with), -N(R 4)-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with); or p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with

[0260] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 It is a thiazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is thiadiazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,3,4-oxadiazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrazole substituted with. In certain embodiments, X 1 is -N(R 4)-[C(R 5 )(R 6 )] m -(p R 7 It is oxazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is imidazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 It is a chromanyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrobenzofuranyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydrofuro[3,2-c]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R5 )(R 6 )] m -(p R 7 It is 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 It is a phenyl substituted with . In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is a pyridinyl substituted with. In certain embodiments, X 1 is p R 7 phenyl substituted with is. In certain embodiments, X 1 is p R 7 phenyl substituted with is. In certain embodiments, X 1 is p R7 phenyl substituted with am.

[0261] In a specific embodiment, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is benzo[d]imidazoleyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is indazolyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is isoindolin-1-o'neil substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 It is 1,2-dihydro-3H-indazole-3-onyl substituted with. In certain embodiments, X 1 is -N(R 4 )-[C(R 5 )(R 6 )] m-(p R 7 It is 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with. In certain embodiments, X 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with

[0262] In a specific embodiment, X 1 It is selected from the group of compounds indicated in Table 1 below.

[0263] Generally, as described above, R 1 C 1-4 It is an alkyl. In certain embodiments, R 1 C 1-2 It is an alkyl. In certain embodiments, R 1 is -CH3. In certain embodiments, R 1 It is selected from the group of compounds indicated in Table 1 below.

[0264] Generally, as described above, R 2 is hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B It is replaced by. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is a halo. In certain embodiments, R 2 is C 1-4 It is an alkyl. In certain embodiments, R 2 -S(O)2R 8 is. In certain embodiments, R 2is cyano. In certain embodiments, R 2 is C 1-4 It is an alkoxyl. In certain embodiments, R 2 is a hydroxyl. In certain embodiments, R 2 is C 1-4 It is a haloalkyl. In certain embodiments, R 2 is a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring has q R 2B It is replaced by. In certain embodiments, R 2 is a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and the ring has q R 2B It is replaced by. In certain embodiments, R 2 is hydrogen, halo, or C 1-4 It is an alkyl. In certain embodiments, R 2 It is selected from the group of compounds indicated in Table 1 below.

[0265] Generally, as described above, R 2B C independently in each case 1-3 Represents an alkyl or halo. In certain embodiments, R 2B C independently in each case 1-3 Represents an alkyl group. In certain embodiments, R 2B represents a halo independently in each case. In certain embodiments, R 2B It is selected from the group of compounds indicated in Table 1 below.

[0266] Generally, as described above, R 3 is hydrogen; fluoro; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B It is replaced by. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a fluoro. In certain embodiments, R 3 is C 1-4 It is an alkyl. In certain embodiments, R 3 -S(O)2R 8 is. In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 1-4 It is an alkoxyl. In certain embodiments, R 3 is a hydroxyl. In certain embodiments, R 3 is C 1-4 It is a haloalkyl. In certain embodiments, R 3 is a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring has q R 2B It is replaced by. In certain embodiments, R 3 is a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring has q R 2B It is replaced by. In certain embodiments, R 3 is q R 2B C substituted with 3-5 It is a cycloalkyl. In certain embodiments, R 3 It is selected from the group of compounds indicated in Table 1 below.

[0267] Generally, as described above, R 4 is hydrogen, C 1-4 Alkyl, -C(O)(C 1-4 alkyl), or -S(O)2(C 1-4 It is an alkyl). In certain embodiments, R 4 is hydrogen or C 1-4 It is an alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C 1-4 It is an alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is ethyl. In certain embodiments, R 4 is -C(O)(C 1-4 It is an alkyl). In certain embodiments, R 4 is -S(O)2(C 1-4 It is an alkyl). In certain embodiments, R 4 It is selected from the group of compounds indicated in Table 1 below.

[0268] Generally, as described above, R 5 and R 6 In each case, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, -C 1-3 Alkylene-N(R 8 )2, -(R 8 C substituted with 1-6 Aliphatic), or -(CH2) 0-3 -O-(CH2) 0-3 -CH3 or; R 5 and R 6 They are taken together to form a C3-5 saturated carbocyclic ring. In certain embodiments, R 5 and R 6 In each case, independently hydrogen or C 1-4 Represents an alkyl group. In certain embodiments, R 5 and R 6 are each hydrogen. In certain embodiments, R5 is hydrogen, and R 6 is -CH3. In certain embodiments, R 5 and R 6 C independently in each case 1-4 Represents an alkyl group. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 6 C independently in each case 3-5 It represents a cycloalkyl group. In certain embodiments, R 6 C independently in each case 1-4 It represents a hydroxyalkyl group. In certain embodiments, R 6 -C independently in each case 1-3 Alkylene-N(R 8 Represents )2. In certain embodiments, R 6 -(R 8 C substituted with 1-6 It represents an aliphatic. In certain embodiments, R 6 -(CH2) independently in each case 0-3 -O-(CH2) 0-3 - Represents CH3. In certain embodiments, R 5 and R 6 They together form a C3-5 saturated carbocyclic ring. In certain embodiments, R 5 is selected from the group of compounds listed in Table 1 below. In certain embodiments, R 6 It is selected from the group of compounds indicated in Table 1 below.

[0269] Generally, as described above, R 7 C independently in each case 1-6 Alkyl, halo, cyano, -C(O)N(R 8 )2, -N(R 8 )C(O)-R 8 , -C(O)-R 8 , -(R 8 C substituted with 1-3 Aliphatic), C 1-6Alkoxyl, C 3-6 Cycloalkyl, -S(O)2N(R 8 )2, -S(O)2R 8 , -N(R 8 )S(O)2R 8 , C 1-3 Alkylene-C(O)N(R 8 )2, -S(O)(NH)R 8 , C 3-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from cycloalkyl, or nitrogen, oxygen, and sulfur, said ring having s R 7B It is replaced by. In certain embodiments, R 7 C independently in each case 1-6 Represents an alkyl group. In certain embodiments, R 7 represents a halo independently in each case. In certain embodiments, R 7 represents cyano independently in each case. In certain embodiments, R 7 -C(O)N(R) independently in each case 8 Represents )2. In certain embodiments, R 7 -S(O)(NH)R independently in each case 8 It represents. In certain embodiments, R 7 C independently in each case 1-3 Alkylene-C(O)N(R 8 Represents )2. In certain embodiments, R 7 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7 -N(R 8 )C(O)-R 8 It represents. In certain embodiments, R 7 -C(O)-R independently in each case 8 It represents. In certain embodiments, R 7 -(R 8C substituted with 1-3 It represents an aliphatic. In certain embodiments, R 7 C independently in each case 1-6 Represents an alkoxyl. In certain embodiments, R 7 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7 -S(O)2N(R) independently in each case 8 Represents )2. In certain embodiments, R 7 -S(O)2R independently in each case 8 It represents. In certain embodiments, R 7 -N(R 8 )S(O)2R 8 It represents. In certain embodiments, R 7 represents a 5 to 6-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring having s R 7B It is replaced by. In certain embodiments, R 7 -C(O)-R 8 or -C(O)N(R 8 )2. In certain embodiments, R 7 In each case, it independently represents cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo. In certain embodiments, R 7 It is selected from the group of compounds indicated in Table 1 below.

[0270] Generally, as described above, R 7B C independently in each case 1-3 Alkyl, halo, hydroxyl, or C 3-6 It represents a cycloalkyl group. In certain embodiments, R 7B C independently in each case 1-3 Represents an alkyl group. In certain embodiments, R 7Brepresents a halo independently in each case. In certain embodiments, R 7B represents a hydroxyl independently in each case. In certain embodiments, R 7B C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 7B It is selected from the group of compounds indicated in Table 1 below.

[0271] Generally, as described above, R 8 In each case, hydrogen independently; C 1-6 Aliphatic, hydroxyl, -NH2, -S(O)2CH3, C 3-6 Cycloalkyl, cyano, phenyl, C 1-4 It represents a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from haloalkyl, nitrogen, oxygen, and sulfur, or a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 8 represents hydrogen independently in each case. In certain embodiments, R 8 C independently in each case 1-6 It represents an aliphatic. In certain embodiments, R 8 represents a hydroxyl independently in each case. In certain embodiments, R 8 represents -NH2 independently in each case. In certain embodiments, R 8 represents -S(O)2CH3 independently in each case. In certain embodiments, R 8 C independently in each case 3-6 It represents a cycloalkyl group. In certain embodiments, R 8 represents cyano independently in each case. In certain embodiments, R 8represents phenyl independently in each case. In certain embodiments, R 8 C independently in each case 1-4 It represents a haloalkyl. In certain embodiments, R 8 represents a 5 to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case. In certain embodiments, R 8 represents a 5 to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in each case. In certain embodiments, R 8 It is selected from the group of compounds indicated in Table 1 below.

[0272] As generally described above, R 9 Silver is hydrogen, chloro, fluoro, or C 1-3 It is an alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is a fluoro. In certain embodiments, R 9 C 1-3 It is an alkyl. In certain embodiments, R 9 is chloro. In certain embodiments, R 9 It is selected from the group of compounds indicated in Table 1 below.

[0273] Generally, as defined above, m is 0, 1, or 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0274] Generally, as described above, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0275] Generally, as described above, p is 0, 1, or 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0276] Generally, as described above, q and s are independently 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0277] Generally, as described above, t is 1, 2, or 3. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is selected from the corresponding values ​​of the group indicated for the compounds in Table 1 below.

[0278] In certain embodiments, the compound of Formula II additionally has Formula II IIa or IIb or is defined as a pharmaceutically acceptable salt thereof.

[0279]

[0280] In certain embodiments, the compound of Formula II additionally has Formula II IIc , IId , or IIe or is defined as a pharmaceutically acceptable salt thereof.

[0281]

[0282]

[0283] In certain embodiments, the compound of Formula II additionally has Formula II If or IIg or is defined as a pharmaceutically acceptable salt thereof.

[0284]

[0285] In certain embodiments, the compound of Formula II additionally has Formula II IIh or IIi or is defined as a pharmaceutically acceptable salt thereof.

[0286]

[0287] In certain embodiments, the compound of Formula II additionally has Formula II IIj, IIk, IIl, IIm, IIn, or IIo or is defined as a pharmaceutically acceptable salt thereof.

[0288]

[0289]

[0290] In certain embodiments, the compound of Formula II additionally has Formula II IIp, IIq, or IIr or is defined as a pharmaceutically acceptable salt thereof.

[0291]

[0292] In certain embodiments, the compound of Formula II additionally has Formula II IIs , IIt , IIu , or IIv or is defined as a pharmaceutically acceptable salt thereof.

[0293]

[0294]

[0295] In certain embodiments, the compound of Formula II additionally has Formula II IIw or IIx or is defined as a pharmaceutically acceptable salt thereof.

[0296]

[0297] In certain embodiments, the compound of Formula II additionally has Formula II IIy, IIz, or IIaa or is defined as a pharmaceutically acceptable salt thereof.

[0298]

[0299] In certain embodiments, the compound of Formula II additionally has Formula II IIab , IIac , or IIad or is defined as a pharmaceutically acceptable salt thereof.

[0300]

[0301]

[0302] In certain embodiments, the compound of Formula II additionally has Formula II IIae or defined as a pharmaceutically acceptable salt thereof,

[0303]

[0304] In the above formula, ring B 1 is one of the following.

[0305] (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0306] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0307] (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0308] (iv) or (Each of these is p R 7 Substituted with phenyl substituted with); or

[0309] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0310] Generally, as described above, ring B 1 is one of the following.

[0311] (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with;

[0312] (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with;

[0313] (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with;

[0314] (iv) or (Each of these is p R 7Substituted with phenyl substituted with); or

[0315] (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with

[0316] In a specific embodiment, ring B 1 is t R 7 It is a thiazole substituted with. In certain embodiments, ring B 1 is p R 7 It is a thiadiazole substituted with. In certain embodiments, ring B 1 is t R 7 It is 1,3,4-oxadiazoleyl substituted with. In certain embodiments, ring B 1 is p R 7 It is a pyrazole substituted with. In certain embodiments, ring B 1 is p R 7 It is oxazolyl substituted with. In certain embodiments, ring B 1 is p R 7 It is an imidazole substituted with. In certain embodiments, ring B 1 is t R 7 It is a chromanyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydrobenzofuranyl substituted with. In certain embodiments, ring B 1 is p R7 It is 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydrofuro[3,2-c]pyridine substituted with. In certain embodiments, ring B 1 is p R 7 It is 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with. In certain embodiments, ring B 1 is t R 7 Phenyl substituted with p Rs 7 It is a pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 phenyl substituted with is. In a specific embodiment, ring B 1 is p R 7 It is pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7It is a benzo[d]imidazole substituted with. In certain embodiments, ring B 1 is p R 7 It is indazolyl substituted with. In certain embodiments, ring B 1 is p R 7 It is isoindolin-1-o'nyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 1,2-dihydro-3H-indazole-3-onyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with. In certain embodiments, ring B 1 is p R 7 It is 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with. In certain embodiments, ring B 1 It is selected from the group of compounds indicated in Table 1 below.

[0317] Exemplary specific compounds

[0318] In certain embodiments, the compound is a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or Table 2.

[0319] In certain embodiments, the compound is a compound of Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1. In certain embodiments, the compound is a compound selected from compounds I-1 to I-255 of Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from compounds I-1 to I-255 of Table 1.

[0320] In certain embodiments, the compound is a compound of Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 2.

[0321] [Table 1] Exemplary Compounds

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466] [Table 2] Exemplary Compounds

[0467]

[0468] In some embodiments, the present invention is based on the formula defined above. I The above-defined chemical formula for use as a compound or a pharmaceutically acceptable salt or drug thereof IProvides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0469] In some embodiments, the present invention is based on the formula defined above. II The above-defined chemical formula for use as a compound or a pharmaceutically acceptable salt or drug thereof II Provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0470] III. Application of Treatment

[0471] In some embodiments, the present invention provides a method for treating a disorder in which enhanced ABC transporter function is a clinical benefit. For example, in certain embodiments, the disorder is a disorder in which ABC transporter dysfunction is pathogenic to the disease. In some embodiments, the correction of one or more underlying mutations associated with ABC transporter dysfunction is rationalized. In some embodiments, the method of the present invention provides enhancement of one or more unmutated forms of the ABC transporter.

[0472] In some embodiments, the present invention provides a method for treating a disorder in which enhanced ABC transporter function is clinically beneficial, and the method provides a therapeutically effective amount of the compound described herein, e.g., formula 0.00, to a subject in need thereof. I It includes the step of treating a disorder in which enhanced ABC transporter function is clinically beneficial by administering a compound. In certain embodiments, the chemical formula I The specific compound of is a compound defined by one of the embodiments described in Section I above.

[0473] In some embodiments, the present invention provides a method for treating disorders associated with ABC transporter dysfunction, wherein the method provides a therapeutically effective amount of a compound described herein, e.g., of the formula, to a subject in need thereof.I It includes the step of treating a disorder associated with ABC transporter dysfunction by administering a compound. In certain embodiments, the chemical formula I The specific compound of is a compound defined by one of the embodiments described in Section I above.

[0474] In some embodiments, a method is provided to alleviate one or more symptoms of a disorder associated with ABC transporter dysfunction, and the method provides a therapeutically effective amount of a compound described herein, e.g., of the formula, to a subject in need thereof. I It includes the step of treating a disorder associated with ABC transporter dysfunction by administering a compound. In certain embodiments, the chemical formula I The specific compound of is a compound defined by one of the embodiments described in Section I above.

[0475] In some embodiments, the present invention provides a method for treating a disorder in which enhanced ABC transporter function is clinically beneficial, and the method provides a therapeutically effective amount of the compound described herein, e.g., formula 0.00, to a subject in need thereof. II It includes the step of treating a disorder in which enhanced ABC transporter function is clinically beneficial by administering a compound. In certain embodiments, the chemical formula II The specific compound is a compound defined by one of the embodiments described in Section I above. In some embodiments, the present invention provides a method for treating disorders associated with ABC transporter dysfunction, and the method provides a therapeutically effective amount of the compound described herein, e.g., formula 0. to a subject in need thereof. II It includes the step of treating a disorder associated with ABC transporter dysfunction by administering a compound. In certain embodiments, the chemical formula IIThe specific compound of is a compound defined by one of the embodiments described in Section I above. In some embodiments, a method is provided for alleviating one or more symptoms of a disorder associated with ABC transporter dysfunction, and the method provides a therapeutically effective amount of the compound described herein, e.g., formula 0. to a subject in need thereof. II It includes the step of treating a disorder associated with ABC transporter dysfunction by administering a compound. In certain embodiments, the chemical formula II The specific compound of is a compound defined by one of the embodiments described in Section I above.

[0476] In some embodiments, the impairment associated with ABC transporter dysfunction is characterized by a dysfunction of a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0477] In some embodiments, the present invention relates to Tangerine disease, pulmonary surfactant metabolic disorder type 3, autosomal recessive congenital ichthyosis type 4A (ARCI), alymphocyte syndrome type 1, alymphocyte syndrome type 1 due to TAP2 deficiency, hereditary systemic pigmentation type 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis defect type 5, methylmalonicuria and homocystinuria cblJ, citostrolemia, Stargardt disease, PFIC3, PFIC2, elastic pseudoxanthoma, X-linked adrenoleukodystrophy (ALD), cholestasis, hyperbilirubinemia, pregnancy-induced intrahepatic cholestasis, biliary atresia, and allagil The present invention provides a method for treating a disorder selected from syndromes, primary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hirschprung's disease, Zellweger syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile systemic arterial calcification, calciphylaxis, autosomal recessive rod-conus dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, low phospholipid-related cholelithiasis, intrahepatic microcholelithiasis, intrahepatic cholelithiasis, anatomical biliary stenosis, benign recurrent intrahepatic cholestasis, progeria (Hutchinson-Gilford progeria syndrome), chronic kidney disease, hemodialysis, vascular calcification, CKD-related vascular calcification, T2D-related vascular calcification, and calcific uremic ductus arteriosus. In some embodiments, the present invention provides a method for treating cystic fibrosis. In some embodiments, the present invention provides a method for treating primary sclerosing cholangitis. For example, in certain embodiments, the present invention provides a method for treating a disorder, wherein the method comprises a therapeutically effective amount of the compound described herein (e.g., formula) to a subject in need thereof. IIt includes a step of administering a compound (same as) and the disorders include Tangerine's disease, pulmonary surfactant metabolic disorder type 3, autosomal recessive congenital ichthyosis type 4A (ARCI), alymphocyte syndrome type 1, alymphocyte syndrome type 1 due to TAP2 deficiency, hereditary systemic pigmentosa type 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis defect type 5, methylmalonicuria and homocystinuria cblJ, citostrolemia, Stargardt disease, PFIC3, PFIC2, elastic pseudoxanthoma, X-linked adrenoleukodystrophy (ALD), cholestasis, hyperbilirubinemia, pregnancy-induced intrahepatic cholestasis, Biliary atresia, Alagille syndrome, primary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hirschprung's disease, Zellweger syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile systemic arterial calcification, calciphylaxis, autosomal recessive rod-conus dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, low phospholipid-related cholelithiasis, intrahepatic microcholelithiasis, intrahepatic cholelithiasis, anastomotic biliary stenosis, benign recurrent intrahepatic cholestasis, progeria (Hutchinson-Gilford progeria syndrome), chronic kidney disease, hemodialysis, vascular calcification, CKD-related vascular calcification, T2D-related vascular calcification, and from calcific uremic ductus arteriosus It is selected.

[0478] In some embodiments, the disorder associated with ABC transporter dysfunction is cystic fibrosis (CF). Accordingly, in some embodiments, the present invention provides a method for treating cystic fibrosis, wherein the method provides a therapeutically effective amount of a compound described herein, e.g., formula 0.00, to a subject in need thereof. IThe method includes the step of administering a compound thereof. Accordingly, in some embodiments, the present invention provides a method for treating cystic fibrosis, wherein the method administers a therapeutically effective amount of a compound described herein, e.g., of the formula thereof, to a subject in need thereof. II The method includes the step of administering a compound. In some of these embodiments, the method further includes the step of administering one or more additional therapeutic agents described below and additionally herein.

[0479] In some embodiments, the disorder associated with ABC transporter dysfunction is cholestasis. Accordingly, in some embodiments, the present invention provides a method for treating cholestasis, wherein the method provides a therapeutically effective amount of the compound described herein, e.g., formula 0.00, to a subject in need thereof. I It includes the step of administering a compound. In some embodiments, the present invention provides a method for treating cholestasis, wherein the method administers a therapeutically effective amount of a compound described herein, e.g., of the formula to a subject in need thereof. II The method includes the step of administering a compound. Those skilled in the art will recognize that there are various forms of cholestasis, all of which are considered herein for treatment with the method and compound 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.

