MCL-1 inhibitors

Abstract

To provide compounds and pharmaceutical compositions that can be used in methods of treating cancer.SOLUTION: In some embodiments, provided herein is a pharmaceutical composition comprising a compound according to formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, provided herein is a method of inhibiting MCL-1 in a patient comprising administering to the patient a compound according to formula (I), or a tautomer or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 671,306, filed May 14, 2018, and U.S. Provisional Application No. 62 / 749,918, filed October 24, 2018, both of which are incorporated herein in their entireties.

[0002] This application relates generally to certain compounds that inhibit MCL-1, pharmaceutical compositions containing the compounds, uses of the compounds to treat cancer, and methods of making the compounds. [Background technology]

[0003] Apoptosis (programmed cell death) is a process for eliminating unwanted or potentially dangerous cells from an organism. Avoiding apoptosis is crucial for tumor development and sustained growth. Myeloid cell leukemia 1 protein (MCL-1, also abbreviated as Mcl-1 or MCL1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL-1 is overexpressed in many cancers. Overexpression of MCL-1 prevents cancer cells from undergoing apoptosis. Research has shown that MCL-1 inhibitors can be used to treat cancer. Therefore, new compounds that inhibit MCL-1 are needed. Summary of the Invention [Means for solving the problem]

[0004] The above-mentioned needs are addressed by the present disclosure. In particular, inhibitors of MCL-1 are provided herein.

[0005] In one embodiment, the present disclosure provides a compound of formula (I): [ka] Compounds by [In the formula, [ka] is a single or double bond, X is O or NR 7 and R 12 is hydrogen or -C(O)R 1 and R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 7 , or -NR 8 R 9 and Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each selected from 1 to 5 R 10 optionally substituted with a group, R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 cycloalkyl, or 3- to 12-membered heterocyclyl; Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocyclyl are each 1 to 5 R 10 optionally substituted with a group, R 3 and R 4 are independently hydrogen, C 1~6 Alkyl, -OR 7 , C 1~6 Heteroalkyl, -NR 8 R 9 , N.R. 8 C(O)R 9, -NR 8 C(O)OR 9 , C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 , -OC(O)NR 8 R 9 , -CN, or -SO2R 7 and Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each independently selected from 1 to 5 R 10 optionally substituted with a group, R 5 is hydrogen, C 1~6 Alkyl, -(CH2CH2O) p R 7 , C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each independently selected from 1 to 5 R 10 optionally substituted with a group, R 6 is hydrogen or halo, Each R 7 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Said C 1~6 Alkyl, C 3~10Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 10 , where necessary, Each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl or 5-10 membered heteroaryl, or R 8 and R 9 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic ring, Said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 10 , where necessary, Each R 10 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, oxo, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O)NR a R b , -NR a S(O)2Rb , -N3, -CN or -NO2, or two R 10 The group may be a fused, spiro or bridged C 3~10 forming a cycloalkyl or 3- to 12-membered heterocyclyl; Each C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycle, and 5- to 10-membered heteroaryl are each selected from 1 to 5 R 20 optionally substituted with a group, Each R a and R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or R a and R b together with the atoms to which they are attached form a 3- to 12-membered heterocyclyl, Said C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 20 optionally substituted with a group, Each R 20 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1~6 alkyl), -C(O)N(C 1~6 alkyl), -COOH, -C(O)C1~6 Alkyl, -C(O)OC 1~6 alkyl, or halogen; n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2] or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, provided herein is a pharmaceutical composition comprising a compound according to Formula (I), or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In some embodiments, provided herein is a method of inhibiting MCL-1 in a patient, the method comprising administering to the patient a compound according to Formula (I), or a tautomer or pharmaceutically acceptable salt thereof.

[0008] In some embodiments, provided herein is a method of treating cancer in a patient, comprising administering to the patient a compound according to Formula (I), or a tautomer or pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0009] Unless otherwise required by context, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, i.e., "including, but not limited to."

[0010] "C u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0011] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience, and chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. No directionality is indicated or implied by the order in which chemical groups are written or named unless chemically or structurally necessary.

[0012] As shown below, a wavy line on a chemical group, e.g., [ka] indicates a point of attachment, i.e., the bond connecting the group to another described group is broken.

[0013] The term "substituted" means that one or more hydrogen atoms on a hydrocarbon have been replaced with one or more atoms or groups other than hydrogen, provided that the normal valence of the designated carbon atom or atoms is not exceeded. A "substituent," when "substituted," is an atom or group that replaces a hydrogen atom on a hydrocarbon. Unless otherwise specified, when a group is described as optionally substituted, any substituents of that group are themselves unsubstituted.

[0014] The term "about" refers to a value or parameter of ±10% of the stated amount.

[0015] As used herein, "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon. Examples of alkyl groups include methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)). 3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-C H2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)C Examples of methyl 3-pentyl (-H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0016] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkoxy" as used herein refers to a group of the formula -OR A (In the formula, R A refers to a radical of the formula (wherein R is an alkyl radical as defined above). Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy.

[0018] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond.

[0019] "Aryl" refers to a monoradical or diradical aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused ring systems, where one or more of the fused rings are fully or partially unsaturated. As used herein, non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanuyl, and anthryl. However, aryl does not in any way encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl. The monoradical or diradical classification indicates whether the aryl group terminates in a chain (monoradical) or is within a chain (diradical). The above definitions do not exclude additional substituents on the aryl group. For example, as used herein, the aryl group of "A-aryl-B" is a diradical, and the aryl group of "AB-aryl" is a monoradical, although additional substituents may be present on each aryl group.

[0020] The term "aryloxy" refers to the group --O-aryl.

[0021] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] "Halo" and "halogen" are used herein to refer to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0023] The term "haloalkyl," as used herein, refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halogen substituents, which may be the same or different. For example, C 1~6 Haloalkyl is C 1~6 C in which one or more of the alkyl hydrogen atoms are replaced by halo substituents 1~6 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0024] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom group. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms selected from nitrogen, sulfur, phosphorus, and oxygen. The heteroatoms in a "heteroalkyl" may be oxidized, e.g., -N(O)-, -S(O)-, -S(O)-. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH (wherein R is hydrogen or alkyl).

[0025] "Heteroaryl" refers to a monoradical or diradical aromatic group having a single ring, multiple rings, or multiple fused rings with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroatoms in "heteroaryl" can be oxidized, e.g., -N(O)-, -S(O)-, -S(O)2-. The term includes fused ring systems in which one or more fused rings are fully or partially unsaturated. The monoradical or diradical classification indicates whether the heteroaryl group terminates in a chain (monoradical) or is part of a chain (diradical). The above definition does not exclude additional substituents on the heteroaryl group. For example, the heteroaryl group of "A-heteroaryl-B" is a diradical, and the heteroaryl group of "AB-heteroaryl" is a monoradical, although additional substituents may be present on each heteroaryl group. Heteroaryl does not encompass or overlap with aryl, as defined above. Non-limiting examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4(l,4)]dioxolyl, and benzo[b][1,4(l,4)]dioxolyl. Xepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a(l,2-a)]pyridinyl, carbazolyl , cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl-1H(lH)- includes, but is not limited to, pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

[0026] The term "heteroaryloxy" refers to the group --O-heteroaryl.

[0027] The terms "heterocyclyl," "heterocycle," or "heterocyclic" refer to a saturated or unsaturated monoradical or diradical group having a single ring or multiple fused rings with one or more heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen within the ring. The heteroatoms in a "heterocyclyl" may be oxidized, e.g., -N(O)-, -S(O)-, -S(O)2-. A heterocyclyl may be a single ring or multiple rings, and multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of connectivity (i.e., it may be attached via a carbon atom or a heteroatom). Exemplary heterocyclic groups include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0028] The term "cyano" refers to the group --CN.

[0029] The term "oxo" refers to the group =O.

[0030] The term "carboxy" refers to the group -C(O)-OH.

[0031] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0032] "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

[0033] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" is used to designate a racemic mixture when appropriate.

[0034] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0035] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition); b) slowing or halting the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying worsening or progression of a disease or condition); and c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, ameliorating disease symptoms, delaying disease progression, improving quality of life, and / or prolonging survival.

[0036] As used herein, "prevention" or "preventing" refers to a regimen that protects against the occurrence of a disease or disorder, so that the clinical symptoms of the disease or disorder do not develop. Thus, "prevention" relates to administering treatment to a subject before symptoms of the disease become detectable in the subject. The subject may be an individual at risk of developing a disease or disorder, for example, an individual with one or more risk factors known to be associated with the onset or development of a disease or disorder.

[0037] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response when administered to a subject to treat a disease, including an amount of a compound sufficient to effect such treatment for the disease. The effective amount will vary depending on the specific compound and the characteristics of the subject being treated, such as age, weight, etc. An effective amount can include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired treatment endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in combination with one or more other agents, a desired or beneficial result can be achieved or is achieved. The appropriate dose of any compound administered in combination can be reduced as necessary due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0038] As used herein, "co-administration" includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is first administered, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of a compound disclosed herein is first administered, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, followed by a unit dose of one or more additional therapeutic agents several hours (e.g., 1-12 hours) later. In other embodiments, a unit dose of a compound disclosed herein is first administered, followed by a unit dose of one or more additional therapeutic agents several hours (e.g., 1-12 hours) later.

[0039] Also provided herein are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are suitable for use in animal or human medicine.

[0040] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts.Pharmaceutically acceptable salts are the non-toxic salts of the free base form of compounds, which have the desired pharmacological activity of free base.These salts can be derived from inorganic or organic acids or bases.For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compounds with inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyl phosphate ... Examples of suitable pharmaceutically acceptable salts include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0041] Non-limiting examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from appropriate bases, such as alkali metal salts (e.g., sodium, potassium), alkaline earth metal salts (e.g., magnesium), ammonium salts, and NX4. +Also included are salts where X is C1-C4 alkyl. Also included are base addition salts, such as sodium or potassium salts.

[0042] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds but with different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0043] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the aforementioned compounds.

[0044] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0045] The term "prodrug", as used herein, is a biologically inactive derivative of a drug that, when administered to the human body, is converted into the biologically active parent drug following some chemical or enzymatic pathway. List of Abbreviations and Acronyms [Table A-1] [Table A-2] compound

[0046] In some embodiments, the present disclosure provides a compound of formula (I): [ka] Compounds by [In the formula, [ka] is a single or double bond, X is O or NR7 and R 12 is hydrogen or -C(O)R 1 and R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 7 , or -NR 8 R 9 and Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each selected from 1 to 5 R 10 optionally substituted with a group, R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 cycloalkyl, or 3- to 12-membered heterocyclyl; Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl and 3- to 12-membered heterocyclyl are each 1 to 5 R 10 optionally substituted with a group, R 3 and R 4 are independently hydrogen, C 1~6 Alkyl, -OR 7 , C 1~6 Heteroalkyl, -NR 8 R 9 , N.R. 8 C(O)R 9 , -NR 8 C(O)OR 9 , C 6~10 Aryl, C 3~10Cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 8 R 9 , -OC(O)NR 8 R 9 , -CN, or -SO2R 7 and Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each independently selected from 1 to 5 R 10 optionally substituted with a group, R 5 is hydrogen, C 1~6 Alkyl, -(CH2CH2O) p R 7 , C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each independently selected from 1 to 5 R 10 optionally substituted with a group, R 6 is hydrogen or halo, Each R 7 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 10 , where necessary, Each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl or 5-10 membered heteroaryl, or R 8 and R 9 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic ring, Said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 10 , where necessary, Each R 10 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, oxo, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O)NR a R b , -NR a S(O)2R b , -N3, -CN or -NO2, or two R 10The group may be a fused, spiro or bridged C 3~10 forming a cycloalkyl or 3- to 12-membered heterocyclyl; Each C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocycle, and 5- to 10-membered heteroaryl are each selected from 1 to 5 R 20 optionally substituted with a group, Each R a and R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or R a and R b together with the atoms to which they are attached form a 3- to 12-membered heterocyclyl, Said C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each 1 to 5 R 20 optionally substituted with a group, Each R 20 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1~6 alkyl), -C(O)N(C 1~6 alkyl), -COOH, -C(O)C 1~6 Alkyl, -C(O)OC 1~6 alkyl, or halogen; n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2] or a tautomer or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the present disclosure provides a compound of formula (II): [ka] The compound according to claim 1 [In the formula, [ka] is a single or double bond, R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 1~6 Hydroxyalkyl, -OC 1~6 Alkyl, -NHC 1~6 Alkyl, -NHC 1~6 Haloalkyl, 4-6 membered heterocyclyl, C 3~6 Cycloalkyl, -NHC 3~10 Cycloalkyl, or -N(C 1~6 alkyl)2, Said C 1~6 Alkyl is C 1~6 Alkoxy, -N(C 1~6 alkyl) 2, 5-10 membered heteroaryl, C 3~6 Cycloalkyl, -SO2C 1~6optionally substituted with alkyl, phenyl, 5-membered heteroaryloxy, phenoxy, or -O-(4- to 10-membered heterocyclyl); The 5-10 membered heteroaryl is selected from halo, C 1~6 Alkyl, and C 1~6 optionally substituted with 1 or 2 substituents selected from haloalkyl; The 5-membered heteroaryloxy is selected from 1 to 3 C 1~6 optionally substituted with alkyl; The phenyl is selected from the group consisting of 1 to 3 halo or C 1~6 optionally substituted with haloalkyl; -NHC 3~6 Cycloalkyl is C 1~3 optionally substituted with haloalkyl; -NHC 1~6 Alkyl is phenyl, 5-6 membered heteroaryl, or C 3~6 optionally substituted with cycloalkyl; the phenyl is optionally substituted with 1 to 5 halo; The 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 3 halo or C 1~6 optionally substituted with alkyl; Said C 1~6 hydroxyalkyl is optionally substituted with phenyl; Said C 3~6 cycloalkyl is optionally substituted with a 5-membered heteroaryl; The 5-membered heteroaryl is C 1~6 optionally substituted with alkyl; Said-OC 1~6 the alkyl is optionally substituted with a 5-membered heteroaryl; The 5-membered heteroaryl is C 1~6 optionally substituted with alkyl; The 5- to 10-membered heteroaryl is C 1~6 optionally substituted with alkyl; R 2 is hydrogen or C1~6 is alkyl, R 3 is hydrogen or C 1~6 is alkyl, R 4 is hydrogen, R 5 is hydrogen or C 1~6 is alkyl, Said C 1~6 alkyl is optionally substituted with 5- to 6-membered heterocyclyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present disclosure provides a compound of formula (II) according to formula (IIa): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides: R 2 is hydrogen or C 1~3 is alkyl, R 3 is hydrogen or C 1~3 is alkyl, R 4 is hydrogen, R 5 But C 1~3 is alkyl, Said C 1~3 Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with 5- to 6-membered heterocyclyl.

[0051] In some embodiments, the present disclosure provides: R 2 is hydrogen, methyl, or ethyl; R 3 is hydrogen or methyl, R 4 is hydrogen, R5 But hydrogen, methyl, [ka] That is, Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof:

[0052] In some embodiments, the present disclosure provides: R 2 is hydrogen, R 3 But C 1~3 is alkyl, Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof:

[0053] In some embodiments, the present disclosure provides: R 2 But C 1~3 is alkyl, R 3 is hydrogen, Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof:

[0054] In some embodiments, the present disclosure provides: R 2 is hydrogen, R 3 is hydrogen, Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof:

[0055] In some embodiments, the present disclosure provides: R 2 But C 1~3 is alkyl, R 3 But C 1~3 is alkyl, Provided are compounds of formula (I), formula (Ia), formula (II) or formula (IIa), or a pharmaceutically acceptable salt thereof:

[0056] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, R 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 7 , or -NR 8 R 9 and R 1 The above C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are independently selected from 1 to 5 R 10 optionally substituted with a group, Each R 2 , R 3 , R 4 , and R 5 are independently hydrogen or C 1~6 is alkyl, R 6 is hydrogen or halo, Each R 7 are independently hydrogen or C 1~6 is alkyl, Said C 1~6 Alkyl is 1 to 5 R10 , where necessary, Each R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl or 5-10 membered heteroaryl, or R 8 and R 9 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic ring, R 8 and R 9 The above C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are independently selected from 1 to 5 R 10 , where necessary, Each R 10 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, oxo, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O)NR a R b , -NR a S(O)2R b , -N3, -CN or -NO2, or two R 10The group may be a fused, spiro or bridged C 3~10 forming a cycloalkyl or 3- to 12-membered heterocyclyl; R 10 Each C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 The aryl, 3- to 12-membered heterocycle, and 5- to 10-membered heteroaryl are independently selected from 1 to 5 R 20 optionally substituted with a group, Each R a and R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 aryl or 5-10 membered heteroaryl, or R a and R b together with the atoms to which they are attached form a 3- to 12-membered heterocyclyl, R a and R b Each of the above C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl each independently have 1 to 5 R 20 optionally substituted with a group, Each R 20 are independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Heteroalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1~6 alkyl), -C(O)N(C 1~6alkyl), -COOH, -C(O)C 1~6 Alkyl, -C(O)OC 1~6 alkyl, or halogen; n is 0, 1, or 2; q is 0, 1, or 2] to provide.

[0057] In some embodiments, the present disclosure provides a compound of formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof,

[0058] In some embodiments, the present disclosure provides a compound of formula (IIIb): [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, -NHC 1~6 Alkyl, -NHC 1~6 Haloalkyl, 4-6 membered heterocyclyl, C 3~6 Cycloalkyl, -NHC 3~10 cycloalkyl, or -NH(4- to 6-membered heterocyclyl); R 1 Each C 1~6 Alkyl and -NHC 1~6 The alkyl is independently selected from hydroxyl, C 1~6 Alkoxy, 5-10 membered heteroaryl, C 3~6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, phenyl, or -O-(4- to 10-membered heterocyclyl); 5-10 membered heteroaryl, C 3~6 Cycloalkyl, phenyl, and -O-(4- to 10-membered heterocyclyl) are independently selected from halo, C1~6 Alkyl, and C 1~6 optionally substituted with 1 to 4 substituents independently selected from haloalkyl; R 1 Each C 6~10 Aryl and 5-10 membered heteroaryl are substituted with halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, 4- to 6-membered heterocyclyl, and C 3~6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl; R 1 Each 4- to 6-membered heterocyclyl, C 3~6 Cycloalkyl, -NHC 3~10 Cycloalkyl, and -NH (4- to 6-membered heterocyclyl) are substituted with halo, oxo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, -C(O)OR a , C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl; Each C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 Cycloalkyl can independently be selected from halo, C 1~4 Alkyl, and C 1~4 optionally substituted with 1 to 3 substituents independently selected from haloalkyl; Each R 2 , R 3 , R 4 , and R 5 are independently hydrogen or C 1~6 alkyl, and R 6 is hydrogen or halo.

[0059] In some embodiments, the present disclosure provides a compound of formula (IIIc), or a pharmaceutically acceptable salt thereof: [ka] [Each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is defined above or elsewhere in this disclosure].

[0060] In some embodiments, the present disclosure provides a compound of formula (IIId), or a pharmaceutically acceptable salt thereof: [ka] [Each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is defined above or elsewhere in this disclosure].

[0061] In some embodiments, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; R 1 are independently 1 to 4 R 10 , where necessary, Each R 10 are independently halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 cycloalkyl, and 3- to 12-membered heterocyclyl; R 10 C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10Cycloalkyl and 3- to 12-membered heterocyclyl are independently selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 4 substituents independently selected from heteroalkyl; R 2 is hydrogen, C 1~6 Alkyl, or C 1~6 is heteroalkyl, R 2 C 1~6 Alkyl and C 1~6 the heteroalkyl is optionally substituted with 1 to 3 substituents independently selected from halo, oxo, and hydroxyl; R 3 and R 4 are independently hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, -OR 7 , or -SO2R 7 and R 3 and R 4 C 1~6 Alkyl and C 1~6 Heteroalkyl is independently selected from halo, oxo, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are independently selected from halo, C 1~4 Alkyl, and C 1~4 optionally substituted with 1 to 3 substituents independently selected from heteroalkyl; R 5 is hydrogen, C 1~6 Alkyl, or C 1~6 is heteroalkyl, R 5 C 1~6 Alkyl and C 1~6 Heteroalkyl includes halo, oxo, C3~6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 4- to 6-membered heterocyclyl; R 7 are independently hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; R 7 C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 Aryl and 5-10 membered heteroaryl are substituted with halo, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 and optionally substituted with 1 to 4 substituents independently selected from heteroalkyl.

[0062] In some embodiments, the present disclosure provides a compound of formula (IVa): [ka] or a pharmaceutically acceptable salt thereof, [In the formula, R 1 is a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 1 are independently 1 to 4 R 10 , where necessary, Each R 10 are independently halo, hydroxyl, -CN, C 1~4 Alkyl, C 1~4 Alkoxyl, C 3~6 cycloalkyl, and 3- to 6-membered heterocyclyl; and each R 2 , R 3 , and R 4 are independently hydrogen, C 1~4 Alkyl or C 1~4 The compound is an alkoxy group.

[0063] In some embodiments, the present disclosure provides a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein the heterocyclyl group is a partially unsaturated ring system containing one or more double bonds. In some embodiments, the heterocyclyl group is a fused ring system having one aromatic ring and one non-aromatic ring, but not a fully aromatic ring system.

[0064] In some embodiments, the present disclosure provides R 2 is hydrogen, or a tautomer or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the present disclosure provides R 2 But C 1~3 The present invention provides a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein:

[0066] In some embodiments, the present disclosure provides R 2 is methyl, or a tautomer or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the present disclosure provides R 3 But C 1~3 The present invention provides a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein:

[0068] In some embodiments, the present disclosure provides R 3is methyl, or a tautomer or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the present disclosure provides R 4 is hydrogen, or a tautomer or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the present disclosure provides R 5 But C 1~3 The present invention provides a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein:

[0071] In some embodiments, the present disclosure provides R 5 is methyl, or a tautomer or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the present disclosure provides R 6 is Cl, or a tautomer or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the present disclosure provides -C(O)R 1 but, [ka] [ka] selected from the group consisting of Provided are compounds of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof:

[0074] In some embodiments, the present disclosure provides R 1 but, [ka] or a pharmaceutically acceptable salt thereof; Provided are compounds of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or tautomers or pharmaceutically acceptable salts thereof.

[0075] In some embodiments, the present disclosure provides R 1 but, [ka] [ka] or a pharmaceutically acceptable salt thereof; Provided are compounds of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or tautomers or pharmaceutically acceptable salts thereof.

[0076] In some embodiments, the present disclosure provides R 1 but, [ka] Selected from: Provided are compounds of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa) or Formula (IIIb), or tautomers or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, the present disclosure provides R 1 But 1-2 R 10or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the present disclosure provides R 1 but, [ka] each of which is selected from 1 to 2 R 10 In some embodiments, each R is optionally substituted with 10 is independently selected from —CH 3 , —CHF 2 , and —OCH 3 .

[0079] In some embodiments, R 1 is 1 to 2 R 10 , which is replaced as necessary by [ka] In some embodiments, R 1 is 1 to 2 R 10 , which is replaced as necessary by [ka] In some embodiments, R 10 are independently, C 1~4 Alkyl and C 1~4 In some embodiments, R is selected from the group consisting of alkoxyl. 10 is independently selected from —CH and —OCH. In some embodiments, R 1 is substituted with -CH3 and -OCH3 [ka] is.

[0080] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0081] In some embodiments, the present disclosure provides R 2 is hydrogen or C 1~3 In some embodiments, R is a phenyl group, or a pharmaceutically acceptable salt thereof. 2 is selected from hydrogen and methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl.

[0082] In some embodiments, the present disclosure provides R 3 is hydrogen or C 1~3 In some embodiments, R is a phenyl group, or a pharmaceutically acceptable salt thereof. 3 is selected from hydrogen and methyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is hydrogen.

[0083] In some embodiments, the present disclosure provides R 4 But hydrogen, C 1~3 Alkyl, or C 1~3In some embodiments, R is an alkoxyl group. 4 is selected from hydrogen, methyl, and —OCH. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is —OCH. In some embodiments, R 4 is methyl.

[0084] In some embodiments, the present disclosure provides R 2 and R 4 is hydrogen and R 3 In some embodiments, R is methyl. 2 and R 3 is methyl and R 4 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is methyl and R 4 is -OCH3.

[0085] In some embodiments, the present disclosure provides R 5 is hydrogen or C 1~3 In some embodiments, R is an alkyl group, or a pharmaceutically acceptable salt thereof. 5 is methyl. In some embodiments, R 5 is hydrogen.

[0086] In some embodiments, the disclosure provides a compound selected from Examples 1-464.

[0087] In some embodiments, the disclosure provides a compound selected from Examples 1-154.

[0088] In some embodiments, the disclosure provides a compound selected from Examples 155-464.

[0089] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] The present invention provides a compound selected from:

[0091] In some embodiments, the present disclosure provides: [ka] [ka] [ka] The present invention provides a compound selected from:

[0092] In some embodiments, isotopically labeled forms of compounds of Formula (I), Formula (Ia), Formula (II), or Formula (IIa) are provided herein. In some embodiments, isotopically labeled forms of compounds of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa) are provided herein. Isotopically labeled compounds have structures illustrated by the formulas provided herein, except that one or more atoms are replaced by an isotope having a selected atomic mass or mass number. Isotopically labeled compounds have structures illustrated by the formulas provided herein, except that one or more atoms are replaced by an isotope having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H (deuterium, D), 3 H (tritium), 11C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present disclosure, such as, but not limited to, 3 H, 13 C and 14 Compounds incorporating radioactive isotopes such as C are within the scope of the present disclosure. Such isotopically labeled compounds may be useful in metabolic studies, kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in treating patients. Such isotopically labeled analogs of the compounds of the present disclosure may also have improved pharmacokinetic and / or pharmacodynamic properties over unlabeled forms of the same compounds and may therefore be useful in treating the diseases disclosed herein. Such isotopically labeled forms or analogs of the compounds herein are within the scope of the present disclosure. One skilled in the art can prepare and use such isotopically labeled forms according to procedures for isotopically labeling compounds or compound embodiments to arrive at isotopic or radiolabeled analogs of the compounds disclosed herein.

[0093] The compounds disclosed herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Likewise, all tautomeric forms are intended to be included.

[0094] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as described in more detail below.

[0095] The pharmaceutical composition comprising the compound disclosed herein or its pharmaceutically acceptable salt can be prepared using one or more pharmaceutically acceptable excipients that can be selected according to conventional practice. "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is approved by the US Food and Drug Administration as acceptable for use in humans or domestic animals.

[0096] In certain embodiments, the pharmaceutical compositions are provided as solid oral dosage forms, including tablets. Tablets can contain excipients, including glidants, fillers, binders, etc. Aqueous compositions can be prepared in a sterile form and, if intended for delivery by a route other than oral administration, can generally be made isotonic. All compositions can optionally contain excipients, such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0097] The pharmaceutical compositions disclosed herein include those suitable for various routes of administration, including oral administration. The compositions can be presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. Such methods include combining the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately combining the active ingredient with liquid excipients or finely divided solid excipients, or both, and then, if necessary, shaping the product. Techniques and formulations for this purpose can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0098] Compositions described herein suitable for oral administration can be presented as discrete units (unit dosage forms), including, but not limited to, capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0099] The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and, if necessary, other therapeutic agents. Pharmaceutical compositions containing active ingredients can be in any form suitable for the intended administration method. For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet preparation are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0100] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended treatment subject and the particular method of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipients vary from about 5 to about 95% (weight:weight) of the total composition. method

[0101] In some embodiments, the present disclosure provides methods of inhibiting MCL-1. In some embodiments, the present disclosure provides methods of inhibiting MCL-1 in an individual (e.g., a human), comprising administering to the individual a compound of Formula (I), or a tautomer or pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the present disclosure provides a method for treating or preventing cancer. In certain embodiments, the present disclosure provides a method for treating or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), or a tautomer or pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and leukemia.

[0103] The compounds disclosed herein can be administered by any route suitable for use in the methods described herein. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc.

[0104] The compounds disclosed herein can be administered to an individual according to an effective dosing regimen for a desired time or period, such as at least 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months, or longer. In one variation, the compounds are administered daily or on an intermittent schedule for the life of the individual.

[0105] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0106] A therapeutically effective amount of a compound disclosed herein is from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 μg to about 30 mg per day, or such as from about 0.3 μg to about 30 mg per day.

[0107] A compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be combined with one or more additional therapeutic agents in any dosage of the disclosed compound (e.g., 1 mg to 1000 mg of compound). A therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof, may range from about 0.01 mg per dose to about 1000 mg per dose, such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), Formula (Ia), Formula (II) or Formula (IIa) are about 1 mg per dose, or about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), Formula (Ia), Formula (II), or Formula (IIa) are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per dose.

[0108] A therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, may be in the range of from about 0.01 mg per dose to about 1000 mg per dose, such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa) are about 1 mg per dose, or about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa) are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg per dose.

[0109] The single dose can be administered hourly, daily, or weekly. For example, the single dose can be administered every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 8 hours, every 12 hours, every 16 hours, or every 24 hours. The single dose can also be administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or every 7 days. The single dose can also be administered every week, every 2 weeks, every 3 weeks, or every 4 weeks. In certain embodiments, the single dose can be administered once weekly. The single dose can also be administered once monthly. In some embodiments, the compounds disclosed herein are administered once daily in the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the methods disclosed herein.

[0110] The dosing frequency of the compounds disclosed herein is determined by the needs of each patient, and can be, for example, once or twice a day, or more than once a day.The administration of the compound continues as long as necessary to treat cancer.For example, the compounds disclosed herein can be administered to a person with cancer for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0111] Administration can be intermittent, with the patient receiving a daily dose of a compound disclosed herein for several days or longer, followed by a period of several days or longer in which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every two days or three times a week. Again, by way of non-limiting example, the patient can receive a dose of the compound daily for a period of 1-14 days, followed by a period of 7-21 days in which the patient does not receive a dose of the compound, after which, for a subsequent period (e.g., 1-14 days), the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by periods in which the compound is not administered can be repeated as long as clinically necessary to treat the patient. Combination therapy

[0112] Also provided are methods of treatment wherein a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is administered to a patient in combination with one or more additional active agents or therapies.

[0113] Thus, in one embodiment, a method of treating cancer and / or a disease or condition coexisting with, or exacerbated or caused by, cancer, e.g., an allergic disorder and / or an autoimmune disease and / or an inflammatory disease, and / or an acute inflammatory response, comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, optionally in combination with an additional agent (e.g., a second, third, fourth or fifth active agent) that may be useful in treating cancer, an allergic disorder and / or an autoimmune disease and / or an inflammatory disease resulting from or coexisting with cancer, and / or an acute inflammatory response. Treatment with a second, third, fourth, or fifth active agent can occur prior to, concurrently with, or subsequent to treatment with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is combined with another active agent in a single dosage form. Suitable antitumor or anticancer therapeutic agents that can be used in combination with a compound of Formula (I), Formula (Ia), Formula (II), or Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, include, but are not limited to, chemotherapeutic agents such as mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or a combination comprising at least one of the foregoing chemotherapeutic agents. Radiation-based antitumor agents can also be used alone or in combination with chemotherapeutic agents.

[0114] A compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be useful as a chemosensitizer and therefore can be useful in combination with other chemotherapeutic agents, particularly drugs that induce apoptosis. Accordingly, in one embodiment, the present disclosure provides a method for increasing the sensitivity of cancer cells to chemotherapy, the method comprising administering to a patient in need of or undergoing chemotherapy a chemotherapeutic agent together with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, in an amount sufficient to increase the sensitivity of the cancer cells to the chemotherapeutic agent.

[0115] Examples of other chemotherapeutic agents that can be used in combination with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, include topoisomerase I inhibitors (camptothesin or topotecan), topoisomerase II inhibitors (e.g., daunomycin and etoposide), alkylating agents (e.g., cyclophosphamide, melphalan, and BCNU), tubulin-specific agents (e.g., taxol and vinblastine), and biologic agents (e.g., antibodies, such as anti-CD20 antibodies, IDEC8, immunotoxins, and cytokines).

[0116] In some embodiments, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is used in combination with Rituxan® (rituximab) and / or other agents that act by selectively depleting CD20+ B cells.

[0117] Included herein are methods of treatment in which a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include NSAIDs, nonspecific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, and the like. These include, but are not limited to, drugs, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0118] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs include COX-2 specific inhibitors (i.e., IC50 inhibitors for COX-1). 50 IC at least 50 times lower 50 and compounds which inhibit COX-2 in the presence of steroids such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and / or rofecoxib.