[0480] Another aspect of the present invention is to provide an effective amount of the compound described herein, e.g., formula, to a subject. IThe present invention provides a method for increasing the expression of an ABC transporter in a subject, comprising the step of administering a compound to increase the expression of an ABC transporter in a subject. In certain embodiments, the ABC transporter is selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0481] Another aspect of the present invention is to provide an effective amount of the compound described herein, e.g., formula, to a subject. I The present invention provides a method for regulating the function of an ABC transporter in a subject, comprising the step of increasing the expression of an ABC transporter in the subject by administering a compound. In a specific embodiment, the ABC transporter is selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

[0482] object

[0483] In a specific embodiment, the subject is a human. In a specific embodiment, the subject is an adult human. In a specific embodiment, the subject is a child human.

[0484] Medical use

[0485] Another aspect of the present invention is a compound described herein (e.g., chemical formula) in the manufacture of a pharmaceutical drug I or chemical formula II Provides the use of the compound of Section I or other compounds of Section I. In certain embodiments, the agent is intended to treat disorders described herein, such as disorders associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.

[0486] Another aspect of the present invention is a compound described herein (e.g., chemical formula) for treating medical disorders, such as disorders related to ABC transporter dysfunction. I or chemical formula II Provides the use of the compound of Section I or other compounds thereof. Exemplary such impairments are described above and herein.

[0487] Another aspect of the present invention is a compound of the use described herein (e.g., chemical formula) for treating, for example, medical disorders, e.g., disorders related to ABC transporter dysfunction. I or chemical formula II Provides a compound of or other compounds of Section I). Exemplary such disorders are described above and herein.

[0488] IV. Combination therapy

[0489] Another aspect of the present invention provides a combination therapy. Compounds described herein (e.g., chemical formula I or chemical formula II Compounds of or other compounds of Section I) or pharmaceutically acceptable salts thereof may be used in combination with additional therapeutic agents to treat medical disorders such as autoimmune disorders, cancer, etc.

[0490] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising the steps of administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient requiring treatment for the disclosed disease or condition, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises the step of co-administering one additional therapeutic agent. In some embodiments, the method comprises the step of co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and additional therapeutic agents or therapeutic agents acts synergistically.

[0491] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents may be part of a single dosing form mixed with the compound of the present invention in a single composition. When administered as a multiple dosing regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a certain period of time from each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or within 24 hours from each other. In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention are administered as a multiple dosing regimen with an interval of more than 24 hours.

[0492] In some embodiments, the present invention provides a method for treating cystic fibrosis (CF) comprising the step of administering a compound of the present invention together with one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are selected from mucolytics, bronchodilators, antibiotics, anti-infectives, anti-inflammatory agents, cystic fibrosis transmembrane conductivity (CFTR) modulators, nutrient agents, or any agent known to treat CF.

[0493] In some embodiments, one or more additional therapeutic agents are antibiotics. In some embodiments, the antibiotic is selected from penicillin, cephalosporin, tetracycline, macrolide, fluoroquinolone, sulfonamide, glycopeptide, or rifamycin. In certain embodiments, the antibiotic is selected from phenoxymethyl penicillin, dicloxacillin, clavulanic acid and amoxicillin, ampicillin, nafcillin, oxacillin, penicillin V, penicillin G, cefachlor, cefazolin, cefadroxil, cephalexin, cefuroxim, cefixim, cefoxitin, ceftriaxone, doxycycline, minocycline, celecyl, erythromycin, clarithromycin, azithromycin, fidaxomycin, roxithromycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trimethoprim and sulfamethoxazole, sulfasalazine, sulfacetamide, sulfadiazine silver, vancomycin, dalbavancin, orritavancin, telavancin, or rifaximin.

[0494] 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 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 US 8,481,590, WO2012 / 048181, WO2012 / 083165, WO2012 / 083171, or WO 2012 / 170371.

[0495] In some embodiments, one or more additional therapeutic agents are ileal bile transport (IBAT) inhibitors. In some embodiments, the IBAT inhibitor is selected from IBAT inhibitors disclosed in AU2011326873, US2020 / 0330545, WO2012 / 064266, WO2020 / 167964, or in the literature [Front Pharmacol. 2018; 9: 931 (Al-Dury et al., published online August 21, 2018)]. Exemplary IBAT inhibitors include, but are not limited to, odevixivat, erobixivat, maralixivart, linerixivat, GSK2330672, SHP626 (bolixivat), A4250, etc.

[0496] In some embodiments, one or more additional therapeutic agents are peroxisome propellant-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, aleglitazar, muraglitazar, and tesaglitazar, saroglitazar, and celadelfar.

[0497] 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.

[0498] In some embodiments, one or more additional therapeutic agents are disease-modifying antirheumatic drugs (DMARDs). In certain embodiments, the DMARD is selected from azathioprine, hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine.

[0499] 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, zebularin, hydralazine, procaine, MG98, genistein, bobcat 339 hydrochloride, hinokitiol, CM-272, and larsucostrol.

[0500] In some embodiments, one or more additional therapeutic agents are anti-interleukin-17A biological agents. In some embodiments, the anti-interleukin-17A biological agents are selected from secukinumab, ixekizumab, bimekizumab, brodalumab, and necalimumab.

[0501] In some embodiments, one or more additional therapeutic agents are anti-interleukin-23 inhibitors. In certain embodiments, the anti-interleukin-23 inhibitor is selected from guselkumab, risankizumab, tildrakizumab, and ustekinumab.

[0502] In some embodiments, one or more additional therapeutic agents are neutrophil elastase inhibitors. In some embodiments, the neutrophil elastase inhibitor is selected from cybelestat sodium hydrate, AvKTI, and flavonoids.

[0503] In some embodiments, one or more additional therapeutic agents are corticosteroids. In certain embodiments, the corticosteroids are flugestone, fluorometholone, medrisone, prevediolon acetate, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluferolone, fluprednisolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prenisone, thixocortol, triamcinolone, and dexamethasone. , Alclomethasone, Beclomethasone, Betamethasone, Clobetasol, Clobetason, Clocortolone, Desoximethasone, Dexamethasone, Diflorasone, Difluocortolon, Fluchlorolone, Flumethasone, Fluocortin, Fluocortolon, Flupredniden, Fluticasone, Fluticasone Furoate, Halomethasone, Mefrednisone, Mometasone, Mometasone Furoate, Paramethasone, Prednylidene, Rimexolone, Ulobetasol, Amsinod, Budesonide, Ciclesonide, Deflazacort, Desonide, Formocortal, Fluchlorolone Acetonide, Fludroxycortide, Flunisolide, Fluocinolone Acetonide, Fluocinonide, It is selected from halcinod, triamcinolone acetonide, cortibazole, and RU-28362.

[0504] In some embodiments, one or more additional therapeutic agents are protein arginine deiminases 4 (PAD4) inhibitors. In certain embodiments, the PAD4 inhibitor is selected from JBI-589, GSK484, Cl-amidine, azithromycin, clindamycin, leflunomide, and methotrexate.

[0505] 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.

[0506] In some embodiments, one or more additional therapeutic agents are thyroid hormone receptor beta (THR-β) agonists. In some embodiments, the THR-β agonist is selected from Resmetirom, VK2809, and cs27109.

[0507] In some embodiments, one or more additional therapeutic agents are immune checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiflimab, ipilimumab, atezolizumab, avelumab, and durvalumab.

[0508] In some embodiments, one or more additional therapeutic agents are bile acid conjugates. In certain embodiments, the bile acid conjugate is selected from berberine ursodeoxycholate, ursodeoxycholate, and nor-ursodeoxycholate. In certain embodiments, the bile acid conjugate is berberine ursodeoxycholate. In certain embodiments, the bile acid conjugate is ursodeoxycholate. In certain embodiments, the bile acid conjugate is nor-ursodeoxycholate.

[0509] 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, natalizumab, vedolizumab, PLN-1474, risuteganib, THR-687, OT-166, AXT107, tirofiban, eptifivatide, apsiximab, MORF-057, 7HP349, epalizumab, and ripitegrast.

[0510] 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 aldapemin.

[0511] In some embodiments, one or more additional therapeutic agents are monoclonal antibodies. In some embodiments, the monoclonal antibody targets CCL24, lysyl oxidase-like 2 (LOXL2), or vascular adhesion protein (VAP). In some embodiments, the monoclonal antibody is CM-101, simtuzumab, or BTT1023.

[0512] 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.

[0513] 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, erobixivat, A4250, 264W94, 216U90, GSK2330672, ropixivat, SC-435, S-1647, IMB17-15, varibicivat, S-8921, S-8921G, R-146224, BRL-39924A, S0960, bolixivat, and ritibixivat.

[0514] 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, tropexor, bonapexor, and cilofexor.

[0515] In some embodiments, one or more additional therapeutic agents are glucagon-like peptide-1 receptor agonists (GLP-1RA). In some embodiments, the GLP-1RA is selected from dulaglutide, exenatide, liraglutide, liraglutide / insulin degludec, lixisenatide / insulin glargine, semaglutide, and tyrzepatide.

[0516] In some embodiments, one or more additional therapeutic agents are bile acids or analogs thereof. In some embodiments, the bile acid or analogs thereof are selected from ursodeoxycholic acid and 24-norursodeoxycholic acid.

[0517] In some embodiments, one or more additional therapeutic agents are dihydroorotate dehydrogenase inhibitors. In some embodiments, the dihydroorotate dehydrogenase inhibitor is selected from bresinarr sodium, ASLAN003, ML390, BAY2402234, PTC299, leflunomide, vidofludimus calcium, teriflunomide, and IMU-838.

[0518] Additional considerations

[0519] The dosage and administration regimen of the active ingredients used in combination therapy may be determined by the attending clinician. In certain embodiments, the compounds described herein (e.g., chemical formulas I or chemical formula II The compound of or other compounds of Section I) and additional therapeutic agents are administered at doses typically used when these agents are used as monotherapy to treat the disorder. In other embodiments, the compounds described herein (e.g., formula I or chemical formula II The compound of or other compounds of Section I) and additional therapeutic(s) are administered at a lower dose than the dose typically used when these agents are used as monotherapy to treat the disorder. In certain embodiments, the compounds described herein (e.g., formula I or chemical formula II The compound of or other compounds of Section I) and additional therapeutic agents are present in the same composition, which is suitable for oral administration.

[0520] In certain embodiments, the compounds described herein (e.g., chemical formulas I or chemical formula II The compound of (or other compound of Section I) and additional therapeutic(s) may act additionally or synergistically. Synergistic combination may enable the use of lower doses of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower doses or less frequent administration of one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0521] Another aspect of the present invention is a therapeutically effective amount of the compound described herein (e.g., chemical formula I or chemical formula II It is a kit comprising a compound of Section I or another compound of Section I) or a pharmaceutically acceptable carrier, vehicle, or diluent and optionally at least one additional therapeutic agent listed above.

[0522] IV. Pharmaceutical composition and administration considerations

[0523] As specified above, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described above, formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for the following: (1) oral administration, e.g., drench (aqueous or non-aqueous solution or suspension), tablet, for example (1) those targeting buccal, sublingual, and systemic absorption, bolus, powder, granule, or paste for application to the tongue; (2) parenteral administration, for example, as a sterile solution or suspension or sustained-release formulation, for example, by 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) vaginally or rectal, for example, as a pessary, cream, or foam; (5) sublingual; (6) ocular; (7) transdermal; or (8) nasal. In specific embodiments, the present invention relates to the compounds described herein (e.g., formula I or chemical formula II Provides a pharmaceutical composition comprising a compound of (or another compound of Section I) and a pharmaceutically acceptable carrier.

[0524] As used herein, the term "therapeutic effective amount" means a corresponding amount of the compound, material, or composition comprising a compound of the present invention that is effective in producing some desired therapeutic effect in at least a subpopulation of animal cells at a reasonable benefit / risk ratio applicable to any medical treatment.

[0525] The phrase "pharmaceuticalally acceptable" is used herein to refer to these compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications within the scope of sound medical judgment, and correspond to a reasonable benefit / risk ratio.

[0526] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives, and antioxidants may also be present in the composition.

[0527] 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 ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0528] 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 widely known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will generally be the corresponding amount of the compound that produces a therapeutic effect. Generally, in 100 percent, this amount will be a range of active ingredient of about 0.1% to about 99%, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0529] In certain embodiments, the formulation of the present invention comprises cyclodextrin, cellulose, liposomes, micelle forming agents, for example Bile acids, and polymeric carriers, for example It comprises an excipient selected from the group consisting of polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, the aforementioned formulation makes the compound of the present invention bioavailable orally.

[0530] A method for preparing these formulations or compositions comprises the step of associating a compound of the present invention with a carrier and optionally one or more auxiliary components. Generally, a formulation is prepared by uniformly and intimately associating a compound of the present invention with a liquid carrier or a fine solid carrier, or both, and then, if necessary, forming a product.

[0531] Formulations of the present invention suitable for oral administration may exist in the form of capsules, caseos, pills, tablets, lozenges (based on flavoring, generally using sucrose and acacia or tragaccant), powders, granules, or as solutions or suspensions of aqueous or non-aqueous liquids, or as liquid emulsions of oil in water or water in oil, or as elixirs or syrups, or as pastiles (based on inertness, e.g., using gelatin and glycerin or sucrose and acacia) and / or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, a soft pill, or a paste.

[0532] In a solid dosage form of the present invention for oral administration (capsule, tablet, pill, coated tablet, powder, granule, troche, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dical phosphate and / or any of the following: (1) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) a binder, such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) a wetting agent, such as glycerol; (4) a disintegrant, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) a dissolution retardant, e.g., paraffin; (6) an absorption promoter, e.g., a quaternary ammonium compound and a surfactant, e.g., poloxamer and sodium lauryl sulfate; (7) a wetting agent, e.g., cetyl alcohol, glycerol monostearate, and a nonionic surfactant; (8) an absorbent, e.g., kaolin and bentonite clay; (9) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; and (10) a coloring agent; and (11) a control release agent, e.g., crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include a buffer. A similar type of solid composition may also be used as a filler for soft and hard shell gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol, etc.

[0533] Tablets may optionally be manufactured by compression or molding with one or more auxiliary components. Compression tablets may be manufactured using a binder (e.g., gelatin or hydroxypropylmethyl cellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium glycolate starch or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets may be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0534] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as coated tablets, capsules, pills, and granules, may optionally be scored or manufactured with coatings and shells, such as enteric coatings and other coatings widely known in the field of pharmaceutical formulation technology. Additionally, they may be formulated to provide slow or controlled release of the active ingredient within them by using, for example, hydroxypropylmethylcellulose, other polymer substrates, liposomes, and / or microspheres in various proportions to provide a desired release profile. They may be formulated for rapid release, and for example They may be freeze-dried. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain an opacifying agent and may be compositions that release the active ingredient(s) only in specific parts of the gastrointestinal tract, preferentially, or optionally in a delayed manner. Examples of encapsulation compositions that may be used include polymeric materials and waxes. The active ingredient may also be in a microencapsulated form having one or more of the excipients described above, if appropriate.

[0535] 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 forms may contain, for example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof, and inactive diluents commonly used in the art.

[0536] In addition to inactive diluents, the oral composition may also include humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavorings, and preservatives.

[0537] In addition to the active compound, the suspension may contain a suspending agent as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragaccant, and mixtures thereof.

[0538] A formulation of the pharmaceutical composition of the present invention for rectal or vaginal administration may be presented as a suppository, which may 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 salicylate, which will melt in the rectal or vaginal cavity and release the active compound, as it is solid at room temperature but liquid at body temperature.

[0539] The formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.

[0540] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be necessary under sterile conditions.

[0541] Ointments, pastes, creams, and gels may contain excipients in addition to the active compound of the present invention, such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanths, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide, or mixtures thereof.

[0542] The powder and spray may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these materials. The spray may additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0543] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. An absorption promoter may also be used to increase the flow of the compounds through the skin. This flow rate can be controlled by providing a rate control membrane or by dispersing the compounds in a polymer matrix or gel.

[0544] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also considered to be within the scope of the present invention.

[0545] A pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions that may contain a sugar, an alcohol, an antioxidant, a buffer, a bacterial growth inhibitor, a solute or suspending agent or thickening agent that makes the formulation isotonic with the blood of the intended recipient, or one or more compounds of the present invention combined with a sterile powder that may be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0546] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and organic esters for injection, such as ethyl oleate. Suitable fluidity can be maintained by the use of a coating material, such as lecithin, for example, by maintaining the particle size required in the case of a dispersion, and by the use of a surfactant.

[0547] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action on the target compound can be ensured by the inclusion of various antimicrobial and antifungal agents, e.g., parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, e.g., sugars, sodium chloride, etc., into the composition. Additionally, extended absorption in the injectable pharmaceutical form may be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0548] In some cases, to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. In this case, the rate of drug absorption depends on its dissolution rate and, ultimately, on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0549] Injectable depot formulations are prepared by forming a microencapsulation matrix of the target compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the properties of the specific polymer used, the drug release rate can be controlled. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0550] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be provided as they are or as pharmaceutical compositions containing, for example, 0.1 to 99% (more preferably 10 to 30%) of an active ingredient in combination with a pharmaceutically acceptable carrier.

[0551] The formulations of the present invention may be provided orally, parenterally, topically, or rectally. These are, of course, provided in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, ophthalmic solution, ointment, suppository, etc., administered by injection, infusion, or inhalation; administered topically by lotion or ointment; and administered rectally by suppository. Oral administration is preferred.

[0552] The terms 'parenteral administration' and 'parenterally administered' as used herein generally refer to methods of administration other than intestinal and local administration by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intravertebral, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtubercular, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intravertebral, and intrasternal injections and infusions.

[0553] As used herein, the terms 'systemic administration,' 'systemically administered,' 'peripheral administration,' and 'peripherally administered' refer to the administration of a compound, drug, or other substance other than direct administration to the central nervous system, so that it enters the patient's system and thus undergoes metabolism and other similar processes, e.g., subcutaneous administration.

[0554] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally by spray, rectally, vaginally, parenterally, intracerebrospinally, and topically by powder, ointment, or drops.

[0555] Regardless of the selected route of administration, the compounds of the present invention and / or the pharmaceutical compositions of the present invention that can be used in a suitable hydrated form are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0556] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention may vary to obtain an amount of the active ingredient effective in achieving a desired therapeutic response for a specific patient, composition, and mode of administration without toxicity to the patient.

[0557] The selected dosage level will depend on various factors including the activity of the specific compound of the present invention or its ester, salt, or amide used, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or substances used in combination with the specific compound used, the age, gender, weight, condition, general health and previous medical history of the patient being treated, and similar factors widely known in the pharmaceutical field.

[0558] A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the necessary pharmaceutical composition. For example, a physician or veterinarian may disclose a dose of the compound of the present invention used in the pharmaceutical composition at a level lower than necessary to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0559] Generally, a suitable daily dose of the compound of the present invention will be the corresponding amount of the compound that is the lowest effective dose for producing a therapeutic effect. This effective dose will generally depend on the factors described above. Preferably, the compound is administered at 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. The compound described herein is used in another formulation ( for example When co-administered with a sensitizer, the effective dose may be lower than when the preparation is used alone.

[0560] If desired, an effective daily dose of the active compound may optionally be administered individually in unit dosage forms at appropriate intervals throughout the day in subdoses of 2, 3, 4, 5, 6 or more. A preferred dosage is administered once a day. The present invention further provides unit dosage forms (e.g., tablets or capsules) comprising the compound described herein in a therapeutically effective amount for the treatment of the medical disorders described herein.

[0561] Examples

[0562] The invention as generally described will now be more easily understood by referring to the following examples, which are included merely to illustrate specific aspects and embodiments of the invention and are not intended to limit the invention.

[0563] Synthesis method

[0564] The method for preparing the compounds described herein is exemplified by the following synthesis formula. The reaction formula is provided for the purpose of illustrating the invention and is not intended to limit the scope or spirit of the invention. The starting materials shown in the reaction formula may be obtained from commercial sources or prepared based on procedures described in the literature.