[0119] In a further embodiment, the anti-inflammatory agent is a salicylate, including but not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

[0120] The anti-inflammatory agent may be a corticosteroid. For example, the corticosteroid may be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. In some embodiments, the anti-inflammatory therapeutic agent is a gold compound, such as gold sodium thiomalate or auranofin. In some embodiments, the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0121] In one embodiment, the compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is administered in combination with an anti-C5 monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist such as etanercept, or an anti-TNF alpha monoclonal antibody (e.g., ribozyme), It is used in combination with at least one anti-inflammatory compound, the monoclonal antibody infliximab.

[0122] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is used in combination with at least one active agent which is an immunosuppressant compound, e.g., methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0123] In other embodiments, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is used in combination with one or more phosphatidylinositol 3-kinase (PI3K) inhibitors, including, for example, Compounds A, B, and C (the structures of which are provided below), or a pharmaceutically acceptable salt thereof. [ka]

[0124] Compounds A, B, and C are disclosed in WO2015 / 017460 and WO2015 / 100217. Further examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY80-6946), duvelisib, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, taselisib, TG100115, TGR-1202, TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO2005 / 113556 (ICOS), WO2013 / 052699 (Gilead Calistoga), WO2013 / 116562 (Gilead Calistoga), WO2014 / 100765 (Gilead Calistoga), WO2014 / 100767 (Gilead Calistoga), and WO2014 / 201409 (Gilead Sciences).

[0125] In yet another embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, may be used in combination with a spleen tyrosine kinase (SYK) inhibitor. Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in US8450321 (Gilead Connecticut) and US2015 / 0175616.

[0126] In yet another embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be used in combination with a tyrosine kinase inhibitor (TKI). The TKI can target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087, asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, and icoccinib. These include, but are not limited to, nib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, and TH-4000.

[0127] In still other embodiments, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be used in combination with one or more inhibitors of lysyl oxidase-like 2 (LOXL), or a substance that binds to LOXL, including, for example, a humanized monoclonal antibody (mAb) having the immunoglobulin IgG4 isotype that targets human LOXL2. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO2009 / 017833 (Arresto Biosciences), WO2009 / 035791 (Arresto Biosciences), and WO2011 / 097513 (Gilead Biologics).

[0128] In yet another embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be used in combination with a Toll-like receptor 8 (TLR8) inhibitor. Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463, and VTX-763.

[0129] In yet another embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be used in combination with a Toll-like receptor (TLR9) inhibitor. Examples of TLR9 inhibitors include, but are not limited to, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042.

[0130] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with a BTK (Bruton's tyrosine kinase) inhibitor for the treatment of cancer. An example of such a BTK inhibitor is the compound disclosed in U.S. Patent 7,405,295. Further examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, HM71224, ibrutinib, M-2951, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), and TAK-020.

[0131] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, in combination with a BET inhibitor is useful for the treatment of cancer. An example of such a BET inhibitor is the compound disclosed in WO2014 / 182929, the entire contents of which are incorporated herein by reference.

[0132] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with a TBK (Tank-binding kinase) inhibitor for the treatment of cancer. An example of such a TBK inhibitor is a compound disclosed in WO2016 / 049211.

[0133] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with an OX40 inhibitor for the treatment of cancer. An example of such an OX40 inhibitor is a compound disclosed in US 8,450,460, the entire contents of which are incorporated herein by reference.

[0134] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with a JAK-1 inhibitor for the treatment of cancer. An example of such a JAK-1 inhibitor is a compound disclosed in WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), and XL019.

[0135] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with an indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitor for the treatment of cancer. An example of such an IDO inhibitor is a compound disclosed in WO2016 / 186967. In one embodiment, the compounds of Formula (I), Formula (Ia), Formula (II), or Formula (IIa) are useful in combination with IDO1 inhibitors, including but not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, for the treatment of cancer.

[0136] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in combination with a mitogen-activated protein kinase (MEK) inhibitor for the treatment of cancer. MEK inhibitors useful for combination treatment with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa) include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib, and trametinib.

[0137] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful in the treatment of cancer in combination with an apoptosis signal-regulating kinase (ASK) inhibitor. ASK inhibitors include, but are not limited to, those described in WO2011 / 008709 (Gilead Sciences) and WO2013 / 112741 (Gilead Sciences), including, for example, selonsertib.

[0138] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be combined with a cluster of differentiation 47 (CD47) inhibitor. Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621.

[0139] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be combined with a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors include inhibitors of CDK1, 2, 3, 4, 6, and 9, such as abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, and TG-02.

[0140] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be combined with a discoidin domain receptor (DDR) inhibitor for the treatment of cancer. DDR inhibitors include inhibitors of DDR1 and / or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO2014 / 047624 (Gilead Sciences), US2009-0142345 (Takeda Pharmaceutical), US2011-0287011 (Oncomed Pharmaceuticals), WO2013 / 027802 (Chugai Pharmaceutical), and WO2013 / 034933 (Imperial Innovations).

[0141] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, may be combined with a histone deacetylase (HDAC) inhibitor, such as those disclosed in U.S. Patent 8,575,353 and equivalents thereof. Further examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907, entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), and vorinostat.

[0142] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is useful for the treatment of cancer in combination with the standard of care in the treatment of the respective cancer. One of skill in the art will be aware of the standard of care in a particular cancer treatment area or for a given cancer at a given date.

[0143] Certain embodiments of the present application include or use one or more additional therapeutic agents. The one or more additional therapeutic agents may be agents useful for treating cancer, inflammation, autoimmune diseases, and / or related conditions. The one or more additional therapeutic agents may be chemotherapeutic agents, anti-angiogenic agents, anti-fibrotic agents, anti-inflammatory agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, radiation therapy agents, anti-neoplastic agents, anti-cancer agents, anti-proliferative agents, or any combination thereof. In some embodiments, the compounds described herein may be used or combined with chemotherapeutic agents, anti-angiogenic agents, anti-fibrotic agents, anti-inflammatory agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, radiation therapy agents, anti-neoplastic or anti-cancer agents, anti-proliferative agents, or any combination thereof.

[0144] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, optionally in combination with an additional anti-cancer agent as described herein, can be used or combined with an anti-neoplastic or anti-cancer agent, an anti-fibrotic agent, an anti-inflammatory agent, or an immunomodulatory agent.

[0145] In one embodiment, a kit is provided that includes a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (II), or Formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof, at least one additional anti-cancer agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In one embodiment, a kit is provided that includes a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, at least one additional anti-cancer agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In one embodiment, the kit includes instructions for use in the treatment of cancer. In one embodiment, the instructions in the kit are directed to using the pharmaceutical composition for the treatment of hematological malignancies, multiple myeloma, breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and / or leukemia.

[0146] The present application also provides a method for treating a subject receiving one or more standard therapies, such as chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof, comprising administering or co-administering to the subject a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer or pharmaceutically acceptable salt thereof. Thus, one or more compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer or pharmaceutically acceptable salt thereof, can be administered before, during, or after the administration of chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof.

[0147] In one embodiment, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) has relapsed after chemotherapy treatment, or both (i) and (ii). In some embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).

[0148] In one embodiment, the subject is receiving fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab, and other chemotherapy treatments, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-HyperCVAD (rituximab-HyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade ( and is refractory to at least one, at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy) selected from: Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and DTPACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).

[0149] Other examples of chemotherapy treatments (including standard or experimental chemotherapy) are described in: Additionally, treatments for certain lymphomas are described in Cheson, BD, Leonard, JP, "Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma," The New England Journal of Medicine, Vol. 1, No. 1, pp. 111-114, 2002. The incidence patterns of lymphoma in the United States are reviewed in Morton, Journal of Medicine 2008, 359(6), pp. 613-626, and Wierda, WG, "Current and Investigational Therapies for Patients with CLL" Hematology 2006, pp. 285-294. Profiled in LM, et al. "Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001" Blood 2006, 107(1), p. 265-276.

[0150] Examples of immunotherapeutic agents for treating lymphoma or leukemia include, but are not limited to, rituximab (e.g., Rituxan), alemtuzumab (e.g., Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapeutic agents include the use of cancer vaccines based on the genetic makeup of an individual patient's tumor, for example an example of a lymphoma vaccine is GTOP-99 (MyVax®).

[0151] Examples of chemotherapeutic agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta-arretin, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, cladribine (Leustarin). , chlorambucil (Leukeran), curcumin, cyclosporine, cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine , denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, doxorubicin (Adriamycin®, Adriblastin), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, flavopiridol, fludarabine (Fludara), geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer -cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasens), obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, pegylated liposomal doxorubicin hydrochloride, pegfilgrastim, pentostatin (Pentstatin), perifosine, prednisolone, prednisone, R-roscovitine (Seri Siribu, CYC202), recombinant interferon alpha, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), vincristine (Oncovin) , vincristine sulfate, vinorelbine tartrate, vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone,These include methotrexate, cytarabine), ICE (ifosfamide, carboplatin, and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab-ICE), and R-MCP (rituximab-MCP).

[0152] In some embodiments, the cancer is melanoma. Suitable agents for use in combination with the compounds described herein include, but are not limited to, dacarbazine (DTIC) (optionally combined with other chemotherapy drugs such as carmustine (BCNU) and cisplatin), the "Dartmouth regimen" (consisting of DTIC, BCNU, cisplatin, and tamoxifen), a combination of cisplatin, vinblastine, and DTIC, temozolomide, or YERVOY™. The compounds disclosed herein can also be combined with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF), in the treatment of melanoma.

[0153] The compound described herein can also be used in combination with vaccine therapy in the treatment of melanoma.Anti-melanoma vaccine is similar in some respects to the antiviral vaccine used to prevent diseases caused by viruses such as polio, measles and mumps.Weakened melanoma cells or the part of melanoma cells called antigen can be injected into patient to stimulate the body's immune system to destroy melanoma cells.

[0154] Melanoma confined to the arms or legs can also be treated with a combination of drugs, including one or more compounds described herein, using, for example, the hyperthermic isolated limb perfusion technique. This treatment protocol temporarily isolates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the arteries supplying the limb, thus delivering a high dose to the tumor area without exposing internal organs to these doses, which could otherwise cause severe side effects. Typically, the fluid is warmed to 102°-104°F. Melphalan is the drug most often used in this chemotherapy procedure. It can be given in combination with another agent called a tumor necrosis factor (TNF), optionally in combination with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa).

[0155] Therapeutic treatments can complement or be combined with any of the aforementioned treatments using stem cell transplantation or treatment. One example of a modified approach is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle, such as indium In111, yttrium Y90, or iodine I-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (Bexxar®), yttrium-90 ibritumomab tiuxetan (Zevalin®), and Bexxar® with CHOP.

[0156] Other therapeutic procedures useful in combination with treatment with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow ablation with stem cell support, in vitro treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, pharmacological studies, low LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0157] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, in combination with an MMP9 binding protein and / or one or more additional therapeutic agents, and a pharmaceutically acceptable diluent, carrier, or excipient. In one embodiment, the pharmaceutical composition comprises an MMP9 binding protein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) and anti-MMP9 antibody AB0045.

[0158] In one embodiment, the pharmaceutical composition comprises a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, anti-MMP9 antibody AB0045, at least one additional therapeutic agent that is an immunomodulatory agent, and a pharmaceutically acceptable diluent, carrier, or excipient. In certain other embodiments, the pharmaceutical composition comprises anti-MMP9 antibody AB0045, at least one additional therapeutic agent that is an anti-inflammatory agent, and a pharmaceutically acceptable diluent, carrier, or excipient. In certain other embodiments, the pharmaceutical composition comprises a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, anti-MMP9 antibody AB0045, at least one additional therapeutic agent that is an anti-neoplastic or anti-cancer agent, and a pharmaceutically acceptable diluent, carrier, or excipient. In one embodiment, MMP9 compounds useful for combination treatment with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV) or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, include, but are not limited to, marimastat (BB-2516), sipemastat (Ro32-3555), and those described in WO2012 / 027721 (Gilead Biologics).

[0159] In one embodiment, the one or more additional therapeutic agents are immunomodulatory agents, such as immunostimulatory agents or immunosuppressants. In certain other embodiments, the immunomodulatory agent is an agent capable of altering the function of immune checkpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or PD-1 pathways. In other embodiments, the immunomodulatory agent is an immune checkpoint modulator. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies, anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or anti-CD137L antibodies, anti-OX40 or anti-OX40L antibodies, anti-CD40 or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs. For certain such immune pathway gene products, the use of either antagonists or agonists of such gene products, such as small molecule modulators of such gene products, is contemplated. In one embodiment, the immunomodulator is an anti-PD-1 or anti-PD-L1 antibody. In some embodiments, immunomodulatory agents include agents capable of altering the function of mediators in cytokine-mediated signaling pathways.

[0160] In some embodiments, the one or more additional therapies or anti-cancer agents are cancer gene therapy or cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modification to silence mutated genes; genetic techniques to directly kill cancer cells; infusion of immune cells designed to replace a large portion of the patient's own immune system or activate the patient's own immune system (T cells or natural killer cells) to kill or detect and kill cancer cells to enhance the immune response to cancer cells; genetic techniques to modify cell activity to further alter endogenous immune responsiveness to cancer. Non-limiting examples include Algenpantucel-L (2 pancreatic cell line), Sipuleucel-T, SGT-53 liposomal nanodelivery of gene p53 (scL); T cell therapy, such as CD19 CAR-T. Tisagenlecleucel-T (CTL019) (WO2012079000, WO2017049166), axicabtagene ciloleucel (KTE-C19) (US7741465, US6319494), JCAR-015 (US7446190), JCAR-014, JCAR-020, JCAR-024, JCAR-023, JTCR-016, JCAR-018 (WO201609019 0), JCAR-017 (WO2016196388, WO2016033570, WO2015157386), BPX-501 (US9089520, WO2016100236), AU-105, UCART-22, ACTR-087, P-BCMA-101; activated allogeneic natural killer cells CNDO-109-AANK, FATE-NK100, and LFU-835 hematopoietic stem cells.

[0161] In one embodiment, one or more additional therapeutic agents are immune checkpoint inhibitors. Tumors subvert the immune system by exploiting a mechanism known as T cell exhaustion, which arises from chronic exposure to antigens and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0162] PD-1 and its co-inhibitory receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223), are often referred to as checkpoint regulators. Checkpoint regulators act as molecular determinants that influence whether cell cycle progression and other intracellular signaling processes should proceed based on extracellular signals.

[0163] In addition to specific antigen recognition via the T cell receptor (TCR), T cell activation is controlled by the balance of positive and negative signals provided by costimulatory receptors. These surface proteins are typically members of either the TNF receptor or B7 superfamily. Agonistic antibodies against activating costimulatory molecules and blocking antibodies against negative costimulatory molecules can enhance T cell stimulation and promote tumor destruction.

[0164] Programmed cell death protein 1 (PD-1 or CD279), a 55-kD single-pass transmembrane protein, is a member of the CD28 family of T cell costimulatory receptors, which includes the immunoglobulin superfamily members CD28, CTLA-4, inducible costimulatory substance (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected at various expression levels on memory T cell subsets. Two specific ligands for PD-1 have been identified: programmed death-ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD-1 in both mouse and human systems (Okazaki et al., Int. Immunol., 2007; 19: 813-824). PD-1, expressed on antigen-presenting cells (APCs) and dendritic cells (DCs) The interaction of PD-L1 with its ligands, PD-L1 and PD-L2, transmits negative regulatory stimuli to down-modulate activated T cell immune responses. Blockade of PD-1 suppresses this negative signal and amplifies T cell responses. Numerous studies have shown that the tumor microenvironment manipulates the PD-L1 / PD-1 signaling pathway, and that induction of PD-L1 expression is associated with inhibition of immune responses against cancer, thus enabling cancer progression and metastasis. The PD-L1 / PD-1 signaling pathway is a major mechanism of cancer immune evasion for several reasons. This pathway is involved in the negative regulation of immune responses by activated T effector cells found in the periphery. While PD-L1 is upregulated in the tumor microenvironment, PD-1 is also upregulated on activated tumor-infiltrating T cells, potentially enhancing the vicious cycle of inhibition. This pathway is also intricately involved in both innate and adaptive immune regulation through bidirectional signaling. These factors make the PD-1 / PD-L1 complex a focal point through which cancer can manipulate the immune response and promote its own progression.

[0165] The first immune checkpoint inhibitor tested in clinical trials was the CTLA-4 mAb, ipilimumab (Yervoy, Bristol-Myers Squibb). CTLA-4 belongs to the immunoglobulin superfamily of receptors, which also includes PD-1, BTLA, TIM-3, and V-domain immunoglobulin inhibitor of T-cell activation (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that release "quiet" from both naive and antigen-experienced cells.

[0166] Treatment enhances the antitumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ regulatory T cells, and inhibits the suppressive function of regulatory T cells. TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. Mouse models of cancer have shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually coexpress PD-1 and LAG-3. LAG-3 is another recently identified inhibitory receptor that acts to limit effector T cell function and enhance the suppressive activity of regulatory T cells. Recently, it has been shown that PD-1 and LAG-3 are widely coexpressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 elicits a potent, synergistic antitumor immune response in mouse models of cancer.

[0167] Thus, in one embodiment, the present disclosure provides for the use of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, in combination with one or more additional immune checkpoint inhibitors. In one embodiment, the present disclosure provides for the use of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, one or more immune checkpoint inhibitors, and an anti-MMP9 antibody or antigen-binding fragment thereof, to treat or prevent cancer. In some embodiments, the immune checkpoint inhibitor may be an anti-PD-1 antibody and / or an anti-PD-L1 antibody, or an anti-PD-1 / PD-L1 interaction inhibitor. In some embodiments, the anti-PD-L1 antibody may be a B7-H1 antibody, a BMS936559 antibody, a MPDL3280A (atezolizumab) antibody, a MEDI-4736 antibody, a MSB0010718C antibody, or a combination thereof. According to another embodiment, the anti-PD-1 antibody may be a nivolumab antibody, a pembrolizumab antibody, a pidilizumab antibody, or a combination thereof.

[0168] Furthermore, PD-1 can also be targeted by AMP-224, a PD-L2-IgG recombinant fusion protein. Additional antagonists of inhibitory pathways in the immune response include IMP321, a soluble LAG-3 Ig fusion protein, and MHC class II agonists used to enhance immune responses against tumors. Lirilumab is an antagonist of KIR receptors, and BMS986016 is an antagonist of LAG3. The TIM-3-galectin-9 pathway is another inhibitory checkpoint pathway that is also a promising target for checkpoint inhibition. RX518 targets and activates the glucocorticoid-inducible tumor necrosis factor receptor (GITR), a member of the TNF receptor superfamily expressed on the surface of multiple types of immune cells, including regulatory T cells, effector T cells, B cells, natural killer (NK) cells, and activated dendritic cells. Thus, in one embodiment, a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, is used in combination with IMP321, lirilumab and / or BMS986016.

[0169] Anti-PD-1 antibodies that may be used in the compositions and methods described herein include nivolumab / MDX-11, a fully human IgG (IgG)4 anti-PD-1 monoclonal antibody. Anti-PD-L1 antibodies that may be used in the compositions and methods described herein include, but are not limited to, avelumab, the fully human IgG4 antibody BMS-936559, the human monoclonal antibody atezolizumab (MPDL3280A / RG-7446), MEDI4736, MSB0010718C, and MDX1105-01.

[0170] In one embodiment, a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is administered to a patient in need thereof in combination with the anti-PD-1 antibodies nivolumab, pembrolizumab, and / or pidilizumab. In one embodiment, the anti-PD-L1 antibody useful for combination treatment with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, is BMS-936559, atezolizumab, or avelumab. In one embodiment, the immunomodulator inhibits an immune checkpoint pathway. In another embodiment, the immune checkpoint pathway is selected from CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and PD-1. Additional antibodies that may be used in combination with a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof, in the compositions and methods described herein include the anti-PD-1 antibodies and anti-PD-L1 antibodies disclosed in U.S. Patent Nos. 8,008,449 and 7,943,743, respectively.

[0171] In one embodiment, the one or more additional therapeutic agents are anti-inflammatory agents. In certain other embodiments, the anti-inflammatory agent is a tumor necrosis factor alpha (TNF-α) inhibitor. As used herein, the terms "TNF alpha," "TNF-α," and "TNFα" are interchangeable. TNF-α is a pro-inflammatory cytokine secreted primarily by macrophages, but also by various other cell types, including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neural tissue. TNF-α is also known as serum endotoxin-inducing factor, cachectin, and differentiation-inducing factor. The tumor necrosis factor (TNF) family includes TNF-alpha, TNF-beta, CD40 ligand (CD40L), Fas ligand (FasL), TNF-related apoptosis-inducing ligand (TRAIL), and LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes), some of the most important cytokines of which have been implicated in the initiation of systemic inflammation, tumor lysis, apoptosis, and the acute phase response, among other physiological processes.

[0172] When used in combination with the compounds disclosed herein, the aforementioned therapeutic agents may be used, for example, in amounts indicated in a reference manual, such as the Physicians' Desk Reference, or in amounts generally known to medical practitioners, i.e., those skilled in the art. In the methods of the present disclosure, such other therapeutic agents may be administered before, simultaneously with, or after the administration of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer or pharmaceutically acceptable salt thereof. Certain other therapeutic agents may be combined into a single formulation or kit, if appropriate. For example, a tablet, capsule, or liquid formulation may be combined with other tablet, capsule, or liquid formulations into a single fixed-dose or combined-dose formulation or regimen. Other combinations may also be given separately, simultaneously, or otherwise. Preparation of compounds

[0173] Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

[0174] The compounds described herein can be purified by any of the methods known in the art, including chromatographic methods such as high performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal phase and reverse phase and ionic resins. Most typically, the disclosed compounds are purified via silica gel and / or alumina chromatography.

[0175] During any of the processes for preparing the compounds of interest, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This is conventionally done as described in standard texts such as T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006. This can be achieved by using a protecting group of the formula: which can be removed at a convenient subsequent stage using methods known in the art. General synthetic scheme Scheme 1: Preparation of optically pure compounds of formula (I) [ka]

[0176] Intermediates A and E can be prepared using the procedures described in WO 2016 / 033486.

[0177] Step 1: Intermediate B can be prepared by treating a solution of A in a suitable solvent such as THF with a suitable base such as sodium hydride, followed by treatment with a suitable alkylating agent such as iodomethane.

[0178] Step 2: Intermediate C can be prepared by treating a solution of B in a suitable solvent, such as DMF, with a suitable base, such as sodium hydride, and then treating the mixture with a suitable alkylating agent, such as iodomethane.

[0179] Step 3: Intermediate D can be prepared by treating intermediate C with a suitable base, such as aqueous NaOH, KOH, or LiOH, in a suitable solvent, such as MeOH, EtOH, or THF, at elevated temperature, preferably 60° C., overnight. After the mixture is cooled, acidified with a suitable acidic agent, such as HCl, concentrated, and filtered, the resulting solid carboxylic acid is dissolved in a suitable solvent, such as CHCl or 1,2-dichloroethane. Addition of a suitable acid chloride-forming agent, such as thionyl chloride or oxalyl chloride, can provide intermediate D, which can be used immediately in the next step.

[0180] Step 4: Intermediate F can be prepared by dissolving intermediate E in a suitable solvent such as THF, DMF or CH2Cl2 and treating with a suitable organic base such as trimethylamine, diisopropylethylamine or imidazole and a suitable silylating agent such as TBDMSCl or TBDMSOTf at a suitable temperature, preferably 0°C.

[0181] Step 5: Intermediate G can be prepared by suspending Ph3PCl2 in a suitable solvent such as CHCl or 1,2-dichloroethane under a N2 atmosphere, adding a suitable organic base such as trimethylamine or diisopropylethylamine, followed by addition of a solution of intermediate F in a suitable solvent such as CHCl or 1,2-dichloroethane, followed by bubbling ammonia gas.

[0182] Step 6: Intermediate H can be prepared by dissolving intermediate D in a suitable polar solvent, such as acetonitrile, adding pyridazine, followed by adding intermediate G in a suitable polar solvent, such as acetonitrile.

[0183] Step 7: Intermediates I-1 and I-2 can be prepared by adding triethylamine and an acid chloride to a solution of intermediate H in a suitable solvent, such as CHCl or 1,2-dichloroethane, under ice-bath cooling. The two stereoisomers can be separated during purification.

[0184] Steps 8 and 9: J-1 and J-2 can be prepared by stirring intermediates I-1 or I-2, respectively, with Hoveyda Grubbs second generation catalyst in a suitable solvent, such as CHCl or 1,2-dichloroethane, at elevated temperature, preferably 60° C. After concentration, the residue can be purified by preparative HPLC or silica gel column chromatography. Scheme 2: Preparation of optically pure compounds of formula (I) [ka]

[0185] J-1 and J-2 can also be prepared from H as shown in Scheme 2. A solution of intermediate H in a suitable solvent, such as CHCl or 1,2-dichloroethane, can be treated with di-tert-butyl dicarbonate in the presence of a suitable base, such as DIPEA or TEA, under ice-bath cooling and stirred at rt overnight. After concentration and purification by silica gel chromatography, the mixture of Boc-protected diastereomers can be treated with Hoveyda Grubbs second-generation catalyst in a suitable solvent, such as CHCl or 1,2-dichloroethane, at elevated temperatures, preferably 60°C. After concentration, the mixture of diastereomers L can be acylated with a suitable acylating agent, such as an acid chloride and an organic base, or a carboxylic acid, EDCI, and an organic base. Scheme 3: Preparation of optically pure compounds of formula (I)

[0186] J-1 and J-2 can also be separated by either silica gel column chromatography or chiral HPLC after acylation of intermediate H and macrocyclization of intermediate I with Hoveyda Grubbs second generation catalyst. [ka] Scheme 4: Preparation of optically pure compounds of formula (I) [ka]

[0187] Step 1: Intermediates K-1 and K-2 can be prepared by adding triethylamine and di-tert-butyl dicarbonate to a solution of intermediate H in a suitable solvent, such as CHCl or 1,2-dichloroethane, under ice-bath cooling and stirring the mixture at rt overnight. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography to separate the diastereomers.

[0188] Steps 2 and 3: J-1 and J-2 can be prepared by stirring intermediate K-1 or K-2 and Hoveyda Grubbs second generation catalyst in a suitable solvent, such as CHCl or 1,2-dichloroethane, at elevated temperature, preferably 60° C. After concentrating the reaction mixture and purifying the residue by preparative HPLC, a suitable acylating agent, such as an acid chloride and an organic base, or a carboxylic acid, EDCI, and an organic base, is added to acylate intermediate L-1 or L-2, which can be purified by preparative HPLC or silica gel column chromatography to give J-1 or J-2. Scheme 5: Preparation of optically pure compounds of formula (I)

[0189] Intermediates L-1 and L-2 can be Boc-protected and macrocyclized with Hoveyda Grubbs second-generation catalyst, separated by either silica gel column chromatography or chiral HPLC, and then acylated to provide J-1 and J-2, respectively. [ka] Scheme 6: Preparation of optically pure compounds of formula (I) [ka]

[0190] N-1 and N-2 can be prepared from L as shown in Scheme 6 and separated by either silica gel column chromatography or chiral HPLC after acylation and macrocyclization with the Hoveyda Grubbs second generation catalyst. Schemes 7 and 8: -C(O)R 1 -C(O)NHR 8 Preparation of a compound of formula (I) [ka]

[0191] M-2 can be prepared from L-2 by adding triethylamine and a substituted isocyanate in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane, under ice bath cooling.

[0192] Alternatively, the two stereoisomers M-1 and M-2 can be separated by treating L-2 with a substituted isocyanate in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane, in the presence of a suitable base, such as triethylamine, followed by either silica gel column chromatography or chiral HPLC. [ka] Scheme 9: -C(O)R 1 -C(O)NR8 R 9 Preparation of a compound of formula (I) [ka]

[0193] M-3 can be prepared by treating L-2 with diphenyl carbonate followed by treatment with an appropriate amine (Scheme 9). Schemes 10, 11, and 12:-C(O)R 1 -C(O)OR 7 Preparation of a compound of formula (I)

[0194] O-2 can be prepared by treating L-2 with an appropriate chlorocarbonate and a suitable base, such as trimethylamine, in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane. [ka] [ka]

[0195] Alternatively, O-2 can be prepared by treating L-2 with diphenyl carbonate followed by treatment with an appropriate alcohol.

[0196] Alternatively, the two stereoisomers can be separated by treating the diastereomeric mixture L with diphenyl carbonate followed by treatment with an appropriate alcohol as a nucleophile or with a substituted chloroformate under ice-bath cooling, followed by either silica gel column chromatography or chiral HPLC to give O-2 (Scheme 12). [ka] [Example]

[0197] Exemplary chemical entities of the present disclosure are provided in the specific examples below. Those skilled in the art will recognize that to obtain the various compounds herein, starting materials can be appropriately selected so that the ultimately desired substituents are maintained throughout the reaction scheme, with or without appropriate protection, to give the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is maintained throughout the reaction scheme and can be replaced with the desired substituent as appropriate. Furthermore, those skilled in the art will recognize that the transformations shown in the schemes below can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0198] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds.It should be understood that the individual steps described herein may be combined.It should also be understood that separate batches of compounds may be combined and then carried forward to the next synthetic step.

[0199] In the following description of examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made, without departing from the scope of the present disclosure. Therefore, the following description is not intended to limit the scope of the present disclosure. Example 1 [ka]

[0200] Step 1: Preparation of methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate (1-1): (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl) in THF (10 mL) To a stirred solution of 1.02 g (2.18 mmol) of 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (prepared according to the procedure described in International Patent Application No. WO 2016 / 033486) was added sodium hydride (60% in mineral oil, 183.1 mg, 4.57 mmol) in an ice bath, followed by the addition of iodomethane (618.7 mg, 4.359 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then poured into ice-cold HO and extracted with CHCl. The organic layer was concentrated and purified by silica gel column (EtOAc / hexane=2 / 3) to give methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate. LCMS-ESI+: (m / z): C 28 H 32 Calculated [M+H]+ for ClNO4: 482.0; found: 482.2.

[0201] Step 2: Preparation of methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate (1-2): Dissolve methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxycyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate in DMF (8 mL). To a stirred solution of (hydroxyallyl)cyclobutyl)methyl-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate (707.0 mg, 1.4 mmol), sodium hydride (60% in mineral oil, 88.0 mg, 2.2 mmol) was added in an ice bath, followed by the addition of iodomethane (312.3 mg, 2.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then poured into ice-cold HO and extracted with CHCl. The organic layer was concentrated and purified by silica gel column (EtOAc / hexane=1 / 4) to give methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate. LCMS-ESI+: (m / z): C 29 H 34 Calculated [M+H]+ for ClNO4: 496.0; Found: 496.2.

[0202] Step 3: Preparation of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl chloride (1-3): Methyl (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (659.0 mg, 1.33 mmol) was stirred in 2 N aqueous NaOH (3 mL) and MeOH (8 mL) at 60° C. overnight. After cooling, the mixture was acidified with HCl and concentrated. The resulting solid was treated with CHCl and filtered. The filtrate was concentrated, and 174.5 mg (0.36 mmol) was dissolved in CHCl (6 mL). Thionyl chloride (1.5 mL) was added to the solution in an ice bath. The resulting mixture was stirred at room temperature for 2 hours and concentrated. The crude (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl chloride was used directly in the next step.

[0203] Step 4: Preparation of (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide (1-4): To a stirred solution of (2R,3S)-3-methylhex-5-ene-2-sulfonamide (2.00 g, 11.28 mmol) in THF (16 mL), triethylamine (3.15 mL, 22.57 mmol) was added in an ice bath, followed by the slow addition of TBDMSCl (2.13 g, 14.10 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 2 days. The precipitate was filtered and washed with ether. The filtrate was concentrated and purified on a silica gel column (EtOAc / hexane = 1 / 4) to give (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide. 1H NMR (400 MHz, chloroform-d) δ 5.76 - 5.67 (m, 1H), 5.08 - 5.02 (m, 2H), 3.95 (s, 1H), 3.95 - 2.97 (m, 1H), 2.44 - 2.41 (m, 1H), 2.14 - 2.08 (m, 1H), 2.02 - 1.96 (m, 1H), 1.27 (d, J = 8.0 Hz, 3H), 1.02 (d, J = 8.0 Hz, 3H), 0.94 (m, 9H), 0.27 - 0.26 (m, 6H).

[0204] Step 5: Preparation of (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimideamide (1-5): To a stirred suspension of PhPCl (754.33 mg, 2.264 mmol) in CHCl (4.0 mL) under a N atmosphere, trimethylamine (0.43 mL, 3.087 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then cooled to 0 °C, and a solution of (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide (600.00 mg, 2.058 mmol) in CHCl (4 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. Ammonia gas was bubbled through the reaction mixture. The reaction vessel was sealed and stirred at 0 °C for 2 hours. The resulting precipitate was filtered and washed with CH2Cl2. The filtrate was concentrated and purified by silica gel column (EtOAc / hexane = 1 / 4) to give (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimideamide (1-5). 1 H NMR (400 MHz, chloroform) Lum-d) δ 5.80 - 5.69 (m, 1H), 5.08 - 5.02 (m, 2H), 4.17 (w, 2H), 3.06 - 2.98 (m, 1H), 2.54 - 2.46 (m, 1H), 2.11 - 1.95 (m, 2H), 1.29 - 1.26 (m, 3H), 1.01 - 0.98 (m, 3H), 0.92 - 0.88 (m, 9H), 0.13 - 0.11 (m, 6H).