[0565] In the reaction scheme, it is understood by those skilled in the art that the functionality present in the various parts of the molecule must be compatible with the proposed reagents and reaction. Substituents that are not compatible with the reaction conditions will be obvious to those skilled in the art, and thus alternative methods (e.g., the use of protecting groups or alternative reactions) are specified. Protecting group chemistry and strategies are well known in the art, for example, the literature whose entire contents are referenced herein by way of ["Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3 rdIt is described in detail in the [ed., John Wiley & Sons, 1999] edition. The modular synthesis route exemplified in Scheme 1 can also be readily modified by those skilled in the art to provide additional compounds by performing functional group conversions on the intermediates and final compounds. Such functional group conversions are widely known in the art, for example, as described in “Comprehensive Organic Synthesis” (BM Trost & I. Fleming, eds., 1991-1992).

[0566] The abbreviation 'TFA' refers to trifluoroacetic acid. The abbreviation 'FA' refers to formic acid.

[0567] Preparative HPLC Method:

[0568] HPLC Method 1.

[0569] Device: Shimadzu LCMS system equipped with UV and MS detectors

[0570] Mobile phase: 0.225% formic acid (solvent A) and CH3CN (solvent B) in water,

[0571] Gradient: Use a dissolution gradient of 30% to 70% (solvent B) over 10 minutes.

[0572] Flow rate: 35 ml / min;

[0573] Column: Phenomenex Gemini-NX 150*30 mm*5 mm

[0574] Wavelength: UV 220 nm and 254 nm

[0575] Column temperature: 30 o C;

[0576] MS Ionization: ESI

[0577] HPLC Method 2.

[0578] Devices: GILSON 215 and Shimadzu LCMS 2010A

[0579] Column: Agela Durashell C18 250*20 mm *5 µm

[0580] Mobile phase A: 0.1% ammonium bicarbonate (m / m) in water

[0581] Mobile phase B: Acetonitrile

[0582] Gradient: Linear from 80% A / 20% B to 60% A / 40% B within 10.0 minutes, maintained at 0% A / 100% B until 12.0 minutes.

[0583] Flow rate: 35 mL / min or 30 mL / min

[0584] HPLC Method 3.

[0585] Device: Shimadzu LCMS system equipped with DAD detector

[0586] Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in CH3CN (solvent B),

[0587] Gradient: Use of elution gradient from 5% to 95% (solvent B) over 0.7 minutes and hold at 95% for 0.4 minutes at a flow rate of 1.5 ml / min;

[0588] Column: Chromolish.Flash RP-18e 25-2 mm

[0589] Wavelength: UV 220 nm (or 215 nm, 254 nm)

[0590] Column temperature: 50 o C;

[0591] MS Ionization: ESI

[0592] HPLC Method 4A.

[0593] Device: Gilson-GX281

[0594] Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B),

[0595] Gradient: Use an elution gradient from 5% to 95% (solvent B) over 25 minutes.

[0596] Flow rate: 25 ml / min;

[0597] Column: Nanomicro-UniSil 5-120 C18, 5 µm, 30 x 150 mm

[0598] Wavelength: UV (220 nm and 254 nm)

[0599] Column temperature: 25°C;

[0600] MS Ionization: ESI.

[0601] HPLC Method 4B.

[0602] Device: Gilson-GX281

[0603] Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B),

[0604] Gradient: Use an elution gradient from 5% to 95% (solvent B) over 25 minutes.

[0605] Flow rate: 25 ml / min;

[0606] Column: YMC-Actus Triart C18 250*20 mm*5 um

[0607] Wavelength: UV (220 nm and 254 nm)

[0608] Column temperature: 25°C;

[0609] MS Ionization: ESI.

[0610] HPLC Method 4C.

[0611] Device: Gilson-GX281

[0612] Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B),

[0613] Gradient: Use an elution gradient from 5% to 95% (solvent B) over 25 minutes.

[0614] Flow rate: 25 ml / min;

[0615] Column: YMC-Actus Triart C18 250*20 mm*5 um

[0616] Wavelength: UV (220 nm and 254 nm)

[0617] Column temperature: 25°C;

[0618] MS Ionization: ESI.

[0619] HPLC Method 5A.

[0620] Device: LC-8A

[0621] Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B),

[0622] Gradient: Use an elution gradient from 20% to 95% (solvent B) over 18 minutes.

[0623] Flow rate: 18 ml / min;

[0624] Column: Metasll Cloak C18 21.2*250 mm, 5 mm

[0625] Wavelength: UV 220 nm and 254 nm

[0626] Column temperature: 25°C;

[0627] MS Ionization: ESI.

[0628] HPLC Method 5B.

[0629] Device: LC-8A

[0630] Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B),

[0631] Gradient: Use an elution gradient from 30% to 95% (solvent B) over 18 minutes.

[0632] Flow rate: 15 ml / min;

[0633] Column: Metasil Cloak C18 21.2*250 mm, 5 mm

[0634] Wavelength: UV 220 nm and 254 nm

[0635] Column temperature: 25°C;

[0636] MS Ionization: ESI.

[0637] HPLC Method 6A.

[0638] Device: LH-40

[0639] Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B),

[0640] Gradient: Use an elution gradient from 5% to 95% (solvent B) over 30 minutes.

[0641] Flow rate: 15 ml / min;

[0642] Column: YMC-Actus TriartC18 250*20 mm*5 um

[0643] Wavelength: UV (220 nm and 254 nm)

[0644] Column temperature: 25°C;

[0645] MS Ionization: ESI.

[0646] HPLC Method 6B.

[0647] Device: LH-40

[0648] Mobile phase: H2O (0.1% TFA) (solvent A) and CH3CN (solvent B),

[0649] Gradient: Use an elution gradient from 40% to 95% (solvent B) over 20 minutes.

[0650] Flow rate: 20 ml / min;

[0651] Column: YMC-Actus TriartC18 250*20 mm*5 um

[0652] Wavelength: UV (220 nm and 254 nm)

[0653] Column temperature: 25°C;

[0654] MS Ionization: ESI.

[0655] HPLC Method 6C.

[0656] Device: LH-40

[0657] Mobile phase: H2O (0.1% NH4OH) (solvent A) and CH3CN (solvent B),

[0658] Gradient: Use an elution gradient from 30% to 98% (solvent B) over 20 minutes.

[0659] Flow rate: 18 ml / min;

[0660] Column: YMC-ActusTriart C18 250*20 mm S-5 µm, 12 nm

[0661] Wavelength: UV (220 nm and 254 nm)

[0662] Column temperature: 25°C;

[0663] MS Ionization: ESI.

[0664] HPLC Method 7A.

[0665] Device: LC-LHS

[0666] Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B),

[0667] Gradient: Use an elution gradient from 40% to 95% (solvent B) over 22 minutes.

[0668] Flow rate: 15 ml / min;

[0669] Column: YMC-Actus Triart C18 / S-5 µm / 12 nm Lot Number 18849

[0670] Wavelength: UV (220 nm and 254 nm)

[0671] Column temperature: rt;

[0672] MS Ionization: ESI.

[0673] HPLC Method 7B.

[0674] Device: LC-LHS

[0675] Mobile phase: H2O (0.1% NH4OH) (solvent A) and CH3CN (solvent B),

[0676] Gradient: Use an elution gradient from 30% to 95% (solvent B) over 22 minutes.

[0677] Flow rate: 15 ml / min;

[0678] Column: YMC-Actus Triart C18 / S-5 µm / 12 nm Lot Number 18849

[0679] Wavelength: UV (220 nm and 254 nm)

[0680] Column temperature: rt;

[0681] MS Ionization: ESI.

[0682] HPLC Method 8A.

[0683] Device: LC-LHS

[0684] Mobile phase: H2O (0.1% FA) (solvent A) and CH3CN (solvent B),

[0685] Gradient: Use an elution gradient from 20% to 95% (solvent B) over 18 minutes.

[0686] Flow rate: 18 ml / min;

[0687] Column: Shim-pack Scepter C18 50*4.6 mm, 5 µm, 5 µm

[0688] Wavelength: UV 220 nm and 254 nm

[0689] Column temperature: 25°C;

[0690] MS Ionization: ESI.

[0691] Analytical LCMS method.

[0692] Analytical LC / MS Analysis Method A.

[0693] ESI+ / - Ion Mode 90-900

[0694] Wavelength: UV 254 nm / ELSD

[0695] Column: Kinetex EVO C18, 30*3.0 mm, 2.6 µm

[0696] Temperature: 30°C

[0697] gradient:

[0698]

[0699] Analytical LC / MS Method B.

[0700] ESI+ / - Ion Mode 90-900

[0701] Wavelength: UV 254 nm / ELSD

[0702] Column: Halo C18, 30*3.0 mm, 2.0 µm

[0703] Temperature: 40°C

[0704] gradient:

[0705]

[0706] Analytical LC / MS Analysis Method C.

[0707] ESI+ / - Ion Mode 90-900

[0708] Wavelength: UV 254 nm / ELSD

[0709] Column: Kinetex EVO, 100*4.6 mm, 2.6 µm

[0710] Temperature: 40°C

[0711] gradient:

[0712]

[0713] Analytical LC / MS Method D.

[0714] ESI+ / - Ion Mode 90-900

[0715] Wavelength: UV 254 nm / ELSD

[0716] Column: Kinetex EVO, 100*4.6 mm, 2.6 µm

[0717] Temperature: 40°C

[0718] gradient:

[0719]

[0720] Analytical LC / MS Analysis Method E.

[0721] ESI+ / - Ion Mode 90-900

[0722] Wavelength: UV 254 nm / ELSD

[0723] Column: Kinetex EVO C18, 30*3.0 mm, 2.6 µm

[0724] Temperature: 30°C

[0725] gradient:

[0726]

[0727] Analytical LC / MS Analysis Method F.

[0728] ESI+ / - Ion Mode 90-900

[0729] Wavelength: UV 254 nm / ELSD

[0730] Column: Kinetex EVO C18, 30*3.0 mm, 2.6 µm

[0731] Temperature: 30°C

[0732] gradient:

[0733]

[0734] Analytical LC / MS Method G.

[0735] ESI+ / - Ion Mode 90-900

[0736] Wavelength: UV 254 nm / ELSD

[0737] Column: Kinetex EVO C18, 100*4.6 mm, 2.6 µm

[0738] Temperature: 40°C

[0739] gradient:

[0740]

[0741] Analytical LC / MS Analysis Method H.

[0742] ESI+ / - Ion Mode 90-900

[0743] Wavelength: UV 254 nm / ELSD

[0744] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0745] Temperature: 30°C

[0746] gradient:

[0747]

[0748] Analytical LC / MS Analysis Method I.

[0749] ESI+ / - Ion Mode 90-900

[0750] Wavelength: UV 254 nm / ELSD

[0751] Column: Halo C18, 30*3.0 mm, 2.0 µm

[0752] Temperature: 40°C

[0753] gradient:

[0754]

[0755] Analytical LC / MS Analysis Method J.

[0756] ESI+ / - Ion Mode 90-900

[0757] Wavelength: UV 254 nm / ELSD

[0758] Column: Shim-pack Scepter C18-120, 33*3.0 mm, 3 µm

[0759] Temperature: 30°C

[0760] gradient:

[0761]

[0762] Analytical LC / MS Method K.

[0763] ESI+ / - Ion Mode 90-900

[0764] Wavelength: UV 254 nm / ELSD

[0765] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0766] Temperature: 30°C

[0767] gradient:

[0768]

[0769] Analytical LC / MS Analysis Method L.

[0770] ESI+ / - Ion Mode 90-900

[0771] Wavelength: UV 254 nm / ELSD

[0772] Column: Halo C18, 30*3.0 mm, 2.2 µm

[0773] Temperature: 40°C

[0774] gradient:

[0775]

[0776] Analytical LC / MS Method M.

[0777] ESI+ / - Ion Mode 90-900

[0778] Wavelength: UV 220 nm / ELSD

[0779] Column: Shim-pack C18, 33*3.0 mm, 3.0 µm

[0780] Temperature: 30°C

[0781] gradient:

[0782]

[0783] Analytical LC / MS analysis method O.

[0784] ESI+ / - Ion Mode 90-900

[0785] Wavelength: UV 220 nm / ELSD

[0786] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0787] Temperature: 30°C

[0788] gradient:

[0789]

[0790] Analytical LC / MS Analysis Method P.

[0791] ESI+ / - Ion Mode 90-900

[0792] Wavelength: UV 254 nm / ELSD

[0793] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0794] Temperature: 30°C

[0795] gradient:

[0796]

[0797] Analytical LC / MS Analysis Method Q.

[0798] ESI+ / - Ion Mode 90-900

[0799] Wavelength: UV 254 nm / ELSD

[0800] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0801] Temperature: 30°C

[0802] gradient:

[0803]

[0804] Analytical LC / MS Analysis Method R.

[0805] ESI+ / - Ion Mode 90-900

[0806] Wavelength: UV 220 nm / ELSD

[0807] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0808] Temperature: 30°C

[0809] gradient:

[0810]

[0811] Analytical LC / MS Analysis Method S.

[0812] ESI+ / - Ion Mode 90-900

[0813] Wavelength: UV 254 nm / ELSD

[0814] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0815] Temperature: 30°C

[0816] gradient:

[0817]

[0818] Analytical LC / MS Analysis Method T.

[0819] ESI+ / - Ion Mode 90-900

[0820] Wavelength: UV 254 nm / ELSD

[0821] Column: Halo C18, 30*3.0 mm, 2.0 µm

[0822] Temperature: 40°C

[0823] gradient:

[0824]

[0825] Analytical LC / MS Analysis Method U.

[0826] ESI+ / - Ion Mode 90-900

[0827] Wavelength: UV 254 nm / ELSD

[0828] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0829] Temperature: 40°C

[0830] gradient:

[0831]

[0832] Analytical LC / MS Analysis Method V.

[0833] ESI+ / - Ion Mode 90-900

[0834] Wavelength: UV 254 nm / ELSD

[0835] Column: Shim-pack C18, 50*4.6 mm, 5 µm

[0836] Temperature: 40°C

[0837] gradient:

[0838]

[0839] Analytical LC / MS Analysis Method W.

[0840] ESI+ / - Ion Mode 90-900

[0841] Wavelength: UV 254 nm / ELSD

[0842] Column: Shim-pack C18, 50*4.6 mm, 5 µm

[0843] Temperature: 40°C

[0844] gradient:

[0845]

[0846] Analytical LC / MS Method X.

[0847] ESI+ / - Ion Mode 90-900

[0848] Wavelength: UV 254 nm / ELSD

[0849] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0850] Temperature: 40°C

[0851] gradient:

[0852]

[0853] Analytical LC / MS Method Y.

[0854] ESI+ / - Ion Mode 90-900

[0855] Wavelength: UV 254 nm / ELSD

[0856] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0857] Temperature: 40°C

[0858] gradient:

[0859]

[0860] Analytical LC / MS Analysis Method Z.

[0861] ESI+ / - Ion Mode 90-900

[0862] Wavelength: UV 254 nm / ELSD

[0863] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0864] Temperature: 40°C

[0865] gradient:

[0866]

[0867] Analytical LC / MS Analysis Method ZA.

[0868] ESI+ / - Ion Mode 90-900

[0869] Wavelength: UV 254 nm / ELSD

[0870] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0871] Temperature: 40°C

[0872] gradient:

[0873]

[0874] Analytical LC / MS method ZB.

[0875] ESI+ / - Ion Mode 90-900

[0876] Wavelength: UV 254 nm / ELSD

[0877] Column: UniHybrid 5-120 C8, 150*4.6 mm, 5 µm

[0878] Temperature: 40°C

[0879] gradient:

[0880]

[0881] Analytical LC / MS method ZC.

[0882] ESI+ / - Ion Mode 90-900

[0883] Wavelength: UV 254 nm / ELSD

[0884] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0885] Temperature: 40°C

[0886] gradient:

[0887]

[0888] Analytical LC / MS Analysis Method ZD.

[0889] ESI+ / - Ion Mode 90-900

[0890] Wavelength: UV 254 nm / ELSD

[0891] Column: Kromasil-C18, 50*4.6 mm, 5 µm

[0892] Temperature: 40°C

[0893] gradient:

[0894]

[0895] Analytical LC / MS Analysis Method ZE.

[0896] ESI+ / - Ion Mode 90-900

[0897] Wavelength: UV 220 nm / ELSD

[0898] Column: ACQUITY UPLC BEH Shield RP18 1.7 um 2.1*50 mm

[0899] Temperature: 40°C

[0900] gradient:

[0901]

[0902] Analytical LC / MS method ZF.

[0903] ESI+ / - Ion Mode 90-900

[0904] Wavelength: UV 254 nm / ELSD

[0905] Column: YMC-Triart C18, 50*4.6 mm, 5 µm

[0906] Temperature: 40°C

[0907] gradient:

[0908]

[0909] Analytical LC / MS analysis method ZG.

[0910] ESI+ / - Ion Mode 90-900

[0911] Wavelength: UV 254 nm / ELSD

[0912] Column: Shim-pack C18, 33*3.0 mm, 3 µm

[0913] Temperature: 30°C

[0914] gradient:

[0915]

[0916] Analytical LC / MS method ZH.

[0917] ESI+ / - Ion Mode 90-900

[0918] Wavelength: UV 254 nm / ELSD

[0919] Column: Shim-pack C18, 33*3.0 mm, 3.0 µm

[0920] Temperature: 30°C

[0921] gradient:

[0922]

[0923] Analytical LC / MS Analysis Method ZI.

[0924] ESI+ / - Ion Mode 90-900

[0925] Wavelength: UV 254 nm / ELSD

[0926] Column: Shim-pack C18, 33*3.0 mm, 3.0 µm

[0927] Temperature: 30°C

[0928] gradient:

[0929]

[0930] Analytical LC / MS method ZJ.

[0931] ESI+ / - Ion Mode 90-900

[0932] Wavelength: UV 254 nm / ELSD

[0933] Column: Shim-pack C18, 33*3.0 mm, 3.0 µm

[0934] Temperature: 30°C

[0935] gradient:

[0936]

[0937] Analytical LC / MS method ZK.

[0938] ESI+ / - Ion Mode 90-900

[0939] Wavelength: UV 220 nm / ELSD

[0940] Column: Kinetex EVO C18, 30*3.0 mm, 2.6 µm

[0941] Temperature: 30°C

[0942] gradient:

[0943]

[0944] Analytical LC / MS method ZL.

[0945] ESI+ / - Ion Mode 90-900

[0946] Wavelength: UV 254 nm / ELSD

[0947] Column: Halo C18, 30*3.0 mm, 2.2 µm

[0948] Temperature: 40°C

[0949] gradient:

[0950]

[0951] Analytical LC / MS method ZM.

[0952] ESI+ / - Ion Mode 90-900

[0953] Wavelength: UV 254 nm / ELSD

[0954] Column: Halo C18, 30*3.0 mm, 2.0 µm

[0955] Temperature: 40°C

[0956] gradient:

[0957]

[0958] Analytical LC / MS method ZN.

[0959] ESI+ / - Ion Mode 90-900

[0960] Wavelength: UV 254 nm / ELSD

[0961] Column: CORTECS T3, 30*2.1 mm, 2.7 µm

[0962] Temperature: 40°C

[0963] gradient:

[0964]

[0965] Analytical LC / MS analysis method ZO.

[0966] ESI+ / - Ion Mode 90-900

[0967] Wavelength: UV 254 nm / ELSD

[0968] Column: Shim-pack Scepter C18, 33*3.0 mm, 3 µm

[0969] Temperature: 40°C

[0970] gradient:

[0971]

[0972] Analytical LC / MS method ZP.

[0973] ESI+ / - Ion Mode 90-900

[0974] Wavelength: UV 254 nm / ELSD

[0975] Column: Shim-pack C18, 33*3.0 mm, 3 µm

[0976] Temperature: 30°C

[0977] gradient:

[0978]

[0979] Example 1: Method A: Synthesis of Compounds I-16 and I-17

[0980]

[0981] Step 1: 1-(6-bromopyridine-3-yl) ethane-1-one in THF (5 mL) R-1 In a stirred solution of , 2.0 g, 1.0 mmol, 1.0 equivalent) and 2-methylpropane-2-sulfinamide (1.45 g, 1.2 mmol, 1.2 equivalent) at room temperature, Ti(O i Pr)4 (6.84 g, 3.0 mmol, 3.0 equivalents) was added. The resulting mixture was stirred at 80°C for 2 hours, after which the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 25% PE) Intermediate-1 (2.79 g, 9.24 mmol, 92%) was obtained as a yellow solid. LCMS (ESI) : m / z = 303 [M+H] + .

[0982] Step 2: In MeOH (15 mL) Intermediate-1 0 in a stirred solution of (2.75 g, 9.11 mmol, 1.0 equivalent) o NaBH4 (692 mg, 18.21 mmol, 2.0 equivalents) was slowly added at C. The resulting mixture was stirred at room temperature for 10 minutes, after which the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude Intermediate-2 (2.7 g, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 305 [M+H] + .