[0205] Step 6: Preparation of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (1-6): (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl) in acetonitrile (2.0 mL) To a stirred solution of (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimidamide (126.00 mg, 0.434 mmol) in acetonitrile (2 mL) was added pyridazine (0.03 mL, 0.362 mmol). The resulting mixture was stirred at room temperature for 3 hours. After concentration, the residue was purified by silica gel column (EtOAc / hexane=2 / 3) to give (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide. 1H NMR (400 MHz, クロロホルム-d) δ 7.70 (d, J = 11.6 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.80 - 5.49 (m, 2H), 5.18 - 5.02 (m, 4H), 4.15 (dd, J = 12.0, 5.2 Hz, 1H), 4.05 (dd, J = 12.0, 4.4 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.49 - 3.28 (m, 3H), 3.25 - 3.24 (m, 3H), 2.81 - 2.45 (m, 5H), 2.15 - 1.52 (m, 10H), 1.40 (dd, J = 12.8, 6.8 Hz, 3H), 1.09 (dd, J = 28.4, 6.8 Hz, 3H). LCMS-ESI+: (m / z): [M+H]+ C 35 H 46 ClN3O4S calculated value: 640.3; measured value: 640.3.

[0206] Step 7: Preparation of 1-7 and 1-8: To a stirred solution of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (30.00 mg, 0.047 mmol) in CHCl (4.0 mL), triethylamine (0.01 mL, 0.07 mmol) was added in an ice bath, followed by propionyl chloride (5.20 mg, 0.056 mmol). The resulting mixture was stirred at room temperature for 2 h. After concentration, the residue was purified by preparative HPLC (Phenomenex Luna 5 μm C18(2), 150 × 21.2 mm, 50% to 90–95% acetonitrile / water containing 0.1% trifluoroacetic acid, 15 mL / min, used throughout this experimental section unless otherwise noted) to give 1-7 (more polar fraction) and 1-8 (less polar fraction). LCMS-ESI+: (m / z): C 38 H 50 Calculated [M+H]+ for ClN3O5S: 696.3; found: 696.3.

[0207] Step 8: Preparation of Example 1: The single diastereomer 1-7 from Step 7 (11.0 mg, 0.016 mmol) and Hoveyda Grubbs second generation catalyst (2.0 mg, 0.003 mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60° C. for 4 hours. After concentration, the residue was purified by preparative HPLC to give Example 1. 1 H NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.2, 1.8 Hz, 1H), 7.19–7.16 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.86 - 5.80 (m, 1H), 5.69 (dd, J = 15.8, 7.4 Hz, 1H), 4.30 - 4.26 (m, 1H), 4.05 (dd, J = 22.8, 12.0 Hz, 2H), 3.80 - 3.72 (m, 3H), 3.37 (d, J = 14.4 Hz, 1H), 3.27 (s, 3H), 3.06 (dd, J = 14.8, 10.8 Hz, 1H), 2.85 - 2.75 (m, 3H), 2.58 - 1.68 (m, 14H), 1.42 (d, J = 6.8 Hz, 3H), 1.15 (t, J = 7.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). LCMS-ESI+: (m / z): [M+H]+ C 36 H 46 Calculated for ClN3O5S: 668.3; Found: 668.3. Example 2 [ka]

[0208] Example 2 was synthesized in the same manner as Example 1 (Step 8), using diastereomer 1-8 instead of 1-7. 1 H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.99 - 5.92 (m, 1H), 5.50 (dd, J = 15.2, 8.8 Hz, 1H), 4.47 (w, 1H), 4.13 - 4.04 (m, 2H), 3.82 (d, J = 15.2 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.31 - 3.24 (m, 1H), 3.22 (s, 3H), 2.99 (dd, J = 15.2, 10.0 Hz, 1H), 2.80 - 2.70 (m, 3H), 2.49 - 1.64 (m, 13H), 1.54 (d, J = 6.8 Hz, 3H), 1.42 - 1.36 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 46 Calculated for ClN3O5S: 668.3; Found: 668.3. Examples 3 and 4 [ka]

[0209] Step 1: Preparation of N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide: N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide was prepared in the same manner as Example 1 (Steps 4 and 5) using pent-4-ene-1-sulfonamide instead of (2R,3S)-3-methylhex-5-ene-2-sulfonamide. 1 H NMR (400 MHz, chloro Holm-d) δ 5.78 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.09 - 5.01 (m, 2H), 3.13 - 3.05 (m, 2H), 2.22 - 2.16 (m, 2H), 1.98 - 1.90 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).

[0210] Step 2: Preparation of (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide: N'-(tert-butyldimethylsilyl ) Pent-4-ene-1-sulfonimide amide was treated with (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl chloride in the presence of pyridazine in a manner similar to that in Example 1 (Step 6) to provide the title compound.

[0211] Step 3: Preparation of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide: (3S)-N-(amino(oxo)(pent-4-en-1-yl)propionamido)-16-sulfanylidene in CHCl (5.0 mL) To a stirred solution of 2-(((1R,2R)-1,6-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (66 mg, 0.11 mmol) was added triethylamine (0.02 mL, 0.162 mmol) in an ice bath, followed by the addition of propionyl chloride (11.97 mg, 0.129 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to give (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide.

[0212] Step 4: Preparation of Example 3 and Example 4: (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (55.0 mg, 0.082 mmol) and Hoveyda Grubbs 2nd generation catalyst (5.14 mg, 0.008 mmol) were stirred in 1,2-dichloroethane (16.0 mL) at 60°C for 4 hours. After concentration, the residue was purified by preparative HPLC to give Example 3 (more polar fraction) (LCMS-ESI+(m / z): C 34 H 42 Calculated [M+H] for ClN3O5S: 640.2; Found: 640.2) and Example 4 (less polar fraction) ( 1 H NMR (400 MHz, chloroform-d) δ 7.68 (d, J = 9.2 Hz, 1H), 7.37 - 7.35 (m, 1H), 7.23 (s, 1H), 7.08 - 7.06 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 5.86 - 5.82 (m, 1H), 5.74 - 5.70 (m, 1H), 4.06 (d, J = 12.0 Hz, 1H), 3.99 - 3.95 (m, 2H), 3.81 - 3.71 (m, 4H), 3.59 - 3.57 (m, 1H), 3.34 (d, J = 14.8 Hz, 1H), 3.29 (s, 3H), 3.04 - 2.98 (m, 1H), 2.78 - 2.73 (m, 4H), 2.50 (q, J = 7.4 Hz, 2H), 2.38 - 1.66 (m, 10H), 1.39 - 1.34 (m, 1H), 1.22 (t, J = 7.4 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 34 H 42Calculated for ClN3O5S: 640.2; Found: 640.2). Examples 5 and 6 [ka] Method 1:

[0213] Step 1: tert-butyl ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate and tert-butyl (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate Preparation of (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (Example 3 / 4, Step 2, 32.00 mg, 0.052 mmol) in CHCl (5.0 mL) was added triethylamine (0.02 mL, 0.105 mmol) in an ice bath, followed by di-tert-butyl dicarbonate (17.11 mg, 0.078 mmol). The resulting mixture was stirred at room temperature overnight.After concentration, the residue was purified by preparative HPLC to give tert-butyl((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl from the more polar fractions. The less polar fractions gave tert-butyl (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate.

[0214] Step 2: Preparation of Example 5: tert-butyl (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate (14 mg, 0.02 mmol) and Hoveyda Grubbs 2nd generation catalyst (1.25 mg, 0.002 mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60°C for 4 hours. After concentration, the residue was purified by preparative HPLC to give Example 5. LCMS-ESI+ (m / z): C 31 H 38 Calculated [M+H]+ for ClN3O4S: 584.2; found: 584.2.

[0215] Step 3: Preparation of Example 6: Example 6 was synthesized in the same manner as Example 5 using tert-butyl ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate. LCMS-ESI+(m / z): C 31 H 38 Calculated [M+H]+ for ClN3O4S: 584.2; found: 584.2. Method 2: [ka]

[0216] Step 1: Preparation of tert-butyl ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate: (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-sulfonimidoyl)carbamate in CHCl (5.0 mL). To a stirred solution of (((1R,2R)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide (140.00 mg, 0.229 mmol), triethylamine (0.06 mL, 0.458 mmol) was added in an ice bath, followed by di-tert-butyl dicarbonate (74.97 mg, 0.343 mmol). The resulting mixture was stirred at room temperature overnight. After concentration, the residue was purified by preparative HPLC to give tert-butyl ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate as a mixture of diastereomers.

[0217] Step 2 and Step 3: The Boc-protected mixture of diastereomers from Step 1 of Method 2 (112.0 mg, 0.157 mmol) and Hoveyda Grubbs second-generation catalyst (9.83 mg, 0.016 mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60° C. for 4 hours. After concentration, the residue was purified by preparative HPLC to give Intermediate 5-1 as a mixture of diastereomers, which was purified by silica gel column chromatography (EtOAc / hexane=3 / 2) to give Example 5 (less polar fraction) and Example 6 (more polar fraction). Method 3: [ka]

[0218] Step 1: Preparation of (S)-4-nitrophenyl(1-phenylethyl)carbonate (5-3-1): A mixture of (1S)-1-(4-phenylphenyl)ethanol (8.7 g, 71.2 mmol) was dissolved in MeTHF (90 mL) and cooled to 0 °C. To this cold, stirred solution, pyridine (7.1 mL) was added. A solution of 4-nitrophenylchloroformate (14.4 g, 71.2 mmol) in MeTHF (60.0 mL) was then added dropwise via a dropping funnel. After the addition, the resulting mixture was removed from the cooling bath and stirred at ambient temperature for 2 hours. TLC showed that (1S)-1-(4-phenylphenyl)ethanol had been consumed, but 4-nitrophenylchloroformate still remained. Additional (1S)-1-(4-phenylphenyl)ethanol (2.6 g, 21.3 mmol) and pyridine (1.0 mL) were added, and stirring was continued overnight. The reaction was then washed with 1N HCl (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated. The residue was then dissolved in DCM, mixed with silica gel, concentrated to dryness, and purified in two portions by normal phase chromatography (silica gel, 0–20% EtOAc / hexanes). The desired fractions were combined and concentrated to give 5-3-1. 1H NMR (400 MHz, chloroform-d) δ 8.34–8.16 (m, 2H), 7.48–7.31 (m, 7H), 5.84 (q, J = 6.6 Hz, 1H), 1.70 (d, J = 6.6 Hz, 3H).

[0219] Step 2: A solution of N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide (2.0 g, 7.18 mmol) in THF (100 mL) was cooled to -50 °C. 1.6 M n-BuLi in hexanes (9.65 mL, 15.4 mmol) was added dropwise to this cold solution. The newly formed mixture was stirred at -50 °C for 20 min, after which a solution of (4-nitrophenyl)[(1S)-1-phenylethyl]carbonate in THF (60 mL) was added dropwise slowly. The resulting mixture was stirred at -50 °C for 15 min, then switched to an ice-water bath and stirred at 0 °C for 3 h. The reaction was quenched with ice and extracted with EtOAc (1x). The organic layer was washed with 1N NaOH (3x), brine (1x), dried over sodium sulfate, filtered, concentrated, and purified by normal-phase chromatography (silica gel, 0-20% EtOAc / hexanes). The purification was repeated, and the desired fractions were combined and concentrated to give a mixture of diastereomers (5-3-2) and (5-3-3). The mixture of diastereomers was then separated into single diastereomers by chiral SFC. The first eluting peak was assigned the chirality shown for (5-3-2), and the second eluting peak was assigned the chirality shown for (5-3-3). 1 H NMR (400 MHz, chloroform-d), for a mixture of diastereomers: δ 7.41 - 7.29 (m, 5H), 5.84 - 5.59 (m, 2H), 5.08 - 4.93 (m, 2H), 3.37 - 3.16 (m, 2H), 2.19 - 2.07 (m, 2H), 1.83 (h, J = 7.3, 6.7 Hz, 2H), 1.57 (dq, J = 6.6, 1.8 Hz, 3H), 0.91 - 0.85 (m, 9H), 0.18 ( 2 sets of s, 3H), 0.12 (2 sets of s, 3H). 1H NMR (400 MHz, chloroform-d) for (5-3-2): δ 7.39 - 7.30 (m, 5H), 5.86 - 5.58 (m, 2H), 5.07 - 4.93 (m, 2H), 3.28 (tq, J = 13.9, 7.9, 7.1 Hz, 2H), 2.13 (p, J = 7.7, 7.2 Hz, 2H), 1.85 (p, J = 7.2 Hz, 2H), 1.57 (dd, J = 6.6, 2.2 Hz, 3H), 0.93 - 0.91 (m, 9H), 0.19 (2 sets of s, 6H).

[0220] Step 3: A solution of intermediate (5-3-2) (858 mg, 2.1 mmol) in THF (24 mL) was treated with 1.0 M tetrabutylammonium fluoride in THF (6.3 mL, 6.3 mmol) at room temperature for 60 min. The reaction was then concentrated and purified by normal phase chromatography (silica gel, 0-80% EtOAc / hexanes) to give 5-3-3A. 1H NMR (400 MHz, chloroform-d) δ 7.45 - 7.31 (m, 4H), 5.83 - 5.59 (m, 2H), 5.12 - 4.96 (m, 2H), 3.35 - 3.21 (m, 2H), 2.28 - 2.11 (m, 2H), 2.01 - 1.87 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H).

[0221] Step 4: To a mixture of (3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1'-tetralin]-7-carbonyl chloride (215 mg, 0.45 mmol) in DCM (20 mL) at 0 °C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (152 mg, 0.98 mmol) was added, followed by 4-(dimethylamino)pyridine (120 mg, 0.98 mmol). After stirring for 5 min, a solution of intermediate (5-3-3A) (159 mg, 0.54 mmol) in DCM (3 mL) was added, and the resulting mixture was removed from the cooling bath and stirred at room temperature overnight. The reaction was further diluted with DCM (30 mL), washed with 1 N HCl (15 mL), saturated sodium bicarbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography (silica gel column, 0-80% EtOAc / hexanes) to give intermediate 5-3-4. LCMS-ESI+ (m / z): [M+H]+ calculated: 761.0, found: 759.9. 1 H NMR (400 MHz, chloroform-d) δ 7.67 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.39–7.28 (m, 6H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (p, J = 6.3 Hz, 1H), 5.77 - 5.48 (m, 2H), 5.21 - 5.08 (m, 2H), 5.08 - 4.96 (m, 2H), 4.14 - 4.04 (m, 2H), 3.81 - 3.71 (m, 2H), 3.70 - 3.48 (m, 3H), 3.39 - 3.13 (m, 5H), 2.84 - 2.69 (m, 2H), 2.52 (dd, J = 10.7, 7.4 Hz, 1H), 2.16 (dt, J = 13.3, 7.6 Hz, 3H), 2.01 - 1.74 (m, 7H), 1.70 - 1.39 (m, 7H).

[0222] Step 5: A solution of intermediate 5-3-4 in DCE (10 mL) was sparged with nitrogen for 5 minutes, after which Hoveyda-Grubbs second-generation catalyst (7 mg, 0.011 mmol) was added. The newly formed mixture was degassed for an additional 2 minutes, then capped and heated at 60 °C for 16 hours. The reaction was then cooled to room temperature, concentrated, and purified by normal phase chromatography (silica gel, 0-5% DCM / MeOH (containing 2.0 N NH)) to give Example 5 (first eluting peak: LCMS-ESI+ (m / z): [M+H]+ calculated: 584.2; found: 583.4); and carbamate-protected macrocyclic intermediate 5-3-5 (second eluting peak: LCMS-ESI+ (m / z): [M+H]+ calculated: 732.3; found: 730.8).