[0983] Step 3: In THF (5 mL) Intermediate-2 HCl (2 mL) was slowly added to a stirred solution of (2.7 g, 8.88 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 20 minutes. Subsequently, the reaction mixture was concentrated under reduced pressure. Intermediate-3 (1.6 g, 8.0 mmol, 90%) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 201 [M+H] + .

[0984] Step 4: In DCM (10 mL) Intermediate-3 ( 4 Boc2O (5.23 g, 24.0 mmol, 3.0 equivalents) was added at room temperature to a stirred solution of , 1.6 g, 8.0 mmol, 1.0 equivalent) and TEA (2.424 g, 24.0 mmol, 3.0 equivalents). The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The unrefined residue was purified via silica gel by flash column chromatography (elution with EtOAc in 0 to 25% PE). Intermediate-4 (2.2 g, 7.28 mmol, 92%) was obtained as a colorless oil. LCMS (ESI) : m / z = 301 [M+H] + .

[0985] Step 5: In THF (15 mL) Intermediate-4 -78 in a stirred solution of (500 mg, 1.67 mmol, 1 equivalent) o In C n -BuLi (1.3 mL, 3.33 mmol, 2 equivalents, 2.5 M in THF) was added. The resulting mixture was sterilized under N2 at -78 oThe mixture was stirred at C for 20 minutes, followed by the addition of acetone (1 mL) and stirring the reaction mixture for an additional 15 minutes. Then, the reaction mixture was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The unrefined residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 50% PE). Intermediate-5 (158 mg, 0.56 mmol, 34%) was obtained as a white solid. LCMS (ESI) : m / z = 281 [M+H] + .

[0986] Step 6: In DCM (12 mL) Intermediate-5 TFA (1.2 mL) was slowly added to a stirred solution of (158 mg, 0.56 mmol, 1.0 equivalent) at room temperature. After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to obtain the unpurified Intermediate-6 (142 mg, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 181 [M+H] + .

[0987] Step 7: 6-chloro-1-methyl-1H-indole-2-carboxylic acid in DMF (10 mL) R-2 TEA (402 mg, 3.97 mmol, 3 equivalents) and HATU (605 mg, 1.59 mmol, 1.2 equivalents) in a stirred solution of , 333 mg, 1.59 mmol, 1.2 equivalents) and HATU (605 mg, 1.59 mmol, 1.2 equivalents) and Intermediate-6(240 mg, 1.33 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The unrefined residue was purified by flash column chromatography on silica gel (elution at PE:EtOAc = 1:2). Intermediate-7 (210 mg, 0.56 mmol, 42%) was obtained as a white solid. LCMS (ESI) : m / z = 372 [M+H] + .

[0988] Step 8: Intermediate-7 (210 mg, 0.56 mmol, 1.0 equivalent) was purified by SFC as a white solid I-16 (57.3 mg, 0.15 mmol, 55%) and as a white solid I-17 (55.3 mg, 0.149 mmol, 53%) was obtained.

[0989] Compound I-17: >99% ee. Maintenance time : 2,416 minutes. LC-MS (ESI): m / z =372.1 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO) δ8.95 (d, J = 7.9 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.2, 2.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.5, 1.7 Hz, 1H), 5.27-5.08 (m, 2H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.42 (s, 6H).

[0990] Compound I-16: 98% ee. Maintenance time : 3.711 min. LC-MS (ESI): m / z =372.3 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO) δ8.95 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.2, 2.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.5, 1.6 Hz, 1H), 5.28-5.09 (m, 2H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.42 (s, 6H).

[0991] SFC Method: Device: SHIMADZU PREP SOLUTION SFC, Column: ChiralCel O J , 250×20 mm ID, 5 μm, Mobile phase: CO2 as A and EtOH (0.1% 7 mol / L NH3 in MeOH) as B, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm. Cycle time: 15 min, Elution time: 2 H.

[0992] Analysis Method: Column: ChiralCel OJ, 100×4.6 mm ID, 3 µm, Mobile phase: CO2 as A and EtOH (0.05% DEA) as B, Gradient: 8 min @ B 30%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35°C.

[0993] The following compounds were prepared from suitable amines and carboxylic acids using Method A. Compound I-105 , I-106 , I-109 ,I-110 , I-111 , I-114 , I-116 , I-117 , I-118 , I-126 , I-132 , I-135 , I-137 , I-138 , I-140 , I-141 , I-145 , I-146 , I-147 , I-148 , I-149 , I-151 , I-152 , I-153 , I-154 , I-156 , I-159 , I-160 , I-161 , I-162 , I-163 , I-164 , I-165 , I-166 , I-167 , I-168 , I-169 , I-170 , I-171 , I-172 , I-173 , I-174 , I-175 , I-176 , I-177 , I-178 , I-179 , I-180 , I-181 , I-182 , I-183 , I-184 , I-223 , I-224 , I-237 , I-238 , I-22 , I-23, I-399, I-400, I-415, I-416, I-427, I-428, I-447, I-448, I-469, I-470, I-471, I-472, I-616, I-617, I-624, I-625, I-626 , and I-627 .

[0994] Example 2: Method B: Synthesis of Compound I-139

[0995]

[0996] In EtOH (5 mL) R-3 (80 mg, 0.379 mmol, 1.0 equivalent) and R-4 120 of a solution of (85 mg, 0.57 mmol, 1.5 equivalents) oIt was stirred overnight at C. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound I-139 (6.8 mg, 0.021 mmol, 6%) was obtained as a white solid.

[0997] LCMS (ESI): m / z = 330 [M+H] + . 1 H NMR (400 MHz, DMSO) δ9.95 (t, J = 6.3 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.97-7.87 (m, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.8, 2.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 4.54 (d, J = 6.2 Hz, 2H), 4.44 (d, J = 6.5 Hz, 1H).

[0998] Example 3: Method C: Synthesis of Compound I-123

[0999]

[1000]

[1001] Step 1: Ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate in DMF (5 mL) R-5 NBS (271.2 mg, 1.52 mmol, 1.2 equivalents) was slowly added to a stirred solution of (300 mg, 1.27 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The unrefined residue was purified by flash column chromatography on silica gel (eluting PE:EtOAc = 0 to 10:1). Intermediate-8 (393 mg, 1.25 mmol, 82%) was obtained as a white solid. LCMS (ESI) : m / z = 316 [M+H] + .

[1002] Step 2: In 1,4-dioxane (10 mL) and water (2 mL) Intermediate-8 A mixture of (393 mg, 1.25 mmol, 1 equivalent), methylboronic acid (225 mg, 3.75 mmol, 3.0 equivalents), Pd(dppf)Cl2 (94 mg, 0.13 mmol, 0.1 equivalents), and Cs2CO3 (1.22 g, 3.75 mmol, 3.0 equivalents) was stirred overnight at 105°C 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 phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The unrefined residue was purified by flash column chromatography on silica gel (eluting at PE:EtOAc = 10:1) to obtain ethyl Intermediate-9 (235 mg, 0.94 mmol, 75%) was obtained as yellow oil. LCMS (ESI) : m / z = 252 [M+H] + .

[1003] Step 3: In EtOH (5 mL) Intermediate-9 An aqueous NaOH solution (254 mg, 6.35 mmol, 5.0 equivalents) was slowly added to a stirred solution of (300 mg, 1.27 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was neutralized with an aqueous HCl solution (1 N) until the pH was adjusted to pH = 5 to 6. Subsequently, the solution was extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure Intermediate-10 (200 mg, quantitative value) was obtained and used directly in the next step without further purification. LCMS (ESI) : m / z= 224 [M+H] + .

[1004] Step 4: In DMF (5 mL) Intermediate-10 In a stirred solution of (335 mg, 1.5 mmol, 1.0 equivalent) and HATU (580 mg, 1.5 mmol, 1.0 equivalent), TEA (253 mg, 2.5 mmol, 1.7 equivalents) and ethyl (R)-4-(1-aminoethyl)benzoate ( R-6 290 mg, 1.5 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at room temperature for 30 minutes. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution at PE:EtOAc = 3:1) Intermediate-11 (354 mg, 0.89 mmol, 60%) was obtained as a white solid. LCMS (ESI) : m / z = 399 [M+H] + .

[1005] Step 5: In EtOH (5 mL) Intermediate-11 An aqueous NaOH solution (178 mg, 4.45 mmol, 5.0 equivalents) was slowly added to a stirred solution of (354 mg, 0.89 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was neutralized with an aqueous HCl solution (1 N) until the pH was adjusted to pH = 5 to 6. Subsequently, the solution was extracted with DCM (10 mL x 3), the combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. Intermediate-12 (200 mg, quantitative value) was obtained and used directly in the next step without further purification. LCMS (ESI) : m / z = 371 [M+H] + .

[1006] Step 6: In DMF (5 mL) Intermediate-12 TEA (180 mg, 2.5 mmol, 2.5 equivalents) and NH4Cl (294 mg, 5.5 mmol, 5.5 equivalents) were added to a stirred solution of (371 mg, 1.0 mmol, 1.0 equivalent) and HATU (418 mg, 1.1 mmol, 1.1 equivalent). The resulting mixture was stirred at room temperature for 30 minutes, after which the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The unrefined residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 0 to 2:1). Compound I-123 ( 35 mg, 0.095 mmol, 10%) was obtained as a white solid. LCMS (ESI) : m / z = 370 [M+H] + . 1 1H NMR (400 MHz) , DMSO) δ 8.90 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.62-7.56 (m, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.09 (dd, J = 8.6, 1.7 Hz, 1H), 5.23 (p, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.34 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H)

[1007] The following compounds were prepared from suitable amines and carboxylic acids using Method C. I-127 , I-128 , I-143 , I-144 , I-150 , I-155 , I-157 , I-158 I-439 ,I-453 , I-468 , I-611, I-656, I-657, I-658, I-659, I-662, I-663, I-664, I-665, I-669, I-670, I-671, I-672, I-676, I-679, I-680, I-681, I-682, I-690, I-693, I-694, I-742, I-769, I-771, I-775, and I-743 .

[1008] Example 4: Method D: Synthesis of Compound I-121

[1009]

[1010] In DMF (20 mL) R-2 In a stirred solution of (800 mg, 3.83 mmol, 1.0 equivalent) and HATU (1.6 g, 4.21 mmol, 1.1 equivalent) at room temperature, TEA (1159.8 mg, 11.48 mmol, 3.0 equivalent) and ethyl (R)-4-(1-aminoethyl)benzoate ( R-6, 812.6 mg (4.21 mmol, 1.1 equivalent) was slowly added. The resulting mixture was stirred at room temperature for 1 hour, after which the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 50% PE) Intermediate-13 (700 mg, 1.82 mmol, 48%) was obtained as a white solid. LCMS (ESI) : m / z = 385 [M+H] + .

[1011] In THF (15 mL) Intermediate-13 0 in a stirred solution of (700 mg, 1.89 mmol, 1 equivalent) o DIBAL-H (5 mL, 7.547 mmol, 1.5 M in THF, 4 equivalents) was added at C. The resulting mixture was 0 under N2. oThe mixture was stirred at C for 3 hours. Then, the reaction mixture was quenched with 10 mL of saturated aqueous potassium sodium tartrate, followed by pouring into H2O (15 mL) and extracting with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 80% PE) Compound I-121 (516 mg, 1.51 mmol, 84%) was obtained as a white solid.

[1012] LCMS (ESI): m / z = 343 [M+H] + . 1 H NMR (400 MHz, DMSO) δ8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.18-5.05 (m, 2H), 4.46 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[1013] Example 5: Method E: Synthesis of Compound I-18 and Compound I-19

[1014]

[1015]

[1016] Step 1: 2-bromo-5-fluoroisonicotinic acid in DMF (20 mL) R-7Cs2CO3 (6.0 g, 18.2 mmol, 2.0 equivalents) and MeI (1.9 g, 13.7 mmol, 1.5 equivalents) were added to a stirred solution of (2.0 g, 9.1 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 30 minutes, after which the reaction reached completion. Subsequently, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (40 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc = 0 to 10:1 elution) Intermediate-14 (1.9 g, 8.1 mmol, 89%) was obtained as a white solid. LCMS (ESI) : m / z = 234 [M+H] + .

[1017] Step 2: In toluene (100 mL) Intermediate-14 (1.9 g, 8.1 mmol, 1 equivalent) and tributyl(1-ethoxyvinyl)stanan( R-8 Pd(PPh3)4 (936 mg, 0.81 mmol, 0.1 equivalent) was added to a mixture of (3.2 g, 8.91 mmol, 1.1 equivalent). The resulting mixture was stirred overnight at 110°C 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 phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 0 to 10:1) Intermediate-15 (1.45 g, 6.48 mmol, 80%) was obtained as yellow oil. LCMS (ESI) : m / z = 226 [M+H] + .

[1018] Step 3: In EtOAc (50 mL) Intermediate-15HCl / 1,4-dioxane (20 mL) was added to a stirred solution of (1.45 g, 6.48 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 30 minutes. After completion, the solution was concentrated under reduced pressure. Intermediate-16 (1.28 g, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 198 [M+H] + .

[1019] Step 4: In THF (20 mL) Intermediate-16 In a stirred solution of (1.28 g, 6.48 mmol, 1.0 equivalent) and 2-methylpropane-2-sulfinamide (862 mg, 7.13 mmol, 1.1 equivalent) at room temperature, Ti(O i Pr)4 (3.68 g, 12.96 mmol, 1.5 equivalents) was added. The resulting mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 0 to 4:1) Intermediate-17 (956 mg, 2.9 mmol, 45%) was obtained as a yellow solid. LCMS (ESI) : m / z = 329 [M+H] + .

[1020] Step 5: In MeOH (10 mL) Intermediate-17NaBH4 (138 mg, 3.48 mmol, 1.2 equivalents) was slowly added at room temperature to a stirred solution of (0.9 g, 2.9 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 10 minutes. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc = 2:1 to 1:1 elution) Intermediate-18 (0.8 g, 3 mmol, 86%) was obtained as a white solid. LCMS (ESI) : m / z = 331 [M+H] + .

[1021] Step 6: In MeOH (10 mL) Intermediate-18 HCl / 1,4-dioxane (10 mL) was added to a stirred solution of (0.8 g, 3 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 20 minutes. After completion, the reaction mixture was concentrated under reduced pressure. Intermediate-19 (389 mg, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 227 [M+H] + .

[1022] Step 7: In DMF (10 mL) R-2 TEA (303 mg, 3 mmol, 2 equivalents) and HATU (684 mg, 2.7 mmol, 1.2 equivalents) in a stirred solution of (376 mg, 1.8 mmol, 1.2 equivalents) and HATU (684 mg, 2.7 mmol, 1.2 equivalents) and Intermediate-19(389 mg, 1.5 mmol, 1.2 equivalents) was added. The resulting mixture was stirred at room temperature for 30 minutes. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 0 to 4:1) Intermediate-20 (280 mg, 0.68 mmol, 45%) was obtained as a white solid. LCMS (ESI) : m / z = 418 [M+H] + .

[1023] Step 8: In MeOH (10 mL) Intermediate-20 An aqueous LiOH solution (152 mg, 6.35 mmol, 5.0 equivalents) was slowly added to a stirred solution of (280 mg, 0.68 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was neutralized with an aqueous HCl solution (1 N) until the pH was adjusted to pH = 5 to 6. Subsequently, the solution was extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure Intermediate-21 (200 mg, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 376 [M+H] + .

[1024] Step 9: In DMF (10 mL) Intermediate-21TEA (136 mg, 1.35 mmol, 2.0 equivalents) and NH4Cl (127 mg, 2.4 mmol, 2.5 equivalents) were added to a stirred solution of (253 mg, 0.68 mmol, 1.0 equivalent) and HATU (307 mg, 0.81 mmol, 1.2 equivalents). The resulting mixture was stirred at room temperature for 30 minutes. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with PE:EtOAc = 0 to 2:1) Intermediate-22( 101 mg, 0.27 mmol, 40%) was obtained as a white solid. LCMS (ESI) : m / z = 375 [M+H] + .

[1025] Step 10: Intermediate-22 Further separated by chiral SFC Compound I-19 (15 mg, 30%) and Compound I-18 (16 mg, 32%) was provided.

[1026] Compound I-19: >99% ee. Maintenance time : 2.872 minutes. LC-MS (ESI): m / z = 375.1 [M+H] + ; 1 1H NMR (400 MHz) , DMSO- d 6 ) δ8.97 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.72-7.65 (m, 2H), 7.63 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 0.8 Hz, 1H), 7.12 (dd,J = 8.5, 1.9 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[1027] Compound I-18: >99% ee. Maintenance time : 3,532 minutes. LC-MS (ESI): m / z = 375.1 [M+H] + ; 1 1H NMR (400 MHz) , DMSO- d 6 ) δ8.97 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.72-7.66 (m, 2H), 7.63 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 0.9 Hz, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 3.93 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[1028] SFC Method: Instrument: Waters Thar 80 Preparative SFC, Column: (R,R)-WHELK, 250×30 mm ID, 5 μm, Mobile Phase: CO2 as A and MeOH as B (0.1% 2 mol / L NH3 in MeOH), Gradient: B 45%, Flow Rate: 60 mL / min, Back Pressure: 100 bar, Column Temperature: 40°C, Wavelength: 220 nm, Cycle Time: 8 min, Elution Time: 3 H.

[1029] Analysis Method:Instrument: Waters UPCC, (R,R)-WHELK, 100×4.6 mm ID, 3 μm; Mobile phase: CO2 as A and methanol (0.05% DEA) as B; Gradient: 8 min @ 40% B; Flow rate: 2.0 mL / min; Column temperature: 40°C.

[1030] The following compounds were prepared from suitable amines and carboxylic acids using Method C. I-191 , I-192 , I-20 , I-21 , I-284 , I-285 , I-288 , I-289 , I-290 , I-291 , I-292 , I-293 , I-294 , I-338 , I-339 , I-364 , I-397 , I-398 , I-443 , I-444 , I-495 , and I-496 .

[1031] Example 6: Method F: Compound I-119 , I-120 , Synthesis of and I-122

[1032]

[1033] Step 1: In DMF (3 mL) R-2 In a stirred mixture of (74 mg, 3.54 mmol, 1.5 equivalents) and HATU (180 mg, 4.72 mmol, 2.0 equivalents) R-9 (50 mg, 2.36 mmol, 1.0 equivalent) and DIEA (122 mg, 9.43 mmol, 4.0 equivalent) were added. The resulting mixture was 25 oStirred at C for 2 hours. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30%, EtOAc in PE). Compound I-122 (10 mg, 1.44 mmol, 61%) was obtained as a yellow solid. LCMS (ESI) : m / z = 405.0 [M+H] + .

[1034] 1 1H NMR (400 MHz) , DMSO) δ 9.26 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.48 (s, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 7.11 (dd, J = 8.5, 1.7 Hz, 1H), 3.93 (s, 3H), 1.29 (d, J = 8.1 Hz, 4H).

[1035] Step 2: In DMF (5 mL) Compound I-122 Palladium (0) tetrakis(triphenylphosphine) (23 mg, 0.020 mmol, 0.1 equivalent) and Zn(CN)2 (23 mg, 0.20 mmol, 1.0 equivalent) were added to a stirred mixture of (50 mg, 0.20 mmol, 1.0 equivalent). The resulting mixture was stirred at 120°C for 4 hours. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with EtOAc in 0 to 30% PE) Compound I-119(30 mg, 0.143 mmol, 72%) was obtained as a yellow solid.

[1036] LCMS (ESI): m / z = 350.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ9.32 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.68 (dd, J = 4.9, 3.4 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.27 (s, 1H), 7.12 (dd, J = 8.5, 1.8 Hz, 1H), 3.94 (s, 3H), 1.41 (s, 4H).

[1037] Step 3: In DMSO (20 mL) Compound I-119 (20 mg, 0.057 mmol, 1.0 equivalent) 0 in solution o Add K2CO3 (16 mg, 0.114 mmol, 2.0 equivalents) and H2O2 (2 mL) at C, and the reaction mixture was heated under N2 for 25 o Stirred at C for 2 hours. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with EtOAc in 0 to 30% PE). Compound I-120 (10 mg, 0.027 mmol, 48%) was obtained as a yellow solid. LCMS (ESI): m / z = 368.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ9.28 (s, 1H), 7.89 (s, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.70-7.65 (m, 2H), 7.26 (s, 3H), 7.24 (s, 1H), 7.12 (dd, J = 8.6, 1.7 Hz, 1H), 3.94 (s, 3H), 1.35 (s, 4H).

[1038] The following compounds were prepared from suitable amines and carboxylic acids using Method F. I-99 , I-100 , I-107 , and I-108 .

[1039] Example 7: Method G: Synthesis of Compound I-133

[1040]

[1041]

[1042] Step 1: 6-bromo-1H-indole-2-carboxylic acid in DMF (50 mL) R-10 0 in a stirred solution of , 1.8 g, 7.5 mmol, 1.0 equivalent) o NaH (1.2 g, 30.0 mmol, 4.0 equivalents) was added at C. The resulting mixture was stirred for 0.5 hours, at which point MeI (5.33 g, 37.5 mmol, 5.0 equivalents) was slowly added. The resulting mixture was heated to room temperature and stirred overnight. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 5 to 10% PE) Intermediate-23 (1.9 g, 7.0 mmol, 95%) was obtained as a white solid. LCMS (ESI) : m / z = 268 [M+H] + .

[1043] Step 2: In MeOH (20 mL) and H2O (5 mL) Intermediate-23 LiOH·H2O (315 mg, 7.5 mmol, 2.0 equivalents) was added to the (1.0 g, 3.73 mmol, 1.0 equivalent) solution. The resulting mixture was stirred overnight at room temperature. After completion, the mixture was carefully neutralized with 1 N HCl (aqueous) until the pH was adjusted to pH = 5 to 6. The resulting mixture was extracted with DCM (20 mL x 3), the combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to obtain the unpurified Intermediate-24 (942 mg, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 254 [M+H] + .

[1044] Step 3: In DMF (20 mL) Intermediate-24 In a solution of (0.942 g, 3.71 mmol, 1.0 equivalent) and HATU (1.7 g, 4.45 mmol, 1.2 equivalents) R-4 (668 mg, 4.45 mmol, 1.2 equivalents) and TEA (1.13 g, 11.13 mmol, 3.0 equivalents) were added. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with MeOH in 0 to 3% DCM) Intermediate-25 (0.726 g, 1.88 mmol, 51%) was obtained as a white solid. LCMS (ESI) : m / z = 386 [M+H] + .

[1045] Step 4: In dioxane / H2O (5 mL / 1 mL) Intermediate-25 (50 mg, 0.13 mmol, 1.0 equivalent) andR-11 Na2CO3 (23 mg, 0.26 mmol, 2.0 equivalents) and Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 equivalents) were added to a solution of (26 mg, 0.16 mmol, 1.2 equivalents). The resulting mixture was degassed under vacuum and purged several times with N2. The resulting mixture was stirred at 100°C under N2 for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative HPLC (Welch-Ultimate AQ-C18, 21.2 × 250 mm, 5 μm, H2O / MeCN (10-95%) / 0.1% formic acid) Compound I-133 (1.2 mg, 3.1 μmol, 2%) was obtained as a white solid. LCMS (ESI) : m / z = 388 [M+H] + .

[1046] The following compounds were prepared from suitable amines and carboxylic acids using Method G. I-129 , I-130 , I-131 , I-134 , I-136 , and I-142 .

[1047] Example 8: Method H: Synthesis of Compound I-97 and Compound I-98

[1048]

[1049]

[1050] Step 1: In DMF (20 mL) R-1MeSNa (773.9 mg, 11.06 mmol, 1.1 equivalents) was added to a stirred solution of (2.0 g, 10.05 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 0 to 10:1) Intermediate-26 (1.42 g, 8.50 mmol, 85%) was obtained as a yellow solid. LCMS (ESI) : m / z = 168 [M+H] + .

[1051] Step 2: In THF (20 mL) Intermediate-26 In a stirred solution of (1.42 g, 8.5 mmol, 1.0 equivalent) and 2-methylpropane-2-sulfinamide (1.13 g, 9.35 mmol, 1.1 equivalent) at room temperature, Ti(O i Pr)4 (3.62 g, 12.75 mmol, 1.5 equivalents) was added. The resulting mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc = 0 to 4:1 elution) Intermediate-27 (1.5 g, 5.55 mmol, 65%) was obtained as a yellow solid. LCMS (ESI) : m / z = 271 [M+H] + .

[1052] Step 3: In MeOH (10 mL) Intermediate-27NaBH4 (253 mg, 6.7 mmol, 1.2 equivalents) was slowly added to a stirred solution of (1.5 g, 5.55 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc elution at 2:1 to 1:1) Intermediate-28 (1.3 g, 4.78 mmol, 86%) was obtained as a white solid. LCMS (ESI) : m / z = 273 [M+H] + .

[1053] Step 4: In MeOH (5 mL) Intermediate-28 HCl / dioxane (10 mL) was slowly added to a stirred solution of (1.3 g, 4.78 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 20 minutes. After completion, the reaction mixture was concentrated under reduced pressure. Intermediate-29 (880 mg, quantitative value) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 169 [M+H] + .

[1054] Step 5: In DMF (10 mL) R-2 In a solution of (491.2 mg, 2.35 mmol, 1.2 equivalents), HATU (893 mg, 2.35 mmol, 1.2 equivalents), TEA (396 mg, 3.92 mmol, 2 equivalents), and Intermediate-29(400 mg, 1.96 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at room temperature for 30 minutes. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting PE:EtOAc = 0 to 4:1) Intermediate-30 (450 mg, 1.26 mmol, 64%) was obtained as a white solid. LCMS (ESI) : m / z = 360 [M+H] + .

[1055] Step 6: In THF (5 mL) Intermediate-30 An aqueous oxone solution (0.6 mL, 5 mol / mL, 3.0 equivalents) was slowly added to a stirred solution of (400 mg, 1.02 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography on a C18 column (eluting with TFA aqueous solution (0.1%): MeCN = 1:10 to 1:40) Intermediate-31 (300 mg, 0.767 mmol, 75%) was obtained as a white solid. LCMS (ESI) : m / z = 392 [M+H] + .

[1056] Step 7: Intermediate-31 (300 mg) was further separated by chiral SFC Compound I-98 (80.0 mg, 53%) & Compound I-97 (81.9 mg, 55%) was provided.

[1057] Compound I-98: > 99% ee. Maintenance time : 3.029분. LC-MS (ESI): m / z =392.0 [M+H] + ; 1 1H NMR (400 MHz) , DMSO- d 6 ) δ 9.10 (d, J = 7.5 Hz, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.16 (dd, J = 8.1, 2.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.28 (s, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 5.28 (p, J = 7.2 Hz, 1H), 3.92 (s, 3H), 3.28 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[1058] Compound I-97: >99% ee. Maintenance time : 5.044분. LC-MS (ESI): m / z =392.0 [M+H] + ; 1 1H NMR (400 MHz) , DMSO- d 6 ) δ9.09 (d, J = 7.5 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.16 (dd, J = 8.2, 2.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.28 (s, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 5.28 (p, J= 7.2 Hz, 1H), 3.92 (s, 3H), 3.27 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[1059] SFC Method: Instrument: Shimadzu pre solution SFC, Column: ChiralPak AD, 250×30 mm ID, 5 μm, Mobile phase: CO2 as A and MeOH as B (0.1% 2 mol / L NH3 in MeOH), Gradient: B 45%, Flow rate: 60 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 22 min, Elution time: 2 H.

[1060] Analysis Method: Instrument: Waters UPCC, ChiralPak AD, 100×4.6 mm ID, 3 μm; Mobile phase: CO2 as A and methanol (0.05% DEA) as B; Gradient: 8 min @ 40% B; Flow rate: 2.0 mL / min; Column temperature: 35°C.

[1061] The following compounds were prepared from suitable amines and carboxylic acids using method H. I-103 , I-104 , I-112 , I-113 , I-124 , I-125 , I-215 , I-216 , I-295 , I-308 , I-309 , I-324 , I-325 , I-337 , I-360 , I-361 , I-502 , I-591 , I-592 , I-618 , and I-619 .

[1062] Example 9: Method I: Synthesis of Compound I-188 and Compound I-189

[1063]

[1064] Step 1: In DCM (10 mL) Compound I-121MnO2 (204 mg, 2.35 mmol, 5.0 equivalents) was added to a stirred solution of (160 mg, 0.47 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the suspension was filtered through a Celite® pad, and the filter cake was washed with DCM (10 mL). The combined filtrate was concentrated and dried to obtain the unpurified Intermediate-32 (150 mg, quantitative value) was obtained as a yellow solid and used directly in the next step without further purification. . LCMS (ESI): m / z = 341 [M+H] + .

[1065] Step 2: In THF (5 mL) Intermediate-32 MeMgBr (3.1 mL, 3.08 mmol, 7.0 equivalents, 1 M in THF) was added dropwise to a stirred solution of (150 mg, 0.44 mmol, 1.0 equivalent) at 0°C. After addition, the resulting mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with a saturated aqueous NH4Cl solution (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC. Intermediate-33 (90 mg, 0.25 mmol, 57%) was obtained as a white solid. LCMS (ESI): m / z = 357 [M+H] + .

[1066] Step 3: Intermediate-33 (90 mg, 0.25 mmol, 1.0 equivalent) was purified by SFC as a white solid Compound I-189 (20 mg, 22%) and as a white solid Compound I-188( 20 mg (22%) was obtained.

[1067] Compound I-189: >99% ee. Retention time: 2,280 min. LC-MS (ESI): m / z = 357.4 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.6, 1.7 Hz, 1H), 5.17-5.06 (m, 2H), 4.72-4.64 (m, 1H), 3.93 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H).

[1068] Compound I-188: >99% ee. 유지 시간: 3.220분. LC-MS (ESI): m / z = 357.4 [M+H] + ; 1 1H NMR (400 MHz) , DMSO) δ8.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.6, 1.6 Hz, 1H), 5.19-5.05 (m, 2H), 4.72-4.64 (m, 1H), 3.93 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H).

[1069] SFC Method: Device:Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralCel OJ, 250×20 mm ID, 5 μm, Mobile Phase: CO2 as A and MeOH as B (0.1% 7 mol / L NH3 in MeOH), Gradient: B 40%, Flow Rate: 40 mL / min, Back Pressure: 100 bar, Column Temperature: 35°C, Wavelength: 220 nm, Cycle Time: 15 min, Elution Time: 2 h.

[1070] Analysis Method: Column: ChiralCel OJ, 100×4.6 mm ID, 3 µm, Mobile phase: CO2 as A and MeOH (0.05% DEA) as B, Gradient: 8 min @ B 40%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35°C.

[1071] Example 10: Method K: Synthesis of amine building blocks

[1072]

[1073] Propylaldehyde in DCM (100 mL) R-14 (R)-(2-methylprop-2-yl)(oxo)-λsulfanamine (7.5 g, 61.9 mmol, 1.2 equivalents) and CuSO4 (19.8 g, 103.3 mmol, 2.0 equivalents) were added to a solution of (3.7 mL, 51.6 mmol, 1.0 equivalent), and the reaction mixture was stirred at 25°C for 16 hours. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 25% PE) R-15 (3 g, 18.6 mmol, 36%) was obtained as oil.

[1074] In THF (10 mL) R-16 In a solution (0.76 g, 3.7 mmol, 1.2 equivalents) n -BuLi (2.5 mL, 3.9 mmol, 1.6 M, 2.0 equivalents) was added at -78°C, and the resulting mixture was stirred for 0.5 hours, and at this pointR-15 (0.5 g, 3.1 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 25°C for 0.5 hours. After completion, the reaction mixture was quenched with an NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 30% PE). R-17 (0.35 g, 1.2 mmol, 40%) was provided as oil. LCMS (ESI) : m / z = 286 [M+H] + .

[1075] In DCM (10 mL) R-17 (100 mg, 0.35 mmol, 1.0 equivalent) 0 in solution o HCl (0.9 mL, 3.503 mmol, 4 M in 1,4-dioxane, 10.0 equivalents) was added at C. The resulting mixture was stirred at 30°C for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. R-18 (35 mg, 0.19 mmol, 55%) was provided as a solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 182 [M+H] + .

[1076] Example 11: Method R: Synthesis of Compound I-116

[1077]

[1078] Step 1: In DMF (5 mL) R-40Cs2CO3 (487.5 mg, 1.5 mmol, 1.5 equivalents) and iodomethane (156 mg, 1.1 mmol, 1.1 equivalents) were slowly added to a stirred solution of (300 mg, 1.0 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred overnight at room temperature. After completion, the reaction mixture was poured into H2O (15 mL) and stirred at room temperature for 0.5 hours. The solid was collected by filtration and then concentrated under reduced pressure Intermediate-34 (293 mg, 0.93 mmol, 92%) was obtained as a white solid. LCMS (ESI) : m / z = 317 [M+H] + .

[1079] Step 2: In dioxane (5 mL) Intermediate-34 Xant-Phos (52 mg, 0.09 mmol, 0.1 equivalent), Pd2(dba)3 (83 mg, 0.09 mmol, 0.1 equivalent), and DIPEA (293 mg, 2.27 mmol, 2.5 equivalent) were added to a solution of (290 mg, 0.91 mmol, 1.0 equivalent) and sodium thiomethoxide (96 mg, 1.36 mmol, 1.5 equivalent). The resulting mixture was degassed under vacuum and purged several times with N2. The resulting mixture was stirred overnight at 105°C under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 30% PE) Intermediate-35 (120 mg, 0.42 mmol, 46%) was obtained as yellow oil.

[1080] Step 3: In EtOH / water (8 mL / 8 mL) Intermediate-35NaOH (50 mg, 1.26 mmol, 3.0 equivalents) was added to a stirred solution of (120 mg, 0.42 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 1 hour. After completion, the pH of the reaction mixture was adjusted to 3 using aqueous 1N HCl. The solid was collected by filtration and then concentrated under reduced pressure Intermediate-36 (100 mg, 0.39 mmol, 92%) was obtained as a white solid. LCMS (ESI) : m / z = 256 [M+H] + .

[1081] Step 4: In DMF (8 mL) Intermediate-36 In a stirred solution of (100 mg, 0.39 mmol, 1.0 equivalent), TEA (118 mg, 1.17 mmol, 3.0 equivalent), HATU (163 mg, 0.43 mmol, 1.1 equivalent), and R-4 (58 mg, 0.39 mmol, 1.0 equivalent) was slowly added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with MeOH in 0 to 5% DCM). Intermediate-37 (60 mg, 0.16 mmol, 39%) was obtained as a yellow solid. LCMS (ESI) : m / z = 388 [M+H] + .

[1082] Step 5: In MeOH / H2O (5 mL / 5 mL) Intermediate-37 0 in a stirred solution of (40 mg, 0.1 mmol, 1.0 equivalent) oOxone (69 mg, 0.2 mmol, 2.0 equivalents) was added at C. The resulting mixture was stirred overnight at room temperature. After completion, the reaction mixture was filtered. The filtrate was purified by preparative HPLC (Column: Shim-pack Scepter C18, 50 × 4.6 mm, 5 µm, Mobile phase: Solvent A: H2O / MeCN / FA = 90:10:0.05, Solvent B: CH3CN. Temperature: 40°C. Flow rate: 2.5 mL / min. Method: Positive-Negative 3 min - 1 µm. Run time: 0.01 min @ 20% B, 1.79 min gradient (20–95% B), followed by 0.7 min @ 95% B) Compound I-116 (5.7 mg, 0.01 mmol, 13%) was obtained as a yellow solid. LCMS (ESI): m / z = 420.1 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ9.37-9.29 (m, 1H), 8.44 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.44-7.38 (m, 3H), 7.32 (s, 1H), 4.53 (d, J = 6.0 Hz, 2H), 4.04 (s, 3H), 3.35 (s, 3H).

[1083] Example 12: Method L: Synthesis of amine building blocks

[1084]

[1085] In DCM (100 mL) R-192-methylpropane-2-sulfinamide (5.01 g, 41.3 mmol, 1.2 equivalents) and CuSO4 (13.22 g, 68.8 mmol, 2.0 equivalents) were added to a solution (6 g, 34.4 mmol, 1.0 equivalent). The reaction mixture was stirred at 25 °C for 16 hours. Subsequently, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 25% PE). R-20 (3.7 g, 13.3 mmol, 39%) was obtained as oil.

[1086] In THF (15 mL) R-21 n-BuLi (4.5 mL, 7.2 mmol, 1.6 M, 2.0 equivalents) was added to the (1.02 g, 4.3 mmol, 1.2 equivalents) solution at -78°C, the resulting mixture was stirred for 0.5 hours, and then R-20 (1 g, 3.6 mmol, 1.0 equivalent) was added, and the reaction mixture was stirred at 25 °C for 0.5 hours. Then, the reaction mixture was poured into an NH4Cl solution (50 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 40% PE) R-22 (0.35 g, 0.81 mmol, 18%) was obtained as oil. LCMS (ESI) : m / z = 435 [M+H] + .

[1087] In DCM (10 mL) R-22 HCl (1.8 mL) was added to the (200 mg, 0.46 mmol, 1.0 equivalent) solution. The resulting mixture was stirred at 30°C for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. R-23(80 mg, 0.193 mmol, 55.11%) was provided as a solid. LCMS (ESI) : m / z = 217 [M+H] + .

[1088] Major amine building blocks for the listed compounds were prepared using Method L, and the final compounds were completed using a general amide coupling procedure as shown in Method H. I-440 , I-441 , I-442 , I-450 , I-454 , I-455 , and I-456.

[1089] Example 13 - Method T: Synthesis of Compound I-43

[1090]

[1091] Step 1: BrettPhos (18.48 mg, 0.034 mmol, 0.1 equivalent) and BrettPhos Pd G3 (31.21 mg, 0.034 mmol, 0.1 equivalent) were added to a stirred solution of intermediate-39 (150 mg, 0.024 mmol, 1 equivalent) and zinc dicarbonitrile (60.65 mg, 0.516 mmol, 1.5 equivalent) in DMF (10 mL) at room temperature under an N2 atmosphere. The solution was then stirred at 50°C for 10 hours. The reaction mixture was quenched by adding brine (100 mL) at room temperature, and the resulting mixture was extracted with EA (3 x 60 mL). The combined organic layer was concentrated under reduced pressure to yield an unpurified intermediate-40, which was used directly in the next step without further purification. LC-MS: M+H observed value 382.15.

[1092] Step 2: DBU (199.36 mg, 1.310 mmol, 5 equivalents) was added at room temperature to a stirred solution of intermediate-40 (100 mg, 0.262 mmol, 1 equivalent) in NH3(g) (10 mL, 70.000 mmol, 267.27 equivalents) in MeOH. The solution was then stirred at 70°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 5 / 1). The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 51% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.6) to obtain Compound I-43 (17.8 mg, 18.51%) as a white solid. LC-MS: M+H Observation 367.15. 1 H NMR (400 MHz, DMSO-d6) δ9.28 - 9.24 (t, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.71 - 7.65 (m, 4H), 7.22 (s, 1H), 7.15 - 7.12 (dd, J = 12.0, 4.0 Hz, 1H), 4.62 - 4.61 (d, J = 4.0 Hz, 2H), 3.98 (s, 3H).

[1093] The following compounds were prepared from suitable amines and carboxylic acids using Method T. I-79 , I-80 I-77, I-710, I-726, and I-727.

[1094] Example 14: Method M: Synthesis of amine building blocks

[1095]

[1096] In THF (5 mL) R-24Bromo(cyclopropyl)magnesium (10.0 mL, 10.05 mmol, 3.0 equivalents, 1 M) and NaBH4 (254 mg, 6.70 mmol, 2.0 equivalents) were added to a (500 mg, 3.35 mmol, 1.0 equivalent) solution at 0°C. The mixture was heated to room temperature and stirred for 1 hour. After completion, the reaction mixture was quenched with an NH4Cl solution (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM: MeOH elution at 0 to 10:1) on silica gel, R-25 It was obtained as a white solid. LCMS (ESI) : m / z = 194 [M+H] + .

[1097] Major amine building blocks for the listed compounds were prepared using method M, and the final compounds were completed using a general amide coupling procedure as shown in method H. I-419 and I-420.

[1098] Example 15: Method N: Synthesis of amine building blocks

[1099]

[1100] In THF (20 mL) R-26NaH (120 mg, 60 wt% in mineral oil, 2 equivalents) was added to a stirred solution of (400 mg, 1.5 mmol, 1.0 equivalent) at 0°C, the mixture was stirred at room temperature for 2 hours, and then MeI (280 mg, 2 mmol, 1.3 equivalents) was added dropwise. The reaction mixture was stirred for 2 hours, then diluted with H2O (50 mL), and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 0 to 10% PE) R-27 (300 mg, 1.1 mmol, 71%) was obtained as a white solid. LCMS (ESI) : m / z = 280 [M+H] + .