[0223] Step 6: Intermediate 5-3-5 (15.8 mg, 0.022 mmol) was dissolved in DCM (1.0 mL) at 0 °C. TFA (1.0 mL) was added to the cold solution. The resulting mixture was stirred at 0 °C for 2 minutes, then at room temperature for 1 hour. The reaction was cooled back to 0 °C and basified with 1 N NaOH to pH ∼8. The mixture was extracted with DCM (2x). The combined organic layers were washed with brine (1x), dried over sodium sulfate, filtered, concentrated, and purified by Combiflash (silica gel, 0-100% EtOAc / hexanes) to give Example 5. LCMS-ESI+ (m / z): [M+H]+ calculated: 584.2; found: 583.3. 1 H NMR (400 MHz, chloroform-d) for 8: δ 7.73 (d, J = 8.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.04 - 5.93 (m, 1H), 5.73 - 5.61 (m, 1H), 4.12 - 3.94 (m, 2H), 3.88 - 3.68 (m, 2H), 3.62 - 3.51 (m, 2H). 3.40 - 3.17 (m, 6H), 3.00 (dd, J = 15.0, 11.0 Hz, 1H), 2.82 - 2.63 (m, 4H), 2.47 - 2.20 (m, 4H), 1.99 - 1.59 (m, 6H), 1.37 (t, J = 13.1 Hz, 1H).

[0224] Example 6 was synthesized in the same manner as Example 5 (Method 3 - Steps 3-6), using intermediate 5-3-3 instead of intermediate 5-3-2. Examples 7 and 8 [ka]

[0225] Examples 7 and 8 were prepared in a similar manner to Examples 3 and 4, using 2-methoxyacetyl chloride in place of propionyl chloride.

[0226] Example 7: LCMS-ESI+(m / z):C 34 H 42 Calculated [M+H]+ for ClN3O6S: 656.2; found: 656.2.

[0227] Example 8: LCMS-ESI+(m / z):C 34 H 42 Calculated [M+H]+ for ClN3O6S: 656.2; found: 656.2. Examples 9 and 10 [ka]

[0228] Preparation of Example 9 and Example 10: To a stirred solution of Intermediate 5-1 (Example 5 / 6 Method 2, 10.40 mg, 0.018 mmol) in CHCl (5.0 mL), triethylamine (0.004 mL, 0.027 mmol) was added in an ice bath, followed by the addition of ethyl chloroformate (2.32 mg, 0.021 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to give Example 9 (more polar fraction) (LCMS-ESI+ (m / z): C 34 H 42 [M+H]+ calculated for ClN3O6S: 656.2; found: 656.2) and Example 10 (less polar fractions). Examples 11 and 12 [ka]

[0229] Step 1: Preparation of intermediate 11-1: To a stirred solution of intermediate 5-1 (Example 5 / 6 Method 2, 17.90 mg, 0.031 mmol) in EtOAc (5 mL) was added platinum(IV) oxide (3.48 mg, 0.015 mmol). The resulting mixture was stirred under H2 at room temperature for 0.5 h. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated. The crude product (18.0 mg) was used directly in the next step.

[0230] Step 2: Preparation of Example 11 and Example 12: To a stirred solution of intermediate 11-1 (18.0 mg, 0.031 mmol) in CHCl (4.0 mL), triethylamine (0.006 mL, 0.046 mmol) was added in an ice bath, followed by propionyl chloride (3.41 mg, 0.037 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to give Example 11 (more polar fraction) (LCMS-ESI+ (m / z): C 34 H 44 [M+H]+ calculated for ClN3O5S: 642.3; found: 642.2) and Example 12 (less polar fractions) (LCMS-ESI+ (m / z): C 34 H 44 [M+H]+ calculated for ClN3O5S: 642.3; found: 642.3) was obtained. Examples 13 and 14 [ka]

[0231] Preparation of Example 13 and Example 14: To a stirred solution of intermediate 5-1 (Examples 5 and 6, Method 2, 10.9 mg, 0.019 mmol) in CHCl (4.0 mL) was added triethylamine (0.004 mL, 0.028 mmol) in an ice bath, followed by ethyl isocyanate (1.59 mg, 0.022 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC followed by preparative TLC (5% MeOH / CHCl) to give Example 13 (more polar fraction) (LCMS-ESI+ (m / z): C 34H 43 Calculated [M+H] for ClN4O5S: 655.3; Found: 655.2), and Example 14 (less polar fraction) ( 1 H NMR (400 MHz, chloroform-d) δ 7.71 (w, 1H), 7.31 (w, 1H), 7.16 (w, 2H), 7.02 (w, 1H), 6.78 (w, 1H), 5.76 (w, 2H), 4.02 - 3.94 (m, 2H), 3.72 - 2.65 (m, 11H), 2.34 - 0.84 (m, 17H). LCMS-ESI+ (m / z): [M+H]+ C 34 H 43 The calculated value for ClN4O5S was 655.3; the found value was 655.2. Example 15 [ka]

[0232] To a stirred solution of 3-(dimethylamino)propionic acid hydrochloride (3.94 mg, 0.026 mmol) in CHCl (3 mL) was added EtN (0.01 mL, 0.068 mmol), EDCI (5.32 mg, 0.034 mmol), and DMAP (4.18 mg, 0.034 mmol), followed by Intermediate 5-1 (Example 5 / 6 Method 2, 10.00 mg, 0.017 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by preparative HPLC to give Example 15. LCMS-ESI+ (m / z): C 36 H 47 Calculated [M+H]+ for ClN4O5S: 683.3; found: 683.3. Examples 16 and 17 [ka]

[0233] Step 1: Preparation of intermediate 16-1: To a stirred solution of intermediate 5-1 (Example 5 / 6 Method 2, 20.00 mg, 0.034 mmol) in MeOH (5 mL), Pd / C (10 wt%, 0.36 mg, 0.03 mmol) was added. The resulting mixture was stirred under H2 at room temperature for 1.5 hours. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated. The crude product was used directly in the next step.

[0234] Step 2: Preparation of Example 16 and Example 17: The crude intermediate 16-1 from Step 1 was then coupled with propionyl chloride and purified in a similar manner to Examples 11 and 12 to give Example 16 (less polar fraction) (LCMS-ESI+(m / z): C 34 H 45 [M+H]+ calculated for N3O5S: 607.8; found: 608.3) and Example 17 (more polar fractions) (LCMS-ESI+ (m / z): C 34 H 45 The calculated [M+H]+ for N3O5S was 607.8; the found value was 608.4. Example 18 [ka]

[0235] To a stirred solution of 3-methoxypropionic acid (2.3 mg, 0.022 mmol) in CHCl (2 mL) was added EDCI (4.52 mg, 0.029 mmol) and DMAP (3.56 mg, 0.029 mmol), followed by Example 5 (8.50 mg, 0.015 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by preparative HPLC to give Example 18. 1 H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.29 - 7.28 (m, 1H), 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.88 (dt, J = 15.8, 5.0 Hz, 1H), 5.75 (dd, J = 15.8, 7.8 Hz, 1H), 4.05 (dd, J = 32.4, 12.0 Hz, 2H), 3.95 - 3.73 (m, 6H), 3.60 (dd, J = 8.0, 3.2 Hz, 1H), 3.46 (s, 3H), 3.37 (d, J = 14.4 Hz, 1H), 3.32 (s, 3H), 3.04 (dd, J = LCMS-ESI+ (m / z): [M+H]+ C 35 H 44 Calculated for ClN3O6S: 670.3; Found: 670.4. Example 19 [ka]

[0236] To a stirred solution of Example 5 (8.5 mg, 0.015 mmol) in CHCl (2.0 mL) was added triethylamine (0.003 mL, 0.022 mmol) in an ice bath, followed by isopropyl isocyanate (1.86 mg, 0.022 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC followed by preparative TLC (5% MeOH / CHCl) to give Example 19. LCMS-ESI+ (m / z): C 35 H 45 Calculated [M+H]+ for ClN4O5S: 669.3; found: 691.3. Example 20 [ka]

[0237] Example 20 was synthesized in the same manner as Example 18, using 2-(pyrazin-2-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 37 H 42 Calculated [M+H]+ for ClN5O5S: 704.3; found: 704.4. Example 21 [ka]

[0238] To a stirred solution of Example 5 (10.0 mg, 0.017 mmol) in CHCl (2.0 mL) was added triethylamine (0.004 mL, 0.026 mmol) in an ice bath, followed by cyclopropylacetyl chloride (3.04 mg, 0.026 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to give Example 21. LCMS-ESI+ (m / z): C 36 H 44 Calculated [M+H]+ for ClN3O5S: 666.3; found: 666.3. Example 22 [ka]

[0239] Example 22 was synthesized in the same manner as Example 18, using 3-(1-methyl-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.04 (d, J = 2.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.64 - 6.61 (m, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.82 (d, J = 4.8 Hz, 2H), 3.99 - 3.94 (m, 6H), 3.70 - 3.56 (m, 4H), 3.45 - 3.28 (m, 4H), 3.11 - 2.98 (m, 4H), 2.87 - 2.72 (m, 4H), 2.58 - 1.75 (m, 12H), 1.32 - 1.26 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.3; Found: 720.4. Example 23 [ka]

[0240] Example 23 was synthesized in the same manner as Example 21, using 3,3,3-trifluoropropionyl chloride instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): C 34 H 39 Calculated [M+H]+ for ClF3N3O5S: 694.2; found: 694.4. Example 24 [ka]

[0241] Example 24 was synthesized in the same manner as Example 18, using oxetane-3-carboxylic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 - 7.14 (m, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.06 (dt, J = 15.4, 6.2 Hz, 1H), 5.60 (dd, J = 15.6, 8.8 Hz, 1H), 4.90 - 4.76 (m, 4H), 4.17 - 3.93 (m, 4H), 3.91 - 3.79 (m, 3H), 3.72 - 3.47 (m, 5H), 3.24 (s, 3H), 3.02 (dd, J = 15.0, 10.6 Hz, 1H), 2.83 - 2.69 (m, 2H), 2.65 - 1.37 (m, 11H).LCMS-ESI+ (m / z): [M+H]+ C 35 H 42 Calculated for ClN3O6S: 668.3; Found: 668.6. Example 25 [ka]

[0242] Example 25 was synthesized in the same manner as Example 21, using acetyl chloride instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): C 33 H 40 Calculated [M+H]+ for ClN3O5S: 626.2; found: 626.4. Example 26 [ka]

[0243] Example 26 was synthesized in the same manner as Example 21, using isovaleryl chloride instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): C 36 H 46 Calculated [M+H]+ for ClN3O5S: 668.3; found: 668.4. Example 27 [ka]

[0244] Example 27 was synthesized in the same manner as Example 21, using cyclopropylacetyl chloride instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): C 35 H 42 Calculated [M+H]+ for ClN3O5S: 652.3; found: 652.4. Example 28 [ka]

[0245] Example 28 was synthesized in the same manner as Example 18, using 3-(methylsulfonyl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 35 H 44 Calculated [M+H]+ for ClN3O7S2: 718.3; found: 718.3. Example 29 [ka]

[0246] Example 29 was synthesized in the same manner as Example 18, using 2-(1-methyl-1H-pyrazol-5-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 37 H 44 Calculated [M+H]+ for ClN5O5S: 706.3; found: 706.4. Example 30 [ka]

[0247] Example 30 was synthesized in the same manner as Example 18, using 2-(pyrimidin-2-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 37 H 42Calculated [M+H]+ for ClN5O5S: 704.3; found: 704.3. Example 31 [ka]

[0248] Example 31 was synthesized in the same manner as Example 21, using cyclobutanecarboxylic acid chloride instead of cyclopropylacetyl chloride. 1 H NMR (400 MHz, methanol Le-d4) δ 7.78 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.10 (dt, J = 15.6, 6.4 Hz, 1H), 5.60 (dd, J = 15.6, 8.8 Hz, 1H), 4.25 - 4.13 (m, 1H), 4.03 (dd, J = 21.6, 12.0 Hz, 3H), 3.94 - 3.85 (m, 2H), 3.74 - 3.66 (m, 2H), 3.35 - 3.30 (m, 2H), 3.27 (s, 3H), 3.22 0 3.14 (m, 1H), 3.04 (dd, J = 15.2, 10.4 Hz, 1H), 2.86 - 2.72 (m, 2H), 2.39 - 1.72 (m, 17H), 1.46 - 1.40 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 44 Calculated for ClN3O5S: 666.3; Found: 666.4. Example 32 [ka]

[0249] Example 32 was synthesized in the same manner as Example 19, using 1-isocyanato-1-(trifluoromethyl)cyclopropane instead of isopropyl isocyanate. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.08 - 6.02 (m, 1H), 5.62 - 5.56 (m, 1H), 3.99 (dd, J = 21.8, 12.2 Hz, 3H), 3.83 - 3.76 (m, 2H), 3.67 - 3.64 (m, 3H), 3.34 - 3.30 (m, 2H), 3.24 (s, 3H), 3.07 - 3.00 (m, 1H), 2.83 - 2.69 (m, 2H), 2.53 - 1.68 (m, 11H), 1.44 - 1.37 (m, 1H), 1.22 - 1.04 (m, 4H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 42 Calculated for ClF3N4O5S: 735.3; Found: 735.3. Example 33 [ka]

[0250] Example 33 was synthesized in the same manner as Example 18, using 2-butynoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 35 H 40 Calculated [M+H]+ for ClN3O5S: 650.2; found: 650.3. Example 34 [ka]

[0251] Example 34 was synthesized in the same manner as Example 19, using 1,1,1-trifluoro-2-isocyanato-2-methylpropane instead of isopropyl isocyanate. LCMS-ESI+(m / z): C 36 H 44 Calculated [M+H]+ for ClF3N4O5S: 737.3; found: 737.3. Example 35 [ka]

[0252] Example 35 was synthesized in the same manner as Example 18, using 3-(pyrazin-2-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol Le-d4) δ 8.58 (s, 1H), 8.53 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.24 - 7.18 (m, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.92 - 5.80 (m, 2H), 4.11 - 3.94 (m, 3H), 3.83 - 3.68 (m, 3H), 3.60 - 3.41 (m, 3H), 3.27 (s, 3H), 3.21 - 3.10 (m, 3H), 2.94 (t, J = 7.0 Hz, 2H), 2.85 - 2.78 (m, 4H), 2.48 - 1.80 (m, 10H), 1.45 (t, J = 12.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 44 Calculated for ClN5O5S: 718.3; Found: 718.3. Example 36 [ka]

[0253] Example 36 was synthesized in the same manner as Example 18, using 4,4-dimethylpent-2-ynoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 38 H 46 Calculated [M+H]+ for ClN3O5S: 692.3; found: 692.3. Example 37 [ka]

[0254] Example 37 was synthesized in the same manner as Example 19, using 4-fluorobenzyl isocyanate instead of isopropyl isocyanate. 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.8 Hz, 1H), 7.36 - 7.27 (m, 4H), 7.17 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.04 (t, J = 8.6 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.99 - 5.93 (m, 1H), 5.77 - 5.71 (m, 1H), 4.36 (s, 2H), 4.05 (dd, J = 26.4, 12.0 Hz, 2H), 3.92 (w, 2H), 3.83 (d, J = 15.2 Hz, 1H), 3.72 (d, J = 14.0 Hz, 1H), 3.63 (d, J = 8.8 Hz, 1H), 3.51 - 3.38 (m, 3H), 3.30 (s, 3H), 3.15 - 3.08 (m, 1H), 2.85 - 2.77 (m, 3H), 2.66 - 1.79 (m, 10H), 1.44 (t, J = 12.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 44 ClFN4O5S Calculated: 735.3; Measured: 735.3. Example 38 [ka]

[0255] Example 38 was synthesized in the same manner as Example 18, using 3-pyrimidin-4-yl-propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol Le-d4) δ 9.04 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 9.0, 2.2 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.92 - 5.80 (m, 2H), 4.11 - 3.94 (m, 3H), 3.81 (d, J = 14.8 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.62 - 3.42 (m, 5H), 3.27 (s, 3H), 3.19 - 3.10 (m, 3H), 2.94 (t, J = 7.0 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.54 - 1.78 (m, 10H), 1.45 (t, J = 12.4 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 44 Calculated for ClN5O5S: 718.3; Found: 718.3. Example 39 [ka]

[0256] Example 39 was synthesized in the same manner as Example 18, using 3-pyrazol-1-yl-propionic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methano rule-d4) δ 7.77 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.26 - 6.25 (m, 1H), 5.94 - 5.79 (m, 2H), 4.49 (t, J = 6.6 Hz, 2H), 4.05 (dd, J = 33.4, 12.2 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.81 (d, J = 15.2 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.68 - 3.55 (m, 3H), 3.51 - 3.41 (m, 2H), 3.31 (s, 3H), 3.16 - 3.10 (m, 1H), 2.96 (t, J = 6.6 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.46 - 1.79 (m, 10H), 1.45 (t, J = 12.6 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 44 Calculated for ClN5O5S: 706.3; Found: 706.3. Example 40 [ka]