[1101] Example 16: Method O: Synthesis of amine building blocks

[1102]

[1103] In PPA (10 mL) R-4 1,3-dioxol-2-one (129 mg, 1.5 mmol, 1.5 equivalents) was slowly added to a stirred solution of (150 mg, 1.0 mmol, 1.0 equivalent) at room temperature. The resulting mixture was 170 o The mixture was stirred at C for 3 hours. After completion, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with MeOH in 5 to 8% DCM). R-28 (62 mg, 0.36 mmol, 36%) was obtained as a colorless oil. LCMS (ESI) : m / z =175 [M+H] + .

[1104] Example 17: Method P: Synthesis of amine building blocks

[1105]

[1106] 4-cyanobenzoic acid in THF (20 mL) R-29 0 in a stirred solution of , 500 mg, 3.4 mmol, 1.0 equivalent) o Cyclopropyl magnesium bromide (8.5 mL, 30.0 mmol, 2.5 equivalents) was slowly added at C. The resulting mixture was heated to room temperature and stirred for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure. R-30 (642 mg, quantitative value) was obtained as a white solid and used directly without further purification. LCMS (ESI) : m / z = 188 [MH] - .

[1107] In MeOH (20 mL) R-30 NaBH4 (260 mg, 6.8 mmol, 2.0 equivalents) was added to a solution of (642 mg, 3.4 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. R-31 (650 mg, quantitative value) was obtained as a white solid and used directly without further purification. LCMS (ESI) : m / z = 190 [MH] - .

[1108] In DCM (20 mL) R-31(Boc)2O (667 mg, 5.1 mmol, 1.5 equivalents) and TEA (1.06 g, 10.2 mmol, 3.0 equivalents) were added to a solution of (650 mg, 3.4 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with MeOH in 10 to 15% DCM) R-32 (300 mg, 1.03 mmol, 30%) was obtained as a white solid. LCMS (ESI) : m / z = 236 [M+H-56] + .

[1109] In DMF (10 mL) R-32 NH4Cl (83 mg, 1.55 mmol, 1.5 equivalents), DMAP (13 mg, 0.31 mmol, 0.1 equivalents), and TEA (313 mg, 3.09 mmol, 3.0 equivalents) were added to a solution of (300 mg, 1.03 mmol, 1.0 equivalent) and CMPI (790 mg, 3.0 mmol, 3.0 equivalents). The resulting mixture was stirred at room temperature for 1 hour. After completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with MeOH in 0 to 5% DCM) R-33 (114 mg, 0.39 mmol, 38%) was obtained as a colorless oil. LCMS (ESI) : m / z = 291 [M+H] + .

[1110] In DCM (10 mL) R-33TFA (2 mL) was added to the (114 mg, 0.39 mmol, 1.0 equivalent) solution. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. R-34 (74 mg, quantitative value) was obtained as a colorless oil and used directly in the next step without further purification. LCMS (ESI) : m / z = 191 [M+H] + .

[1111] Example 18 - Method Q: Synthesis of Carboxylic Acid Building Blocks

[1112]

[1113] 5-chloro-N-methyl-2-nitroaniline in EtOH (20 mL) and H2O (5 mL) R-35 Fe powder (1.01 g, 18.1 mmol, 5.0 equivalents) and NH4Cl (1.94 g, 36.2 mmol, 10.0 equivalents) were slowly added at room temperature to a stirred solution of (673 mg, 3.62 mmol, 1.0 equivalent). The resulting mixture was 70 o Stirred at C for 1 hour. After completion, the reaction mixture was filtered and purified by flash column chromatography on silica gel (elution as EtOAc in 15 to 25% PE). R-36 (460 mg, 2.95 mmol, 82%) was obtained as a white solid. LCMS (ESI) : m / z = 155 [MH] - .

[1114] In toluene (20 mL) and AcOH (5 mL) R-36Methyl 2,2,2-trichloroacetimidate (573 mg, 3.25 mmol, 1.1 equivalents) was added to a solution of (460 mg, 2.95 mmol, 1.0 equivalent). The resulting mixture was stirred overnight at 100°C under N2. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with EtOAc in 5 to 10% PE) R-37 (574 mg, 2.02 mmol, 68.58%) was obtained as a white solid. LCMS (ESI) : m / z = 281 [MH] - .

[1115] In MeOH (15 mL) R-37 70 (520 mg, 1.83 mmol, 1.0 equivalent) solution o Stirred at C for 3 days. After completion, the reaction mixture was concentrated under reduced pressure. R-38 (250 mg, 1.11 mmol, 60.98%) was obtained as a white solid. LCMS (ESI) : m / z = 225 [M+H] + .

[1116] Among MeOH (6 ml) and H2O (1 mL) R-38 NaOH (36 mg, 0.89 mmol, 1.0 equivalent) was added to a solution of (200 mg, 0.89 mmol, 1.0 equivalent). The resulting mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was cooled in an ice bath and then carefully neutralized with 1 N HCl (aqueous) until the pH was adjusted to pH = 5 to 6. The resulting mixture was extracted with DCM (10 mL x 3), the combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to obtain the unpurifiedR-39 (187 mg, quantitative value) was provided as a white solid and used directly in the next step without further purification. LCMS (ESI) : m / z = 211 [M+H] + .

[1117] Example 19 - Method S: Synthesis of Compound I-95

[1118]

[1119] Step 1: In THF (5 mL, 61.714 mmol, 74.07 equivalents) R-41 BH3 in a stirred solution (2.6 g, 10.831 mmol, 1 equivalent) at room temperature under an N2 atmosphere . THF (16.25 mL, 16.246 mmol, 1.5 equivalents) was added. Subsequently, the solution was stirred at room temperature for 4 hours. The desired product can be detected by LCMS. The reaction mixture was quenched by adding brine (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (5 / 1) Intermediate-38 (830 mg, 31.40%) was obtained as a yellow solid. LC-MS: M+H observed value 246.00.

[1120] Step 2: In DCM (25 mL) Intermediate-38 (800 mg, 3.278 mmol, 1 equivalent) and R-2EDCI (0.94 g, 4.917 mmol, 1.5 equivalents) and DMAP (0.60 g, 4.917 mmol, 1.5 equivalents) were added to a stirred solution of (1.03 g, 4.917 mmol, 1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of brine (100 mL) at room temperature and rapid cooling. The resulting mixture was extracted with DCM (3 x 60 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (10 / 1) Intermediate-39 (1.22 g, 85.43%) was obtained as a white solid. LC-MS: M+H observed value 437.00.

[1121] Step 3: In DMF (1 mL, 12.922 mmol, 70.37 equivalents) Intermediate-39 To a stirred solution of (80 mg, 0.184 mmol, 1 equivalent), DBU (139.77 mg, 0.920 mmol, 5 equivalents) and NH3(g) (10 mL, 70.000 mmol, 381.24 equivalents) in MeOH were added at room temperature. After stirring the reaction mixture at 70°C for 24 hours, the solvent was removed under vacuum, and the product was precipitated by the addition of EtOAc. The unpurified product was purified by reverse-phase flash under the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05%NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 55% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.72) to obtain compound I-95 (9.4 mg, 12.06%) as a white solid.

[1122] LC-MS: M+H observed value 419.85. 1H NMR (400 MHz, DMSO-d6) δ9.19 (t, J = 6.1 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 17.5 Hz, 2H), 7.37 (d, J = 1.5 Hz, 2H), 7.18 (s, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 4.47 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H).

[1123] The following compounds were prepared from suitable amines and carboxylic acids using method S. I-81 , I-93 , I-92 , I-91 , I-90 , I-89 , I-88 , I-74, I-675, I-687, I-701, and I-725 .

[1124] Example 20: Method U: Synthesis of Compound I-94

[1125]

[1126] Step 1: In DCM (2 mL) R-42 A mixture of (200 mg, 1.211 mmol, 1 equivalent), NH4Cl (97.18 mg, 1.817 mmol, 1.5 equivalents), EDCI (348.29 mg, 1.817 mmol, 1.5 equivalents), and DMAP (221.96 mg, 1.817 mmol, 1.5 equivalents) was stirred at room temperature under an air atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH (15 / 1)). Intermediate-41 (195 mg, 98.08%) was provided as a white solid. LC-MS: M+H Observed: 163.00.

[1127] Step 2: In MeOH (4 mL) Intermediate-41A mixture of (175 mg, 1.066 mmol, 1 equivalent) and Pd / C (35.17 mg, 0.330 mmol, 0.31 equivalents) was stirred at room temperature under an H2 atmosphere for 4 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure, and the unrefined residue was purified by preparative TLC (DCM / MEOH (15 / 1)). Intermediate-42 (48 mg, 26.77%) was obtained as a white solid. LC-MS: M+H Observed: 169.00.

[1128] Step 3: In DCM (1 mL) R-2 (90 mg, 0.429 mmol, 1 equivalent) and Intermediate-42 A mixture of (108.30 mg, 0.643 mmol, 1.5 equivalents), EDCI (123.45 mg, 0.643 mmol, 1.5 equivalents), and DMAP (78.68 mg, 0.643 mmol, 1.5 equivalents) was stirred at room temperature under an air atmosphere for 2 hours. Subsequently, brine (10 mL) was added at room temperature to quench the reaction mixture. The resulting mixture was extracted with DCM (3 x 10 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MEOH (20 / 1)) to obtain an unpurified product, which was then purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 52% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.85; Number of runs: 2). Compound I-94 (17.3 mg, 11.15%) was obtained as a white solid. LC-MS: M+H Observation: 360.00.

[1129] 1H NMR (400 MHz, DMSO-d6) δ9.19 (t, J = 6.1 Hz, 1H), 7.72 - 7.58 (m, 5H), 7.26 - 7.17 (m, 3H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H).

[1130] The following compounds were prepared from suitable amines and carboxylic acids using method U. I-96 , I-85 , I-84 , I-83 , I-82 , and I-71 .

[1131] Example 21: Method V: Synthesis of Compound I-52

[1132]

[1133] Step 1: Among methylbenzene (0.5 mL) and H2O (0.1 mL) Intermediate-39 A mixture of (100 mg, 0.230 mmol, 1 equivalent), cyclopropylboronic acid (29.57 mg, 0.345 mmol, 1.5 equivalents), second-generation XPhos precatalyst / X-Phos aminobiphenyl (36.12 mg, 0.046 mmol, 0.2 equivalents), XPhos (36.11 mg, 0.076 mmol, 0.33 equivalents), and K3PO4 (97.44 mg, 0.460 mmol, 2 equivalents) was stirred at 60°C for 16 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MEOH (20 / 1)). Intermediate-43 (47 mg, 51.60%) was obtained. LC-MS: M+H Observed: 397.15.

[1134] Step 2: In MeOH (0.5 mL) Intermediate-43NaOH (0.5 mL, 0.500 mmol, 4.22 equivalents) was added dropwise to a stirred solution of (47 mg, 0.118 mmol, 1 equivalent) at room temperature. The resulting mixture was stirred at 50°C for an additional 16 hours. The mixture was acidified to pH 1 using HCl (1 mol / L) and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH (5 / 1)) and Intermediate-44 (40 mg, 88.23%) was obtained as a white solid. LC-MS: M+H Observed: 383.15.

[1135] Step 3: In THF (0.3 mL) Intermediate-44 A mixture of (30 mg, 0.078 mmol, 1 equivalent), NH4Cl (4.61 mg, 0.086 mmol, 1.1 equivalents), HATU (44.69 mg, 0.117 mmol, 1.5 equivalents), and DIEA (15.19 mg, 0.117 mmol, 1.5 equivalents) was stirred at 50°C for 2 hours under an air atmosphere. The crude reaction mixture was cooled to room temperature and purified by direct preparative TLC (DCM / MEOH (20 / 1)) to obtain a crude product, which was further purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 56% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.6). Compound I-52 (3 mg, 9.52%) was obtained as a white solid. LC-MS: M+H Observed: 382.10. 1H NMR (400 MHz, DMSO-d6) δ9.10 (t, J = 6.0 Hz, 1H), 7.67 (d, J = 9.1 Hz, 3H), 7.36 (s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.16 - 7.08 (m, 3H), 6.88 (s, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.96 (d, J = 1.5 Hz, 3H), 2.31 (d, J = 6.1 Hz, 1H), 0.92 (d, J = 8.2 Hz, 2H), 0.63 (d, J = 5.3 Hz, 2H).

[1136] The following compounds were prepared from suitable amines and carboxylic acids using Method V. I-51 , I-65 , I-365 , and I-366.

[1137] Example 22: Method W: Synthesis of Compound I-87

[1138]

[1139] Step 1: In DMF (20 mL) R-43 Zn(CN)2 (413.28 mg, 3.520 mmol, 1.2 equivalents) was aliquoted and added to a stirred solution of (1000 mg, 2.933 mmol, 1 equivalent) and Pd(PPh3)4 (169.47 mg, 0.147 mmol, 0.05 equivalents) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 20 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE:EA = 3:1) Intermediate-45 (600 mg, 85.22%) was obtained as a grayish-white solid.

[1140] Step 2: In THF (10 mL) Intermediate-45BH3-THF (7.50 mL, 7.497 mmol, 3 equivalents) was added dropwise to a stirred solution of (600 mg, 2.499 mmol, 1 equivalent) at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours and then concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH 20:1). Intermediate-46 (470 mg, 77.04%) was obtained as a grayish-white solid.

[1141] Step 3: R-2 (579.71 mg, 2.766 mmol, 1.5 equivalents) and DMAP (675.70 mg, 5.532 mmol, 3 equivalents) were aliquoted and added to a stirred solution of intermediate-46 (450 mg, 1.844 mmol, 1 equivalent) and EDCI (706.84 mg, 3.688 mmol, 2 equivalents) in DCM (10 mL) at room temperature under an N2 atmosphere. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours and then concentrated under vacuum. The residue was purified by preparative TLC (PE:EA 3:1) Intermediate-47 (500 mg, 62.25%) was obtained as a grayish-white solid.

[1142] Step 4: In NH3(g) in MeOH(2 mL) Intermediate-47 Solutions of (20 mg, 0.046 mmol, 1 equivalent) and DBU (20.97 mg, 0.138 mmol, 3 equivalents) were stirred at 50°C for 16 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3) + 0.05% NH3·H2O, Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 58% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.93) Compound I-87(6.4 mg, 32.84%) was obtained as a grayish-white solid. LC-MS: (M+H) + Observed value 420.00. 1 H NMR (400 MHz, DMSO-d6) δ9.20 (t, J = 5.9 Hz, 1H), 8.18 - 8.03 (m, 2H), 7.86 (dd, J = 8.0, 1.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.58 - 7.40 (m, 2H), 7.26 (d, J = 0.8 Hz, 1H), 7.13 (dd, J = 8.4, 1.9 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.98 (s, 3H).

[1143] Example 23: Method X: Synthesis of Compound I-15

[1144]

[1145]

[1146] Step 1: In DMF (4 mL) R-44 NaH (41.47 mg, 1.728 mmol, 2 equivalents) was added in a fractional manner at 0°C to a stirred solution of (200 mg, 0.864 mmol, 1 equivalent). The resulting mixture was stirred at 0°C for 0.5 hours, followed by dropwise treatment with SEMCl (288.09 mg, 1.728 mmol, 2 equivalents) at 0°C. The resulting mixture was stirred at room temperature for an additional 2 hours, followed by extraction with EA (3 x 20 ml). The combined organic layer was washed with saturated brine (2 x 50 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA 3:1) Intermediate-48 (250 mg, 79.99%) was obtained as yellow oil. LC-MS: M+H Observed: 361.00.

[1147] Step 2: A mixture of intermediate-48 (240 mg, 0.663 mmol, 1 equivalent), Zn(CN)2 (116.86 mg, 0.995 mmol, 1.5 equivalents), and Pd(PPh3)4 (153.34 mg, 0.133 mmol, 0.2 equivalents) in DMF (3 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with EA (3 x 10 ml), the combined organic layer was washed with saturated brine (2 x 20 ml), and dried under anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 3:1) Intermediate-49 (180 mg, 88.13%) was obtained as a yellow solid. LC-MS: M+H Observed: 308.10.

[1148] Step 3: In THF (2 mL) and H2O (0.7 mL) Intermediate-49 A mixture of (170 mg, 0.552 mmol, 1 equivalent), HCONH2 (170 mg, 3.774 mmol, 6.83 equivalents), and PdCl2 (170 mg, 0.452 mmol, 0.82 equivalents) was stirred at 50°C for 16 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 1:1) and Intermediate-50 (100 mg, 55.57%) was obtained as a yellow solid. LC-MS: M+H Observed: 326.10.

[1149] Step 4: Dioxane (2 mL) and H2O (0.4 mL) Intermediate-50 (90 mg, 0.276 mmol, 1 equivalent) and R-45A mixture of (98.21 mg, 0.414 mmol, 1.5 equivalents), K3PO4 (175.87 mg, 0.828 mmol, 3 equivalents), and CataCxium A Pd G3 (25.85 mg, 0.028 mmol, 0.1 equivalents) was stirred at 100°C for 2 hours under an N2 atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EA (3 x 10 ml), the combined organic layer was washed with saturated brine (2 x 20 ml), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH = 10:1). Intermediate-51 (45 mg, 38.74%) was obtained as a yellow solid. LC-MS: M+H Observed: 421.25.

[1150] Step 5: In DCM (0.5 mL) Intermediate-51 HCl (gas) in 0.25 mL of 1,4-dioxane was added dropwise to a stirred solution of (40 mg, 0.095 mmol, 1 equivalent) at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Intermediate-52 (18 mg, 99.50%) was obtained as a yellow solid. LC-MS: M+H Observed: 191.10.

[1151] Step 6: In DCM (0.5 mL) Intermediate-52 (15 mg, 0.079 mmol, 1 equivalent) and R-2A mixture of (19.84 mg, 0.095 mmol, 1.2 equivalents), EDCI (22.68 mg, 0.118 mmol, 1.5 equivalents), and DMAP (14.45 mg, 0.118 mmol, 1.5 equivalents) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3) + 0.05% NH3·H2O, Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 49% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.93) Compound I-15 (12.6 mg, 41.64%) was obtained as a white solid. LC-MS: M+H Observed: 382.05. 1 H NMR (400 MHz, DMSO-d6) δ13.33 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.24 (s, 1H), 7.13 (dd, J = 8.5, 1.9 Hz, 1H), 4.81 (d, J = 5.9 Hz, 2H), 3.98 (s, 3H).

[1152] Example 24: Method Y: Synthesis of Compound I-78

[1153]

[1154] Step 1: In THF (5 mL) R-46Solutions of (250 mg, 1.041 mmol, 1 equivalent) and BH3-THF (179.00 mg, 2.082 mmol, 2 equivalents) were stirred at room temperature for 2 hours. The reaction mixture was quenched with MeOH (5 ml) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1). Intermediate-53 (150 mg, 59.01%) was obtained as a yellow solid. LC-MS: M+H Observed: 244.00.

[1155] Step 2: In DCM (3 mL) Intermediate-53 A mixture of (140 mg, 0.574 mmol, 1 equivalent), R-2 (132.26 mg, 0.631 mmol, 1.1 equivalents), EDCI (164.93 mg, 0.861 mmol, 1.5 equivalents), and DMAP (105.11 mg, 0.861 mmol, 1.5 equivalents) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and Intermediate-54 (160 mg, 64.03%) was obtained as a white solid. LC-MS: M+H Observed: 435.05.

[1156] Step 3: In NH3(g) in MeOH(3 mL) Intermediate-54 A mixture of (150 mg, 0.344 mmol, 1 equivalent) and DBU (262.06 mg, 1.720 mmol, 5 equivalents) was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, and the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH 15:1). Intermediate-55 (110 mg, 75.95%) was obtained as a white solid. LC-MS: M+Na Observed: 441.95.

[1157] Step 4: In DMF (5 mL) Intermediate-55A mixture of (100 mg, 0.238 mmol, 1 equivalent), Zn(CN)2 (41.87 mg, 0.357 mmol, 1.5 equivalents), BrettPhos Pd G3 (43.10 mg, 0.048 mmol, 0.2 equivalents), and BrettPhos (25.52 mg, 0.048 mmol, 0.2 equivalents) was stirred at 50°C for 3 hours under an N2 atmosphere. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: Xselect CSH C18 OBD column 30*150 mm 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 52% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.9; Number of runs: 2) Compound I-78 (23.0 mg, 25.75%) was obtained as a white solid. LC-MS: M+H Observed: 367.00. 1 H NMR (400 MHz, DMSO-d6) δ9.22 (t, J = 6.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 1.7 Hz, 2H), 7.73 - 7.65 (m, 2H), 7.60 (dd, J = 8.0, 1.7 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.12 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H).

[1158] The following compounds were prepared using Method Y from suitable amine, carboxylic acid, and boronate reagents. I-76 , I-75 , I-66, I-695 , and I-696 .

[1159] Example 25: Method Z: Compound I-72 , Compound I-73, and synthesis of compound I-86

[1160]

[1161] Step 1: In DCM (0.5 mL) R-47 (20 mg, 0.083 mmol, 1 equivalent) and R-2 A mixture of (17.32 mg, 0.083 mmol, 1 equivalent), EDCI (23.75 mg, 0.124 mmol, 1.5 equivalents), and DMAP (15.14 mg, 0.124 mmol, 1.5 equivalents) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 41% B to 66% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.67) Compound I-86 (7.9 mg, 21.94%) was obtained as a white solid. LC-MS: M+H Observed: 432.95. 1 H NMR (400 MHz, DMSO-d6) δ7.69 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.4, 4.0 Hz, 3H), 7.41 (s, 2H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 6.73 (s, 1H), 5.52 (s, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.00 - 3.71 (m, 6H), 3.59 (td, J = 11.7, 2.8 Hz, 1H), 3.20 (s, 1H).

[1162] Step 2: In DMF (5 mL) Compound I-86A mixture of (120 mg, 0.277 mmol, 1 equivalent), Zn(CN)2 (48.73 mg, 0.416 mmol, 1.5 equivalents), BrettPhos Pd G3 (50.16 mg, 0.055 mmol, 0.2 equivalents), and BrettPhos (29.70 mg, 0.055 mmol, 0.2 equivalents) was stirred at 50°C for 3 hours under an N2 atmosphere. The mixture was cooled to room temperature, and the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA 3:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile phase B: I; Flow rate: 60 mL / min; Gradient: 41% B to 66% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.67) Compound I-72 (10.5 mg, 9.93%) was obtained as a white solid. LC-MS: M+H Observed: 380.10.

[1163] 1 H NMR (400 MHz, DMSO-d6) δ7.97 - 7.77 (m, 2H), 7.77 - 7.50 (m, 4H), 7.11 (dd, J = 8.4, 1.8 Hz, 1H), 6.77 (s, 1H), 5.64 (s, 1H), 4.49 (d, J = 12.5 Hz, 1H), 4.01 - 3.80 (m, 6H), 3.61 (td, J = 11.7, 2.8 Hz, 1H), 3.25 (s, 1H).

[1164] Step 3: In THF (3 mL) and H2O (1 mL) Compound I-72A mixture of (100 mg, 0.263 mmol, 1 equivalent), PdCl2 (93.37 mg, 0.526 mmol, 2 equivalents), and HCONH2 (100 mg, 2.220 mmol, 8.43 equivalents) was stirred at 50°C for 2 hours under an N2 atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH 15:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 51% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.22) Compound I-73 (61.1 mg, 57.52%) was obtained as a white solid. LC-MS: M+H Observed: 398.05. 1 H NMR (400 MHz, DMSO-d6) δ7.99 (s, 1H), 7.95 - 7.86 (m, 2H), 7.74 - 7.65 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (s, 2H), 7.39 (s, 1H), 7.10 (dd, J = 8.5, 1.8 Hz, 1H), 6.74 (s, 1H), 5.59 (s, 1H), 4.50 (d, J = 12.3 Hz, 1H), 3.96 - 3.79 (m, 6H), 3.60 (td, J = 11.7, 2.8 Hz, 1H), 3.25 (s, 1H).

[1165] The following compounds were prepared from suitable amine compounds using Method Z. I-67 , I-68 , I-63 , I-64 , I-61 , I-62 , I-59 , I-60 , I-53 , I-54, I-55 , I-56 , I-57 , I-58 , I-49 , I-48 , I-46 , I-47 , I-48 , and I-44 .

[1166] Example 26: Method ZA: Synthesis of Compound I-42 and Compound I-41

[1167]

[1168] Step 1: In DCM (15 mL) R-2 (200 mg, 0.954 mmol, 1 equivalent) and R-48 EDCI (274.34 mg, 1.431 mmol, 1.5 equivalents) and DMAP (174.84 mg, 1.431 mmol, 1.5 equivalents) were added to a stirred solution of (234.96 mg, 1.431 mmol, 1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of brine (150 mL) at room temperature and rapid cooling. The aqueous layer was extracted with EA (3 x 50 mL), and the combined layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (2 / 1) Intermediate-56 (305 mg, 89.85%) was obtained as a white solid. LC-MS: M+H observed value 356.10

[1169] Step 2: In THF (12 mL) and H2O (4 mL, 160.962 mmol, 197.50 equivalents) Intermediate-56PdCl2 (289.05 mg, 1.630 mmol, 2 equivalents) was added at room temperature to a stirred solution of (290 mg, 0.815 mmol, 1 equivalent) and formamide (293.69 mg, 6.520 mmol, 8 equivalents). The resulting reaction mixture was stirred at room temperature for 2 hours, and then quenched by adding brine (150 mL) at room temperature. The aqueous layer was extracted with EA (3 x 60 mL), and the combined layer was concentrated under reduced pressure to yield an unpurified residue, which was purified by silica gel column chromatography eluted with PE / EA (1 / 1). The unpurified product was further purified by reverse-phase flash under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05%NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 58% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.62) Intermediate-57 (195 mg, 64.00%) was obtained as a white solid. LC-MS: M+H observed value 374.10.

[1170] Step 3: Intermediate-57 (20 mg, 0.054 mmol, 1 equivalent) was purified by chiral HPLC as a white solid Compound I-42 (3.4 mg, 16.47%) and as a white solid Compound I-41 (4.8 mg, 23.86%) was obtained. LC-MS: M+H observed value 374.15.

[1171] Compound I-42: 1H NMR (400 MHz, DMSO-d6) δ9.03 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.74 - 7.67 (m, 2H), 7.71 - 7.61 (m, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J = 0.8 Hz, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.43 - 5.29 (m, 1H), 3.91 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[1172] Compound I-41: 1 H NMR (400 MHz, DMSO-d6) δ9.03 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.73 - 7.66 (m, 2H), 7.69 - 7.60 (m, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.30 (s, 1H), 7.12 (dd, J = 8.5, 1.9 Hz, 1H), 5.36 (dt, J = 17.6, 8.9 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[1173] The following compounds were prepared from a suitable amine using method ZA. I-70 , I-69 , I-40 , I-39 , I-32 , I-31 , I-583 , I-584, I-708, and I-709.

[1174] Example 27: Method ZB: Synthesis of Compound I-50

[1175]

[1176] Step 1: In DCM (4 mL) R-49 (200 mg, 0.858 mmol, 1 equivalent) and R-2EDCI (246.77 mg, 1.287 mmol, 1.5 equivalents) and DMAP (157.27 mg, 1.287 mmol, 1.5 equivalents) were added in aliquots to a stirred solution of (269.85 mg, 1.287 mmol, 1.5 equivalents) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=3:1) and Intermediate-58 (180 mg, 49.39%) was obtained as a yellow solid. LC-MS: M+H Observed: 425.0

[1177] Step 2: In dioxane (2 mL) Intermediate-58 (100 mg, 0.235 mmol, 1 equivalent) and R-50 EPhos Pd G4 (32.45 mg, 0.035 mmol, 0.15 equivalents) and Cs2CO3 (153.45 mg, 0.470 mmol, 2 equivalents) were added in portions to a stirred solution of (74.50 mg, 0.470 mmol, 2 equivalents) at room temperature. The resulting mixture was stirred at 100°C for 16 hours under an N2 atmosphere and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain an unpurified product. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 48% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7; Number of runs: 1) Compound I-50 (32.1 mg, 29.79%) was obtained as a white solid. LC-MS: MH Observed: 455.0. 1H NMR (400 MHz, DMSO-d6) δ10.67 - 8.53 (m, 4H), 7.60 (d, J = 5.0 Hz, 4H), 7.35 - 6.84 (m, 6H), 4.30 (d, J = 6.1 Hz, 2H), 4.04 - 3.85 (m, 3H).

[1178] Example 28: Method ZC: Synthesis of Compound I-35 and Compound I-36

[1179]

[1180] Step 1: NH3(g) in MeOH(5 mL) and in MeOH(2 mL) R-51 A mixture of (500 mg, 3.122 mmol, 1 equivalent) and Ti(Oi-Pr)4 (8872.08 mg, 31.220 mmol, 10 equivalents) was stirred at room temperature for 48 hours. NaBH4 (118.09 mg, 3.122 mmol, 1 equivalent) was added to the mixture at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was filtered, and the filter cake was washed with MeOH (3 x 10 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with DCM / MeOH (1:1). Intermediate-59 (250 mg, 49.68%) was obtained as a white solid. LC-MS: M-NH2+H Observed: 145.10.

[1181] Step 2: In DCM (5 mL) Intermediate-59A mixture of (250 mg, 1.551 mmol, 1 equivalent), R-2 (390.11 mg, 1.861 mmol, 1.2 equivalents), EDCI (445.93 mg, 2.326 mmol, 1.5 equivalents), and DMAP (284.19 mg, 2.326 mmol, 1.5 equivalents) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain an unpurified product. The crude product was purified by reverse-phase flash under the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: MeOH:DCM=11--HPLC; Flow rate: 20 mL / min; Gradient: Isosolvent 20; Wavelength: 220 / 254 nm; RT1(min): 13.49; RT2(min): 20.84; Sample solvent: MeOH:DCM=1:1-HPLC; Injection volume: 0.5 mL; Run count: 10) Intermediate-60 (150 mg, 27.41%) was obtained as a white solid. LC-MS: M+H Observed: 353.05.

[1182] Step 3: Intermediate-60 It was further purified by preparative chiral HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH) -HPLC, Mobile phase B: MeOH:DCM=11--HPLC; Flow rate: 20 mL / min; Gradient: Isosolvent 20; Wavelength: 220 / 254 nm; RT1(min): 13.49; RT2(min): 20.84; Sample solvent: MeOH:DCM=1:1-HPLC; Injection volume: 0.5 mL; Number of runs: 10) as a white solid Compound I-36 (68.8 mg, 45.50%) and as a white solid Compound I-35 (70.9 mg, 46.98%) was obtained. LC-MS: M+H Observed: 353.05.

[1183] Compound I-36:1 H NMR (400 MHz, DMSO-d6) δ12.99 (s, 1H), 8.93 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 1.2 Hz, 1H), 7.75 (s, 1H), 7.69 - 7.64 (m, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.7, 1.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.27 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H).

[1184] Compound I-35: 1 H NMR (400 MHz, DMSO-d6) δ12.99 (s, 1H), 8.93 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 1.2 Hz, 1H), 7.74 (s, 1H), 7.70 - 7.62 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.7, 1.6 Hz, 1H), 7.24 (d, J = 0.8 Hz, 1H), 7.11 (dd, J = 8.6, 1.8 Hz, 1H), 5.27 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H).

[1185] The following compounds were prepared from suitable ketones and amines using method ZC. I-37 , I-38 , I-560 , I-561 , I-562 , and I-563 .

[1186] Example 29: Method ZD: Synthesis of Compound I-33 and Compound I-34

[1187]

[1188]

[1189] Step 1: In DMF (10 mL)R-52 (900 mg, 4.568 mmol, 1 equivalent) and R-8 Pd(PPh3)2Cl2 (644 mg) was added to a mixture of (3315 mg) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was extracted with 3 x 20 mL of ethyl acetate. The combined organic phase was washed with 5 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with (DCM:MeOH=10:1) and Intermediate-61 (850 mg, 98.86%) was obtained as a yellow oil. LC-MS: (ES, m / z): RT = 0.736 min, LCMS: m / z = 189.20 [M+H].

[1190] Step 2: In HCl (3.5 mL) and THF (7 mL) at room temperature under an air atmosphere Intermediate-61 A mixture of (930 mg, 4.941 mmol, 1 equivalent) was stirred at room temperature for 1 hour. Subsequently, the mixture was acidified to pH 7 using NaOH (2 mol / L). The resulting mixture was concentrated under reduced pressure to obtain the unpurified Intermediate-62 It was provided and used directly in the next step without further purification. LC-MS: (ES, m / z): RT = 0.517 min, LCMS: m / z = 161.05 [M+H].

[1191] Step 3: In MeOH (6 mL) and in NH3 (g) in MeOH (6 mL) Intermediate-62A mixture of (650 mg, 4.058 mmol, 1 equivalent) and Ti(OiPr)4 (11537 mg) was stirred at room temperature under an air atmosphere for 36 hours. Subsequently, the reaction mixture was treated with NaBH4 (155 mg), and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure, and the unrefined residue was purified by silica gel column chromatography eluted with MeOH (100%). Intermediate-63 (350 mg, 53.50%) was obtained as a yellow solid. LC-MS: (ES, m / z): RT = 0.371 min, LCMS: m / z = 162.00 [M+H].

[1192] Step 4: In DCM (5 mL) Intermediate-63 (300 mg, 1.861 mmol, 1 equivalent) and R-2 EDCI (536 mg, 2.796 mmol, 1.50 equivalents) and DMAP (341 mg, 2.791 mmol, 1.50 equivalents) were added to a mixture of (351 mg, 1.674 mmol, 0.90 equivalents) at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EA (2:1) to obtain an unpurified product. The crude product was further purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 53% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.73). As a result Intermediate-64 (102 mg, 15.54%) was obtained as a white solid. LC-MS: (ES, m / z): RT = 0.830 min, LCMS: m / z = 353.05 [M+H].

[1193] Step 5: Intermediate-64 (102 mg, 0.289 mmol, 1 equivalent) was purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: ETOH: DCM=1:1; Flow rate: 20 mL / min; Gradient: Isosolvent 20; Wavelength: 220 / 254 nm; RT1(min): 8.53; RT2(min): 10.85; Sample solvent: MEOH: DCM=1:1; Injection volume: 0.5 mL; Number of runs: 13). As a result, as a white solid Compound I-34 (36.3 mg, 35.02%) and as a white solid Compound I-33 (35.6 mg, 34.59%) was obtained. LC-MS: (ES, m / z): RT =0.989 min, LCMS: m / z =353.05 [M+H],

[1194] Compound I-33: 1 ¹H NMR (400 MHz, DMSO- d 6) δ11.30 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.70 - 7.65 (m, 2H), 7.62 (t, J = 3.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.4, 1.8 Hz, 1H), 6.53 (t, J = 2.5 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H). LC-MS: (ES, m / z): RT =0.983 min, LCMS: m / z =353.05 [M+H].

[1195] Compound I-34: 1 ¹H NMR (400 MHz, DMSO- d6) δ11.25 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.61 (t, J = 3.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.6, 1.8 Hz, 1H), 6.52 (t, J = 2.6 Hz, 1H), 5.31 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H). LC-MS: (ES, m / z): RT =0.989 min, LCMS: m / z =353.05 [M+H].

[1196] The following compounds were prepared using method ZD from appropriate reagents. I-335 , I-336 , I-340 , I-341 , I-377 , I-378 , I-379 , I-380 , I-385 , I-386 , I-389 , I-401 , I-402 , I-411 , I-412 , I-437 , I-438 , I-545 , I-546 , I-547 , I-548 , I-549 , I-550 , I-603, I-604, I-607 , I-608 , I-609 , I-610, I-702, I-703, I-704, and I-705.

[1197] Example 30: Method ZE: Synthesis of Compound I-30

[1198]

[1199] Step 1: In DCM (2 mL) R-53 (150 mg, 0.776 mmol, 1 equivalent) and R-2 EDCI (223.20 mg, 1.164 mmol, 1.5 equivalents) and DMAP (142.25 mg, 1.164 mmol, 1.5 equivalents) were added to a stirred solution of (244.08 mg, 1.164 mmol, 1.5 equivalents) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1 / 1) and Intermediate-65 (83 mg, 10.84%) was obtained as a white solid. LC-MS: M+H Observed: 385.20.

[1200] Step 2: In NH3(g) in MeOH(2 mL) at room temperature Intermediate-65 A stirred solution of (73 mg, 0.190 mmol, 1 equivalent) and DBU (144.38 mg, 0.950 mmol, 5 equivalents) was heated to 70°C and stirred at that temperature for 16 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to yield an unpurified product, which was further purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3)+0.05% NH3·H2O, Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.07) Compound I-30 (6.6 mg, 9.27%) was obtained as a white solid. LC-MS: M+H Observed: 370.05. 1H NMR (400 MHz, DMSO-d6) δ8.62 (s, 1H), 7.88 (s, 1H), 7.83 - 7.76 (m, 2H), 7.70 - 7.62 (m, 2H), 7.50 - 7.43 (m, 2H), 7.29 - 7.23 (m, 2H), 7.12 (dd, J = 8.5, 1.8 Hz, 1H), 3.83 (s, 3H), 1.68 (s, 6H).

[1201] Example 31: Method ZF: Compound I-2 , Compound I-28 , and synthesis of compound I-29

[1202]

[1203] Step 1: In MeOH (4 mL) and NH3 (g) in MeOH (4 mL) at room temperature under air R-54 A mixture of (800 mg, 4.166 mmol, 1 equivalent) and Ti(OiPr)4 (11082 mg) was stirred for 36 hours and then treated with NaBH4 (149 mg). The resulting reaction mixture was stirred at room temperature for an additional 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH (100%). Intermediate-66 (300 mg, 34.77%) was obtained as a yellow oil. LC-MS: (ES, m / z): RT = 0.127 min, LCMS: m / z = 209.00 [M+H].

[1204] Step 2: In DCM (0.5 mL) Intermediate-66 (20 mg, 0.097 mmol, 1 equivalent) and R-2EDCI (28 mg) and DMAP (18 mg) were added to a mixture of (18 mg) at room temperature under air. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EA (2:1) to obtain an unpurified product, which was further purified by preparative HPLC under the following conditions (Column: ER Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 64% B within 8 min; Wavelength: 220 nm; RT1 (min): 7.75). As a result Compound I-2 (7.9 mg, 20.41%) was obtained as a white solid. LC-MS: (ES, m / z): RT = 1.257 min, LCMS: m / z = 399.90 [M+H]. 1 ¹H NMR (400 MHz, DMSO- d 6) δ8.93 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 1.0 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 8.4, 1.9 Hz, 1H), 5.25 (p, J = 7.2 Hz, 1H), 4.10 (q, J = 5.3 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 1.51 (d, J = 7.0 Hz, 3H).

[1205] Step 3: In DMSO (1 mL) Compound I-2 (100 mg, 0.251 mmol, 1 equivalent) and R-55CuI (5 mg), L-proline (7 mg), and NaOH (1.4 mg) were aliquotedly added to a stirred solution of (52 mg) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 7 hours. The resulting mixture was extracted with EA (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM: MeOH = 20:1) to obtain the crude product. As a result Intermediate-67 (90 mg, 90.18%) was obtained as a yellow solid. LC-MS: (ES, m / z): RT = 0.927 min, LCMS: m / z = 398.00 [M+H].

[1206] Step 4: Intermediate-67 (110 mg, 0.276 mmol, 1 equivalent) was further purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B within 19 min; Wavelength: 220 / 254 nm; RT1 (min): 10.835; RT2 (min): 13.168; Sample solvent: EtOH: DCM=1: 1--HPLC; Injection volume: 0.5 mL; Number of runs: 12). As a result, Compound I-29 (19.5 mg, 16.93%) was obtained as a white solid, LC-MS: (ES, m / z): RT = 1.594 min, LCMS: m / z = 397.95 [M+H], Compound I-28 (23.4 mg, 19.80%) was obtained as a white solid, LC-MS: (ES, m / z): RT =1.601 min, LCMS: m / z =397.95 [M+H].

[1207] Compound I-28: 1 ¹H NMR (400 MHz, DMSO- d6) δ9.04 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.26 (s, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 5.36 (p, J = 7.0 Hz, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H).

[1208] Compound I-29: 1 ¹H NMR (400 MHz, DMSO- d 6) δ9.04 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 0.9 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.28 - 7.23 (m, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 5.36 (p, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H).

[1209] The following compounds were prepared using the method ZF from appropriate reagents. I-403 , I-404 , I-424 , I-435 , I-601 , I-602 , I-612, I-613, I-620, I-621, I-636 , I-637 , -646, I-647, I-667, I-668, I-677, I-678, I-691, I-692, I-706, I-707, I-241 , and I-242.