[0257] Example 40 was synthesized in the same manner as Example 18, using 3-pyridinepropionic acid instead of 3-methoxypropionic acid.1 H NMR (400 MHz, methanol-d4) δ 8.78 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H) 7.90 (dd, J = 8.0, 6.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.6, 2.2 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.95 (m, 4H), 3.81 - 3.73 (m, 2H), 3.56 - 3.43 (m, 4H), 3.32 (s, 3H), 3.25 - 3.11 (m, 3H), 2.90 (t, J = 6.8 Hz, 2H), 2.85 - 2.78 (m, 2H), 2.26 - 1.80 (m, 11H), 1.44 (t, J = 12.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 45 Calculated for ClN4O5S: 717.3; Found: 717.4. Example 41 [ka]

[0258] Example 41 was synthesized in the same manner as Example 18, using 3-(pyridin-4-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol Le-d4) δ 8.64 (d, J = 6.0 Hz, 2H), 7.93 (d, J = 5.6 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.97 (m, 3H), 3.81 - 3.73 (m, 2H), 3.55 - 3.43 (m, 3H), 3.32 (s, 3H), 3.31 - 3.20 (m, 3H), 3.17 - 3.11 (m, 1H), 2.94 (t, LCMS-ESI+ (m / z): [M+H]+ C 39 H 45 Calculated for ClN4O5S: 717.3; Found: 717.3. Example 42 [ka]

[0259] Example 42 was synthesized in the same manner as Example 18, using 3-(1H-1,2,4-triazol-1-yl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 36 H 43 Calculated [M+H]+ for ClN6O5S: 707.3; found: 707.3. Example 43 [ka]

[0260] Example 43 was synthesized in the same manner as Example 18, using 3-(1-methyl-1H-imidazol-2-yl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 38 H 46 Calculated [M+H]+ for ClN5O5S: 720.3; found: 721.3. Example 44 [ka]

[0261] Example 44 was synthesized in the same manner as Example 18, using 3-(pyrimidin-2-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methano rule-d4) δ 8.73 (d, J = 4.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.93 - 5.79 (m, 2H), 4.10 - 3.93 (m, 3H), 3.80 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 14.4 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.55 (dd, J = 8.2, 3.0 Hz, 1H), 3.43 (d, J = 14.4 Hz, 1H), 3.35 - 3.30 (m, 4H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 3.00 (t, J = 6.8 Hz, LCMS-ESI+ (m / z): [M+H]+ C 38 H 44 Calculated for ClN5O5S: 718.3; Measured Value: 719.4. Example 45 [ka]

[0262] Example 45 was synthesized in the same manner as Example 18, using 3-(1-ethyl-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 7.77 (d, J = 8.4 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 5.93 - 5.81 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.11 - 3.94 (m, 3H), 3.81 (d, J = 14.8 Hz, 1H), 3.74 (d, J = 14.8 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.44 (d, J = 14.4 Hz, 1H), 3.34 - 3.31 (m, 2H), 3.31 (s, 3H), 3.17 - 3.10 (m, 1H), 3.02 -3.00 (m, 2H), 2.87 - 2.79 (m, 5H), 2.55 - 1.79 (m, 10H), 1.48 - 1.35 (m, 4H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 48 Calculated for ClN5O5S: 734.4; Found: 734.4. Example 46 [ka]

[0263] Example 46 was synthesized in the same manner as Example 18, using 3-(2-methyl-2H-1,2,3-triazol-4-yl)propanoic acid instead of 3-methoxypropionic acid.1 H NMR (400 MHz, methanol-d4) δ 7.77 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.96 - 5.90 (m, 1H), 5.82 (dd, J = 16.2, 8.6 Hz, 1H), 4.10 - 3.94 (m, 6H), 3.82 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 14.4 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.42 (d, J = 14.4 Hz, 1H), 3.34 - 3.32 (m, 2H), 3.31 (s, 3H), 3.16 - 3.09 (m, 1H), 3.01 (t, J = 7.2 Hz, 2H), 2.85 - 2.75 (m, 5H), 2.50 - 1.78 (m, 10H), 1.48 - 1.42 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 45 Calculated for ClN6O5S: 721.3; Found: 721.3. Example 47 [ka]

[0264] Example 47 was synthesized in the same manner as Example 18, using 2-pyridinepropanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 8.60 (d, J = 5.6 Hz, 1H), 8.26 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 6.6 Hz, 1H). 7.40 (s, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.92 - 5.79 (m, 2H), 4.12 - 3.92 (m, 3H), 3.82 - 3.74 (m, 2H), 3.57 - 3.51 (m, 2H), 3.44 (d, J = 14.8 Hz, 1H), 3.29 (s, 3H), 3.33 - 3.24 (m, 4H), 3.17 - 3.11 (m,1H), 2.96 (t, J = 6.8 Hz, 2H), 2.92 - 2.78 (m, 3H), 2.49 - 1.81 (m, 10H), 1.48 - 1.41 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 45 Calculated for ClN4O5S: 717.3; Found: 717.5. Example 48 [ka]

[0265] Example 48 was synthesized in the same manner as Example 18, using 3-(1-methyl-1H-pyrazol-5-yl)propanoic acid and Example 6 instead of 3-methoxypropionic acid and Example 5. LCMS-ESI+(m / z): C 38 H 46 Calculated [M+H]+ for ClN5O5S: 720.3; found: 720.0. Example 49 [ka]

[0266] Step 1: (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxamide in CHCl (15.0 mL) To a stirred solution of 1-6 (309.00 mg, 0.483 mmol), triethylamine (0.14 mL, 0.965 mmol) was added in an ice bath, followed by DMAP (23.58 mg, 0.193 mmol) and di-tert-butyl dicarbonate (157.99 mg, 0.724 mmol). The resulting mixture was stirred at room temperature overnight. After concentration, the diastereomeric mixture was separated by preparative HPLC to give 49-1 (less polar fraction) and 49-2 (more polar fraction).

[0267] Step 2: Intermediate 49-3 was synthesized from intermediate 49-1 using a procedure similar to that shown in Example 5, Method 1, Step 2.

[0268] Step 3: Example 49 was synthesized in the same manner as Example 18 using 3-(1-methyl-1H-pyrazol-5-yl)propanoic acid and intermediate 49-3. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 6.00 - 5.93 (m, 1H), 5.60 (dd, J = 15.4, 9.0 Hz, 1H), 4.32 - 4.28 (m, 1H), 4.09 (s, 2H), 3.85 - 3.81 (m, 4H), 3.75 - 3.67 (m, 3H), 3.51 - 3.79 (m, 1H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 3.01 (t, J = 7.2 Hz, 2H), 2.85 - 2.79 (m, 5H), 2.48 - 1.77 (m, 10H), 1.51 - 1.44 (m, 4H), 1.06 (d, J = 5.6 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 50 ClN5O5S Calculated: 748.4; Measured: 748.0. Example 50 [ka]

[0269] Example 50 was synthesized according to the procedure described in Example 49 (Step 2 and Step 3), using intermediate 49-2 instead of intermediate 49-1. LCMS-ESI+(m / z): C 40 H 50 Calculated [M+H]+ for ClN5O5S: 748.4; found: 748.0. Example 51 [ka]

[0270] Example 51 was synthesized in the same manner as Example 18, using 3-(1-methyl-1H-pyrazol-3-yl)propanoic acid instead of 3-methoxypropionic acid. 1H NMR (400 MHz, methanol-d4) δ 7.77 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.94 - 5.81 (m, 2H), 4.11 - 3.94 (m, 3H), 3.83 - 3.80 (m, 4H), 3.75 (d, J = 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.43 (d, J = 14.8 Hz, 1H), 3.34 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.94 (t, J = 7.8 Hz, 2H), 2.85 - 2.78 (m, 3H), 2.74 (t, J = 7.6 Hz, 2H), 2.53 - 1.78 (m, 10H), 1.45 (t, J = 12.6 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.3; Found: 720.0. Example 52 [ka]

[0271] Example 52 was synthesized in the same manner as Example 18, using 3-indazol-1-yl-propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 41 H 46 Calculated [M+H]+ for ClN5O5S: 756.4; found: 756.2. Example 53 [ka]

[0272] Example 53 was synthesized in the same manner as Example 18, using 3-(pyrimidin-5-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methano rule-d4) δ 9.00 (s, 1H), 8.74 (s, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.91 (m, 3H), 3.82 - 3.68 (m, 2H), 3.60 - 3.50 (m, 2H), 3.43 (d, J = 14.4 Hz, 1H), 3.35 - 3.33 (m, 5H), 3.16 - 3.10 (m, 1H), 3.02 (t, J = 7.3 Hz, 2H), 2.87 - 2.78 (m, 4H), 2.55 - 1.78 (m, 10H), 1.44 (t, J = 12.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 44 Calculated for ClN5O5S: 718.3; Found: 718.1. Example 54 [ka]

[0273] Example 54 was synthesized in the same manner as Example 18, using sodium 3-(1H-1,2,3-triazol-1-yl)propanoate instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 36 H 43 Calculated [M+H]+ for ClN6O5S: 707.3; found: 707.1. Example 55 [ka]

[0274] Example 55 was synthesized in the same manner as Example 18, using 3-(4-chloro-1H-pyrazol-1-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 7.77 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.94 - 5.79 (m, 2H), 4.44 (t, J = 6.2 Hz, 2H), 4.05 (dd, J = 33.8, 12.2 Hz, 2H), 3.97 - 3.89 (m, 1H), 3.81 (d, J = 14.8 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.64 - 3.50 (m, 2H), 3.43 (d, J = 14.4 Hz, 1H), 3.34 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.96 (t, J = 6.4 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.53 - 1.79 (m, 10H), 1.45 (t, J = 12.6 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 43 Calculated for Cl2N5O5S: 740.7; Found: 740.0. Example 56 [ka]

[0275] Example 56 was synthesized in the same manner as Example 18 using 3-(5-methyl-1H-pyrazol-1-yl)propanoic acid. LCMS-ESI+(m / z): C 38 H 46 Calculated [M+H]+ for ClN5O5S: 720.3; found: 720.1. Example 57 [ka]

[0276] Example 57 was synthesized in the same manner as Example 18, using 3-isoxazol-4-yl-propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, Tanol-d4) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.93 - 5.81 (m, 2H), 4.11 - 3.92 (m, 3H), 3.81 (d, J = 15.2 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.64 - 3.49 (m, 2H), 3.44 (d, J = 14.4 Hz, 1H), 3.36 - 3.31 (m, 7H), 3.17 - 3.10 (m, 1H), 2.87 - 2.77 (m, 3H), 2.70 (t, J = 7.2 Hz, 2H), 2.55 - 1.79 (m, 10H), 1.45 (t, J = 12.6 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 43 Calculated for ClN4O6S: 707.3; Found: 707.1. Example 58 [ka]

[0277] Example 58 was synthesized in the same manner as Example 18, using 3-(1,2-oxazol-3-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 5.95 - 5.89 (m, 1H), 5.82 (dd, J = 16.0, 8.4 Hz, 1H), 4.11 - 3.92 (m, 3H), 3.82 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.42 (d, J = 14.4 Hz, 1H), 3.35 - 3.32 (m, 2H), 3.31 (s, 3H), 3.16 - 3.04 (m, 3H), 2.85 - 2.72 (m, 5H), 2.51 - 1.78 (m, 10H), 1.45 (t, J = 12.6 Hz, 1H).LCMS-ESI+ (m / z): [M+H]+ C 37 H 43 Calculated for ClN4O6S: 707.3; Found: 707.0. Example 59 [ka]

[0278] Example 59 was synthesized in the same manner as Example 18, using 3-(3-methyl-1H-pyrazol-1-yl)propanoic acid instead of 3-methoxypropionic acid. H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 5.95 - 5.80 (m, 2H), 4.39 (t, J = 6.6 Hz, 2H), 4.06 (dd, J = 34.2, 12.2 Hz, 2H), 3.98 - 3.91 (m, 1H), 3.81 (d, J = 15.2 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.43 (d, J = 14.4 Hz, 1H), 3.35 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.93 (t, J = 6.4 Hz, 2H), 2.85 - 2.75 (m, 3H), 2.53 - 1.79 (m, 13H), 1.45 (t, J = 12.6 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.3; Found: 720.1. Example 60 [ka]

[0279] Example 60 was synthesized in the same manner as Example 18, using lithium 3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoate instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 37 H44 Calculated [M+H]+ for ClN5O6S: 722.3; found: 722.1. Example 61 [ka]

[0280] Example 61 was synthesized in the same manner as Example 18, using 3-(4-methyl-1H-pyrazol-1-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 7.77 (d, J = 8.4 Hz, 1H), 7.41 (s, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.93 - 5.80 (m, 2H), 4.40 (td, J = 6.4, 2.4 Hz, 2H), 3.81 (dd, J = 34.0, 12.4 Hz, 2H), 3.97 - 3.90 (m, 1H), 3.81 (d, J = 14.8 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.63 - 3.47 (m, 2H), 3.43 (d, J = 14.8 Hz, 1H), 3.35 - 3.33 (m, 5H), 3.17 - 3.10 (m, 1H), 2.92 (t, J = 6.6 Hz, LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.3; Found: 720.1. Examples 62 and 63 [ka]

[0281] Step 1: To a stirred solution of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (2.0 g, 4.27 mmol) in tetrahydrofuran, pyridine (1.0 g, 8.5 mmol) and acetic anhydride (1.3 g, 8.5 mmol) were added. The mixture was stirred at room temperature for 48 hours, followed by evaporation of the solvent. The residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated to give crude anhydride 62-1.

[0282] Step 2: A stirred solution of anhydride 62-1 (2.0 g, 3.6 mmol) in CH2Cl2 was cooled to 0 °C. To this mixture, SOCl2 (2 mL) was added dropwise with vigorous stirring. The mixture was stirred at 0 °C and allowed to warm slowly to room temperature. After the reaction was complete, it was evaporated to remove excess SOCl2 to give acid chloride intermediate 62-2, which was used immediately in the next step.

[0283] Step 3: To a solution of 62-2 (200 mg, 0.38 mmol) and pyridazine (30 mg, 0.38 mmol) in acetonitrile stirred at room temperature for 5 min, a racemic mixture of (S)-N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide and (R)-N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide (99 mg, 0.38 mmol) was added. After completion of the reaction, the residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by reverse-phase chromatography (acetonitrile-water 50%-90% 30 min) to give a diastereomeric mixture of intermediate IV.

[0284] Step 4: A mixture of sulfonimidamide intermediate IV (150 mg, 0.23 mmol), propionyl chloride (26 mg, 0.29 mmol), and triethylamine (0.29 mmol) was stirred in CHCl at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reverse-phase chromatography, acetonitrile-water 50–90% elution over 30 min to give 62-3.

[0285] Step 5: Ester intermediate 62-3 (25 mg, 0.036 mmol) and Hoveyda-Grubbs second-generation catalyst (2.2 mg, 0.004 mmol) were sealed in a microwave vial, purged with argon, and then 1,2-DCE was added. The microwave vial was heated to 60 °C for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reverse-phase chromatography (acetonitrile-water 50%-90% 30 min) to give macrocyclic intermediate 62-4 as a mixture of diastereomers.

[0286] Step 6: Intermediate (62-4) was dissolved in methanol (3 mL) and water (0.3 mL). To this solution, K2CO3 (10.8 mg, 0.08 mmol) was added and stirred at room temperature for 7 hours. The mixture was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by reverse phase chromatography (acetonitrile-water 50% to 90% 30 min) to give Example 62 (less polar fraction) and Example 63 (more polar fraction).

[0287] Example 62: 1 H NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.9 Hz, 2H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.00 (dd, J = 15.8, 7.6 Hz, 1H), 5.80 (dt, J = 15.8, 5.2 Hz, 1H), 4.20 - 3.95 (m, 4H), 3.78 (t, J = 14.7 Hz, 3H), 3.53 - 3.40 (m, 3H), 3.34 (d, J = 14.4 Hz, 2H), 3.15 - 3.00 (m, 2H), 2.88 - 2.67 (m, 3H), 2.45 (q, J = 7.5 Hz, 3H), 2.24 (dt, J = 12.7, 6.3 Hz, 2H), 2.12 - 1.63 (m, 4H), 1.40 (d, J = 13.3 Hz, 1H), 1.26 (t, J = 7.1 Hz, 1H), 1.17 (t, J = 7.4 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+C 33 H 40 ClN3O5S calculated value: 626.2; measured value: 626.2.