[1210] Example 32: Method ZG: Synthesis of Compound I-1

[1211]

[1212] In THF (0.3 mL) at -78°C under nitrogen Compound I-2n-BuLi (0.1 mL, 1 M in THF) was added to a mixture of (20 mg, 0.050 mmol, 1 equivalent). The resulting mixture was stirred at -78°C for 10 minutes, and then CO2 was added in portions over 1 minute at -60°C to -78°C. The resulting mixture was stirred at -60°C to -78°C for 15 minutes, and then concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 35% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.5; Number of runs: 2). As a result Compound I-1 (5.5 mg, 29.84%) was obtained as a white solid. LC-MS: (ES, m / z): RT = 0.839 min, LCMS: m / z = 363.95 [M+H]. 1 ¹H NMR (400 MHz, DMSO- d 6) δ9.09 - 8.59 (m, 1H), 7.63 - 7.45 (m, 2H), 7.21 - 6.97 (m, 3H), 5.66 - 5.20 (m, 1H), 3.90 (d, J = 6.8 Hz, 3H), 1.41 (dd, J = 39.6, 6.9 Hz, 3H).

[1213] The following compounds were prepared using Method ZG from appropriate reagents (carbonylation followed by, where appropriate, amide formation). I-333 , I-334 , I-390 , I-426 , I-473 , I-479, I-638, I-639, I-660, I-661, I-757, I-217, I-218, I-220, I-221, I-244, and I-245.

[1214] Example 33 - Method ZH: Compound I-3 , Compound I-26 , and synthesis of compound I-27

[1215]

[1216] Step 1: In DCM (5 mL) R-2 (30 mg, 0.143 mmol, 1 equivalent) and R-56 EDCI (41.15 mg, 0.214 mmol, 1.5 equivalents) and DMAP (26.23 mg, 0.214 mmol, 1.5 equivalents) were added to a stirred solution of (48.96 mg, 0.214 mmol, 1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, at which point the desired product could be detected by LCMS. The reaction mixture was quenched by adding brine (150 mL) at room temperature, and the aqueous layer was extracted with DCM (3 x 50 mL). The combined layer was concentrated under reduced pressure, and the unrefined residue was purified by silica gel column chromatography eluted with PE / EA (2 / 1). The crude product was purified by reverse-phase flash under the following conditions (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.05%NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 80% B within 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.88) Compound I-4 (24.8 mg, 40.63%) was obtained as a white solid. LC-MS: M+H observed value 421.05.

[1217] Compound I-4 : 1H NMR (400 MHz, DMSO-d6) δ8.94 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 6.6 Hz, 2H), 7.14 - 7.01 (m, 3H), 5.23 (q, J = 6.9 Hz, 1H), 4.31 (ddt, J = 15.2, 11.4, 5.6 Hz, 2H), 4.02 (s, 3H), 2.11 (s, 2H).

[1218] Step 2: In DMF (12 mL) Compound I-4 BrettPhos (25.58 mg, 0.048 mmol, 0.1 equivalent) and BrettPhos Pd G3 (43.20 mg, 0.048 mmol, 0.1 equivalent) were added to a stirred mixture of (200 mg, 0.477 mmol, 1 equivalent) and Zn(CN)2 (83.93 mg, 0.716 mmol, 1.5 equivalents) at room temperature under an N2 atmosphere. The resulting reaction mixture was stirred at 60°C for 16 hours, after which H2O (150 mL) was added to quench the reaction mixture, followed by extraction with EA (3 x 40 mL) at room temperature. The organic layers were combined and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 2 / 1) Intermediate-68 (100 mg, 57.36%) was obtained as a white solid. LC-MS: M+H observed value 366.10.

[1219] Step 3: Intermediate-68 (30 mg, 0.082 mmol, 1 equivalent) was purified by chiral HPLC Compound I-27 (4.2 mg, 13.68%) was obtained as a white solid, LC-MS: MH observed value 364.00, Compound I-26 (4.3 mg, 14.33%) was obtained as a white solid. LC-MS: M+H observed value 366.10

[1220] Compound I-26: 1H NMR (400 MHz, DMSO-d6) δ9.00 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.32 (dq, J = 3.1, 1.7 Hz, 2H), 7.18 (s, 1H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.33 (q, J = 6.8, 6.0 Hz, 1H), 4.35 (qp, J = 7.7, 3.8 Hz, 2H), 4.02 (s, 3H), 2.14 (tddt, J = 18.1, 11.5, 7.7, 3.8 Hz, 2H).

[1221] Compound I-27: 1 H NMR (400 MHz, DMSO-d6) δ9.00 (d, J = 8.3 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 0.9 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.18 (d, J = 0.9 Hz, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 5.38 - 5.29 (m, 1H), 4.35 (qp, J = 7.6, 3.6 Hz, 2H), 4.02 (s, 3H), 2.23 - 2.09 (m, 2H).

[1222] The following compounds were prepared from a suitable amine using method ZH. I-3 , I-24 , I-25 , I-326 , I-482, I-760, and I-761 .

[1223] Example 34 - Method ZJ: Synthesis of Compound I-9 and Compound I-10

[1224]

[1225] Step 1: In DCM (5 mL) R-57 (400 mg, 2.190 mmol, 1 equivalent) and R-2EDCI (789 mg) and DMAP (670 mg) were added to a mixture of (630 mg) at room temperature under air. The resulting mixture was stirred at room temperature under air for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE:EA (1:1) and Intermediate-70 (660 mg, 89.21%) was obtained as a white solid. LC-MS: (ES, m / z): RT = 0.972 min, LCMS: m / z = 338.15 [M+H].

[1226] Step 2: In THF (3 mL) Intermediate-70 B2H5-THF (2.5 mL) was added to a (260 mg, 0.770 mmol, 1 equivalent) solution at room temperature under air. The resulting mixture was stirred at room temperature for 2 hours, then the resulting mixture was extracted with EA and NH4Cl (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative flash (DCM: MeOH = 15:1) to obtain an unpurified product. The unpurified product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30*150 mm 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 30% B within 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.12). Due to this Intermediate-71 (11 mg, 4.18%) was obtained as a white solid. LC-MS: (ES, m / z): RT = 0.563 min, LCMS: m / z = 341.10 [M+H].

[1227] Step 3: Intermediate-71(11 mg, 0.032 mmol, 1 equivalent) was purified by preparative chiral HPLC under the following conditions (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile phase A: Hex (0.2% IPAmine), Mobile phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B within 14 min; Wavelength: 220 / 254 nm; RT1 (min): 10.665; RT2 (min): 11.731; Sample solvent: EtOH: DCM=1: 1--HPLC; Injection volume: 0.5 mL; Number of runs: 7). As a result, as a white solid Compound I-10 (3.7 mg, 32.66%) and also as a white solid Compound I-9 (2.7 mg, 22.95%) was obtained.

[1228] Compound I-9: LC-MS: (ES, m / z): RT =0.988 min, LCMS: m / z =340.05 [M+H]. 1 ¹H NMR (400 MHz, DMSO- d 6) δ8.90 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.24 - 6.64 (m, 3H), 5.39 - 4.99 (m, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[1229] Compound I-10: LC-MS: (ES, m / z): RT =0.988 min, LCMS: m / z =340.05 [M+H]; 1 ¹H NMR (400 MHz, DMSO- d 6)...

Claims

Claim 1 Compound represented by the following chemical formula I Or as a pharmaceutically acceptable salt thereof, in the above formula, A 1 is a bicyclic device selected from the following, and or X 1 is one of the following;(i) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 thiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 thiadiazole substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3,4-oxadiazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrazoleyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 oxazolyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 imidazolyl substituted with;(ii) -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 Cromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(t R 7 isochromanyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzofuranyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[3,2-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[3,2-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrofuro[2,3-b]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]oxazole-2-(3H)-one substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-1H-pyrano[4,3-c]pyridine substituted with;(iii) -N(R 4 )-[C(R 5 )(R 6 )] n -(t R 7 phenyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 pyridinyl substituted with), or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrimidinyl substituted with (iv) or (Each of these is p R 7 Substituted with phenyl substituted with);(v) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[d]imidazoleyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Indazolyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-O'Neill substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2-dehydro-3H-indazole-3-onyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with; -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolinyl substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazole[4,5-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1-H-pyrazolo[4,3-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-b]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[3,4-c]pyridinyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dehydro-1H-indenyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 indolin-2-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoindolin-1-one substituted with), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3H-imidazo[4,5-c]pyridine substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1H-pyrazolo[4,3-c]pyridine substituted with;(vi) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 imidazo[2,1-b]thiazolyl substituted with;(vii) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dehydro-1 substituted with H -Benzo[ c ][1,2]thiazinyl 2,2-dioxide), -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydro-2H-benzo[e][1,2]thiazinyl 1,1-dioxide substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Benzo[b]thiophene 1,1-dioxide substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide substituted with;(viii) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Quinazolin-4(3H)-O'Neill), substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 3,4-dihydroquinoline-2(1H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,4-dehydroisoquinoline-3(2H)-o'nyl substituted with -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 isoquinoline-1-(2H)-O'Nill substituted with, or -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 1,2,3,4-tetrahydroisoquinoline substituted with; or (ix) -N(R 4 )-[C(R 5 )(R 6 )] m -(p R 7 Bicyclo[1.1.1]fentanyl substituted with);R 1 C 1-4 It is alkyl or hydrogen; R 2 In each case, independently hydrogen; halo; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 Representing a cycloalkyl group, each ring has q R 2B Replaced with;R 2B C independently in each case 1-3 Representing an alkyl or halo; R 3 is hydrogen; fluoro; C 1-4 Alkyl; -S(O)2R 8 ; Cyano; C 1-4 Alkoxyl, hydroxyl, C 1-4 Haloalkyl; a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or C 3-5 It is cycloalkyl, and each ring has q R 2B Replaced with;R 4 is hydrogen, C 1-4 Alkyl, -C(O)(C 1-4 alkyl), or -S(O)2(C 1-4 alkyl) and;R 5 and R 6 In each case, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, -C 1-3 Alkylene-N(R 8 )2, -(R 8 C substituted with 1-6 Aliphatic), or -(CH2) 0-3 -O-(CH2) 0-3 -CH3 or; R 5 and R 6 They take together to form a C3-5 saturated carbocyclic ring; R 7 C independently in each case 1-6 Alkyl, halo, cyano, hydroxyl, -C(O)N(R 8 )2, -N(R 8 )C(O)-R 8 , -C(O)-R 8 , -(R 8 C substituted with 1-6 Aliphatic), C 1-6 Alkoxyl, C 3-6 Cycloalkyl, -S(O)2N(R 8 )2, -S(O)2R 8 , -N(R 8 )S(O)2R 8 , C 1-3 Alkylene-C(O)N(R 8 )2, -S(O)(NH)R 8 , C 3-6 Cycloalkyl, -C(O)N(R 8 )(C 3-6 cycloalkyl), -C(O)OC 1-3 Alkyl, C 1-3 Haloalkyl, -NH(R 8 ), -C(NH)NH(R 8 ) , -O-( C 3-6 It represents a 5 to 6-membered monocyclic heteroaromatic ring containing 1 to 3 heteroatoms independently selected from cycloalkyl), or nitrogen, oxygen, and sulfur, wherein each cycloalkyl and heteroaromatic ring has s R 7B Replaced with;R 7B C independently in each case 1-3 Alkyl, halo, hydroxyl, or C 3-6 Representing a cycloalkyl group; R 8 In each case, independently hydrogen; C 1-6 Aliphatic, hydroxyl, -NH2, -S(O)2CH3, C 3-6 Cycloalkyl, cyano, phenyl, C 1-4 Haloalkyl, C 1-6 Representing a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from alkoxy, nitrogen, oxygen, and sulfur, or a 5- to 6-membered saturated monocyclic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 9 Silver is hydrogen, chloro, fluoro, or C 1-3 A compound or a pharmaceutically acceptable salt thereof, wherein it is alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3; q and s are independently 0, 1, 2, or 3; t is 0, 1, 2, or 3; and u is 1 or 2. Claim 2 In paragraph 1, R 1 C 1-4 Alkyl compounds. Claim 3 A compound of which is a compound of formula I in claim 1 or 2. Claim 4 In claim 1 or 2, the chemical formula Ia or Ib A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 5 In claim 1 or 2, the chemical formula Ic , Id , or Ie A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 6 In claim 1 or 2, the chemical formula If or Ig A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 7 In claim 1 or 2, the chemical formula Ih or Ii A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 8 In claim 1 or 2, the chemical formula Ij, Ik, Il, Im, In, or Io A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 9 In claim 1 or 2, the chemical formula Ip, Iq, or Ir A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 10 In claim 1 or 2, the chemical formula Is , It , Iu , or Iv A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 11 In claim 1 or 2, the chemical formula Iw or Ix A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 12 In claim 1 or 2, the chemical formula Iy, Iz, or Iaa A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 13 In any one of paragraphs 1 through 12, R 5 and R 6 are compounds, respectively, which are hydrogen. Claim 14 In any one of paragraphs 1 through 12, R 5 is hydrogen, and R 6 is a compound that is -CH3. Claim 15 A compound in which, in any one of paragraphs 1 to 12, m is 0. Claim 16 A compound in any one of paragraphs 1 to 14, wherein m is 1. Claim 17 In any one of paragraphs 1 through 16, R 4 is a compound that is hydrogen. Claim 18 In claim 1 or 2, the chemical formula Iab , Iac , or Iad A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 19 In any one of paragraphs 1 through 18, ring A 1 silver or Phosphorus, compound. Claim 20 In any one of paragraphs 1 through 18, ring A 1 silver or Phosphorus, compound. Claim 21 In any one of paragraphs 1 through 18, ring A 1 silver , or Phosphorus, compound. Claim 22 In any one of paragraphs 1 through 18, ring A 1 silver or Phosphorus, compound. Claim 23 In any one of paragraphs 1 through 21, R 2 is hydrogen, halo, or C 1-4 Alkyl compounds. Claim 24 In any one of paragraphs 1 through 18, ring A 1 silver Phosphorus, compound. Claim 25 In any one of paragraphs 1 through 20 or paragraph 22, R 1 A compound that is -CH3. Claim 26 In claim 1, the above compound is a chemical formula Iae It is a compound of or a pharmaceutically acceptable salt thereof, and In the above equation, ring B 1 is a compound that is one of the following: (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with; (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with; (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with (iv) or (Each of these is p R 7 Substituted with phenyl substituted with ); or (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Benzo[d]imidazole substituted with; p R 7 Indazolyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with Claim 27 In claim 1, the above compound is a chemical formula Iaf It is a compound of or a pharmaceutically acceptable salt thereof, and In the above equation, ring B 1 is a compound that is one of the following: (i) t R 7 A thiazolyl substituted with; p R 7 Thiadiazole substituted with; p R 7 1,3,4-oxadiazoleyl substituted with; p R 7 Pyrazole substituted with; p R 7 Oxazolyl substituted with; or p R 7 Imidazolyl substituted with; (ii) t R 7 Cromanyl substituted with; p R 7 2,3-dihydrobenzofuranyl substituted with; p R 7 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl substituted with; p R 7 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl substituted with; p R 7 2,3-dihydrofuro[3,2-c]pyridine substituted with; p R 7 5,6-dihydrofuro[2,3-d]pyrimidinyl substituted with; p R 7 6,7-dihydrofuro[2,3-b]pyrazinyl substituted with; p R 7 7,8-dihydro-6H-pyrano[2,3-b]pyrazinyl substituted with; or p R 7 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl substituted with; (iii) t R 7 Phenyl substituted with p Rs 7 Pyridinyl substituted with; (iv) or (Each of these is p R 7 Substituted with phenyl substituted with ); or (v) p R 7 Pyrrolo[3,2-b]pyridinyl substituted with; p R 7 Isoindolin-1-O'Neill substituted with; p R 7 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl substituted with; p R 7 1,2-dihydro-3H-indazole-3-onyl substituted with; p R 7 6,7-dihydro-5H-cyclopenta[c]pyridinyl substituted with; or p R 7 6,7-dihydro-5H-cyclopenta[b]pyridinyl substituted with Claim 28 In paragraph 26 or 27, ring B 1 is t R 7 A compound, chromanyl substituted with Claim 29 In paragraph 26 or 27, ring B 1 is p R 7 2,3-dihydrobenzofuranyl substituted with; or ring B 1 is t R 7 A compound that is a thiazoleyl substituted with Claim 30 In paragraph 26 or 27, ring B 1 is t R 7 Phenyl substituted with p Rs 7 A compound that is pyridinyl substituted with Claim 31 In paragraph 26 or 27, ring B 1 is p R 7 Pyrrolo[3,2-b]pyridinyl substituted with or p R 7 isoindolin-1-onyl phosphide substituted with isoindolin-1-onyl phosphide, a compound. Claim 32 A compound according to any one of claims 1 to 31, wherein t is 1, 2, or 3. Claim 33 A compound according to any one of paragraphs 1 to 31, wherein t is 1. Claim 34 A compound according to any one of claims 1 to 31, wherein p is 1, 2, or 3. Claim 35 A compound according to any one of paragraphs 1 to 31, wherein p is 1. Claim 36 In claim 1, the chemical formula Iag A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 37 In claim 1, the chemical formula Iah A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 38 In claim 1, the chemical formula Iai A compound that is a compound or a pharmaceutically acceptable salt thereof. Claim 39 In any one of paragraphs 1 through 38, R 7 It is a haloin, a compound. Claim 40 In any one of paragraphs 1 through 38, R 7 -C(O)-R 8 or -C(O)N(R 8 )2-person, compound. Claim 41 In any one of paragraphs 1 through 38, R 7 A compound that is -C(O)NH2. Claim 42 In any one of paragraphs 1 through 38, R 7 Compounds that, in each case, independently represent cyano, -C(O)NH2, -S(O)2NH2, -S(O)2CH3, -N(H)S(O)2CH3, or halo. Claim 43 Compounds of Table 1 or Table 2 or pharmaceutically acceptable salts thereof. Claim 44 A pharmaceutical composition comprising a compound of any one of claims 1 to 43 and a pharmaceutically acceptable carrier. Claim 45 A method for treating a disorder related to ABC transporter dysfunction, comprising the step of treating the disorder related to ABC transporter dysfunction by administering a therapeutically effective amount of a compound of any one of claims 1 to 43 to a subject requiring such treatment. Claim 46 A method according to claim 45, wherein the dysfunction related to the ABC transporter dysfunction is characterized by a dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4. Claim 47 A method for treating a disorder comprises the step of treating said disorder by administering a therapeutically effective amount of a compound of any one of claims 1 to 43 to a subject requiring such treatment, wherein said disorder is Tangerine's disease, pulmonary surfactant metabolic disorder type 3, autosomal recessive congenital ichthyosis type 4A (ARCI), alymphocyte syndrome type 1, alymphocyte syndrome type 1 due to TAP2 deficiency, hereditary systemic pigmentosa type 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson syndrome, cystic fibrosis (CF), familial hyperinsulinemic hypoglycemia type 1, intellectual disability myopathy syndrome, congenital bile acid synthesis defect type 5, methylmalonicuria and homocystinuria cblJ, citostrolemia, Stargardt disease, PFIC3, PFIC2, elastic pseudoxanthoma, X-linked Adrenoleukodystrophy (ALD), cholestasis, hyperbilirubinemia, gestational intrahepatic cholestasis, biliary atresia, Alagille syndrome, primary cholangitis, primary sclerosing cholangitis, NAFLD / NASH (MASH), Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, Hirschprung's disease, Zellweger syndrome, type 2 diabetes, obesity, type 1 diabetes, atherosclerosis, dyslipidemia, infantile systemic arterial calcification, calciphylaxis, autosomal recessive rod-conus dystrophy, gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, hypophospholipid-related cholelithiasis, intrahepatic microgallstones, intrahepatic cholelithiasis, ostium biliary stenosis, benign recurrent intrahepatic cholestasis, progeria (Hutchinson-Gilford progeria syndrome), chronic kidney disease, hemodialysis, blood vessels A method selected from calcification, CKD-related vascular calcification, T2D-related vascular calcification, and calcific uremic ductus arteriosus. Claim 48 In paragraph 47, the above disorder is cystic fibrosis, method. Claim 49 In paragraph 47, the above disorder is primary sclerosing cholangitis, method. Claim 50 A method in any one of paragraphs 45 through 49, wherein the subject is a human. Claim 51 A method for controlling the function of an ABC transporter in a subject, comprising the step of administering an effective amount of a compound of any one of claims 1 to 43 to the subject to increase the expression of the ABC transporter in the subject. Claim 52 In claim 51, the ABC carrier is selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4.

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