[0288] Example 63: 1 H NMR (400 MHz, クロロホルム-d) δ 8.05 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.18 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.91 (t, J = 8.1 Hz, 1H), 5.91 - 5.71 (m, 2H), 4.15 - 4.00 (m, 3H), 3.99 - 3.85 (m, 1H), 3.71 (d, J = 14.7 Hz, 2H), 3.58 (d, J = 14.9 Hz, 1H), 3.43 (d, J = 14.7 Hz, 1H), 3.27 (s, 2H), 3.00 (s, 2H), 2.95 - 2.87 (m, 2H), 2.80 (d, J = 19.0 Hz, 3H), 2.46 (tt, J = 7.4, 3.4 Hz, 3H), 1.90-1.60 (m, 6H), 1.23 (dt, J = 18.1, 7.3 Hz, 4H). LCMS-ESI+ (m / z): [M+H]+ C 33 H 40 ClN3O5S Calculated: 626.2; Measured: 626.2. Examples 64 and 65 [ka]

[0289] Step 1: Preparation of (R)-N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide: To a stirred solution of (R)-hept-6-ene-3-sulfonamide (prepared according to the procedure in International Publication No. WO 17 / 147410, 1.5 g, 9.2 mmol) in THF, EtN (1.8 g, 18.3 mmol) was added in an ice bath, followed by the addition of tert-butylchlorodimethylsilane (1.7 g, 11.5 mmol) in THF. The resulting mixture was stirred at room temperature for 24 hours. The precipitate was filtered off and washed with ether. The filtrate was concentrated and purified by normal phase chromatography (hexane / EtOAc = 3:1) to give (R)-N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide.

[0290] Step 2: Preparation of (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide: To a stirred suspension of Ph3PCl2 (4.2 g, 12.6 mmol) in CHCl2 under a nitrogen atmosphere, triethylamine (1.2 g, 12.6 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then cooled to 0 °C, and a solution of (R)-N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide (2.2 g, 7.9 mmol) in CHCl2 was added. The reaction mixture was stirred at 0 °C for 1 hour. Ammonia gas was bubbled through the reaction mixture. The mixture was stirred at 0 °C for 2 hours, then at room temperature for 24 hours. The precipitate was filtered off and washed with CHCl2. The filtrate was concentrated and purified on normal phase chromatography (hexane: EtOAc = 7:3) to give (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimideamide. 1 H NMR (400 MHz, chloroform-d) δ 5.78 (ddt, J = 16.9, 10.5, 6.6 Hz, 1H), 5.13 - 4.85 (m, 2H), 4.38 (s, 2H), 2.75 (tt, J = 7.0, 4.8 Hz, 1H), 2.32 - 2.10 (m, 2H), 2.06 - 1.86 (m, 2H), 1.79 - 1.54 (m, 2H), 1.03 (td, J = 7.5, 1.7 Hz, 3H), 0.87 (s, 9H), 0.09 (d, J = 1.1 Hz, 6H).

[0291] Step 3: Examples 64 and 65 were prepared in the same manner as Examples 3 and 4, using (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide instead of N'-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide.

[0292] Example 64 (more polar fraction): 1H NMR (400 MHz, クロロホルム-d) δ 7.70 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 4.2 Hz, 2H), 7.07 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), 5.59 (dd, J = 15.8, 7.8 Hz, 1H), 4.18 - 3.95 (m, 3H), 3.85 - 3.63 (m, 3H), 3.35 - 3.21 (m, 4H), 3.07 - 2.92 (m, 1H), 2.77 (s, 2H), 2.44 (t, J = 7.9 Hz, 7H), 2.18 - 1.57 (m, 10H), 1.25 (s, 1H), 1.13 (dt, J = 28.4, 7.2 Hz, 6H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 46 ClN3O5S calculated value: 668.2; measured value: 668.3.

[0293] Example 65 (よりpolar and でない drawing points): 1 H NMR (400 MHz, クロロホルム-d) δ 7.70 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 10.5 Hz, 2H), 7.08 (s, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.10-6.00 (m, 1H), 5.50 (dd, J = 15.4, 8.5 Hz, 1H), 4.29 - 3.99 (m, 3H), 3.87 - 3.59 (m, 3H), 3.25 (s, 4H), 3.00 (s, 1H), 2.76 (d, J = 13.4 Hz, 2H), 2.43 (dd, J = 19.8, 12.5 Hz, 6H), 2.24 - 1.54 (m, 11H), 1.41 (s, 1H), 1.28 - 1.05 (m, 6H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 46Calculated for ClN3O5S: 668.2; Found: 668.3. Example 66

[0294] Step 1: Preparation of 66-1: A mixture of intermediate IV (900 mg, 1.4 mmol), di-tert-butyl dicarbonate (429 mg, 1.9 mmol), DMAP (17 mg, 0.14 mmol), and triethylamine (0.2 mL) was stirred in CHCl at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (Hex: EtOAc 1:1) to give intermediate 66-1.

[0295] Step 2: In a round bottle flask, 66-1 (880 mg, 1.26 mmol) and Hoveyda-Grubbs second generation catalyst (78 mg, 0.13 mmol) were added. The flask was sealed and purged with argon, and then 1,2-DCE was added. The flask was heated to 60 °C for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give intermediate 66-2. [ka]

[0296] Step 3: Intermediate 66-2 (600 mg, 0.84 mmol) was dissolved in methanol (6 mL) and water (0.6 mL). To this solution, K2CO3 (406 mg, 2.94 mmol) was added and stirred at room temperature for 7 hours. The mixture was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by reverse-phase chromatography (acetonitrile-water 50% to 90% in 30 min) to give diastereomers 66-3 (more polar fraction) and 66-4 (less polar fraction).

[0297] Step 4: Intermediate 66-3 (15 mg, 0.024 mmol) was dissolved in DMF, NaH (4 mg, 0.072 mmol) was added at room temperature, stirred for 10 minutes, and then 2-bromoethyl trifluoromethanesulfonate (12 mg, 0.048 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours, dissolved in ethyl acetate, and washed with water. The organic layer was concentrated to give bromo intermediate 66-5, which was used further without purification.

[0298] Step 5: Bromo intermediate 66-5 (15 mg, 0.02 mmol) was dissolved in morpholine and stirred for 1 h at 50° C. The mixture was evaporated under reduced pressure to give 66-6, which was used further without purification.

[0299] Step 6: Morpholine intermediate 66-6 (9 mg, 0.011 mmol) was treated with a mixture of CHCl (2 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated and purified by reverse-phase chromatography (acetonitrile-water 50%-90% 30 min) to give intermediate 66-7.

[0300] Step 7: Intermediate 66-7 (5 mg, 0.007 mmol), propionyl chloride (1 mg, 0.007 mmol), and triethylamine (0.021 mmol) were stirred in CHCl at room temperature for 1 hour. After completion of the reaction, it was evaporated under reduced pressure, dissolved in DMF, and purified by reverse phase chromatography, acetonitrile-water 50-90% for 30 minutes to give Example 66. H NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 8.5 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.31 (s, 1H), 7.22 - 7.15 (m, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.94 (d, J = 15.8 Hz, 1H), 5.73 (dd, J = 15.9, 7.8 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.03 - 3.75 (m, 7H), 3.66 (t, J = 13.1 Hz, 5H), 3.51 (d, J = 12.0 Hz, 1H), 3.36 (d, J = 14.4 Hz, 2H), 3.27 (s, 2H), 3.14 - 2.92 (m, 3H), 2.76 (d, J = 14.8 Hz, 3H), 2.53 - 2.39 (m, 3H), 2.32 - 1.64 (m, 10H), 1.41 (d, J = 12.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 51 Calculated for ClN4O6S: 739.3; Found: 739.5. Example 67 [ka]

[0301] Example 67 was synthesized in the same manner as Example 66 using intermediate 66-4 (less polar fraction). 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.18 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.83 (s, 2H), 4.11 (d, J = 12.1 Hz, 1H), 3.99 - 3.75 (m, 6H), 3.61 (dd, J = 37.3, 15.1 Hz, 6H), 3.49 (s, 1H), 3.40 (s, 1H), 3.32 - 3.18 (m, 2H), 3.06 - 2.97 (m, 1H), 2.90 (s, 2H), 2.82 - 2.66 (m, 3H), 2.49 (s, 4H), 2.28 - 1.62 (m, 9H), 1.37 (s, 2H), 1.27 - 1.11 (m, 4H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 51 Calculated for ClN4O6S: 739.3; Found: 739.5. Example 68 [ka]

[0302] Example 68 was synthesized in the same manner as Example 67 using intermediate 67-4 (less polar fraction) and 1-methylpiperazine instead of morpholine. 1 H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.5 Hz, 1H), 7.47 - 7.30 (m, 2H), 7.21 - 7.13 (m, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.11 (dd, J = 15.9, 9.0 Hz, 1H), 5.75 (d, J = 15.9 Hz, 1H), 4.12 - 3.93 (m, 4H), 3.85 - 3.49 (m, 8H), 3.36 (t, J = 14.1 Hz, 4H), 3.16 - 3.00 (m, 3H), 2.87 (d, J = 10.7 Hz, 4H), 2.82 - 2.60 (m, 4H), 2.09 (td, J = 15.4, 14.9, 8.0 Hz, 6H), 1.98 - 1.59 (m, 6H), 1.46 (d, J = 3.0 Hz, 1H), 1.42 - 1.20 (m, 2H), 1.12 (t, J = 7.1 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 54 Calculated for ClN5O5S: 752.3; Found: 752.4. Example 69

[0303] Step 1: N'-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimide amide was prepared in the same manner as Example 1 (Steps 4 and 5) using hex-5-ene-1-sulfonamide instead of (2R,3S)-3-methylhex-5-ene-2-sulfonamide. 1 H NMR (400 MHz, chloroform-d) δ 5.87 - 5.63 (m, 1H), 5.07 - 4.84 (m, 2H), 4.71 - 4.01 (m, 2H), 3.04 (dddd, J = 13.4, 10.0, 8.5, 5.0 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.92 - 1.71 (m, 2H), 1.57 - 1.45 (m, 2H), 0.88 (d, J = 5.9 Hz, 9H), 0.11 - 0.2 (m, 6H). [ka]

[0304] Step 2: Preparation of intermediate 69-2: To a mixture of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl chloride (from Example 1, Step 3, 200 mg, 0.40 mmol) and pyridazine (32 mg, 0.40 mmol) in acetonitrile stirred at room temperature for 5 min, N'-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimideamide 70-1 (121 mg, 0.44 mmol) was added. After completion of the reaction, the residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by normal phase chromatography Hex:AtOAc 1:1 to give 69-2 as a mixture of diastereomers.

[0305] Step 3: Preparation of intermediate 69-3: Diastereomeric mixture 69-2 (160 mg, 0.25 mmol), propionyl chloride (28 mg, 0.30 mmol), and triethylamine (0.56 mmol) were stirred in CHCl at room temperature for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reverse-phase chromatography, acetonitrile-water 50-90% for 30 min to give 69-3 as a mixture of diastereoisomers.

[0306] Step 4: Preparation of Example 69: In a microwave vial, intermediate 69-3 (25 mg, 0.037 mmol) and Hoveyda-Grubbs II (2.2 mg, 0.004 mmol) were added. The vial was sealed and purged with argon, and then 1,2-DCE was added. The microwave vial was heated to 60 °C for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reverse phase chromatography (acetonitrile-water 50-90% 30 min) to give Example 69 (less polar fraction). 1 H NMR (400 MHz, chloroform-d) δ 7.67 (dd, J = 8.6, 4.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.32 - 7.05 (m, 3H), 6.96 (dd, J = 18.1, 8.1 Hz, 1H), 5.63 - 5.30 (m, 2H), 4.25 - 4.01 (m, 2H), 3.86 - 3.56 (m, 4H), 3.49 - 3.27 (m, 5H), 3.22 (d, J = 10.0 Hz, 2H), 2.76 (d, J = 10.8 Hz, 2H), 2.58 - 2.37 (m, 4H), 2.15 - 1.74 (m, 10H), 1.63 (dt, J = 18.7, 9.4 Hz, 6H), 1.23 (t, J = 7.5 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 35 H 44 Calculated for ClN3O5S: 654.4; Found: 654.2. Examples 70 and 71 [ka]

[0307] Examples 71 and 72 were synthesized in the same manner as Examples 3 and 4 using (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimideamide (Examples 64 and 65, Step 1) and 3-(1-methyl-1H-pyrazol-5-yl)propanoic acid.

[0308] Example 70: 1 H NMR (400 MHz, chloroform-d) δ 7.69 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.16 (td, J = 8.5, 2.3 Hz, 1H), 7.09 - 7.01 (m, 2H), 7.00 - 6.87 (m, 2H), 6.16 (d, J = 2.1 Hz, 1H), 5.94 - 5.80 (m, 1H), 5.51 (dd, J = 15.3, 8.7 Hz, 1H), 4.31 (s, 1H), 4.12 - 4.02 (m, 2H), 3.93 (s, 2H), 3.78 (t, J = 13.6 Hz, 1H), 3.71 - 3.59 (m, 4H), 3.25 (d, J = 15.2 Hz, 3H), 3.05 - 2.89 (m, 6H), 2.87 - 2.72 (m, 4H), 2.48 - 2.19 (m, 4H), 2.16 - 1.57 (m, 11H), 1.49 - 1.30 (m, 1H), 1.16 (t, J = 7.5 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 50 ClN5O5S calculated value: 748.2; measured value: 748.3.

[0309] Example 71: 1 H NMR (400 MHz, クロロホルム-d) δ 7.70 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.49 - 7.31 (m, 2H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 11.6, 8.3 Hz, 2H), 6.15 (d, J = 2.1 Hz, 1H), 5.72 (td, J = 10.8, 5.0 Hz, 1H), 5.37 (t, J = 10.3 Hz, 1H), 4.10 (q, J = 9.0, 8.0 Hz, 3H), 3.98 - 3.55 (m, 5H), 3.48 - 3.35 (m, 1H), 3.35 - 3.14 (m, 4H), 3.11 - 2.63 (m, 9H), 2.46 - 2.14 (m, 5H), 2.12 - 1.52 (m, 10H), 1.45 - 1.34 (m, 1H), 1.14 (q, J = 5.1, 2.9 Hz, 1H), 1.03 - 0.82 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 50 Calculated for ClN5O5S: 748.2; Found: 748.3. Example 72 [ka]

[0310] Example 72 was synthesized in the same manner as Example 18, using (S)-3-hydroxy-3-phenylpropanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.5 Hz, 1H), 7.44 - 7.27 (m, 6H), 7.16 (d, J = 1.7 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 5.88 - 5.66 (m, 2H), 5.25 (dd, J = 9.9, 2.7 Hz, 1H), 3.99 (q, J = 12.0 Hz, 3H), 3.71 (dd, J = 27.2, 14.6 Hz, 3H), 3.56 (dd, J = 7.5, 3.2 Hz, 1H), 3.32 (s, 4H), 3.03 (dd, J = 15.6, 10.2 Hz, 2H), 2.87 - 2.64 (m, 4H), 2.47 - 2.06 (m, 5H), 2.06 - 1.66 (m, 5H), 1.29 (d, J = 30.9 Hz, 4H). LCMS-ESI+ (m / z): [M+H]+ C 40 H46 Calculated for ClN3O6S: 732.2; Found: 732.0. Example 73 [ka]

[0311] To a solution of Example 5 (12 mg, 0.021 mmol) and diisopropylethylamine (0.041 mmol) in 3 mL of dichloromethane was added dropwise a solution of thiomorpholine-4-carbonyl chloride 1,1-dioxide (8 mg, 0.041 mmol) in 1 mL of dichloromethane, and the mixture was stirred at reflux for 16 hours. LC / MS showed the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified using HPLC to give Example 73. 1 H NMR (400 MHz, chloroform-d) δ 7.77 - 7.62 (m, 1H), 7.23 - 7.11 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 7.04 - 6.81 (m, 2H), 5.93 - 5.74 (m, 1H), 5.53 (dd, J = 15.5, 8.4 Hz, 1H), 4.28 - 3.85 (m, 7H), 3.79 - 3.49 (m, 4H), 3.40 - 3.20 (m, 4H), 2.99 (d, J = 34.6 Hz, 4H), 2.85 - 2.61 (m, 2H), 2.55 - 2.20 (m, 4H), 2.20 - 1.58 (m, 9H), 1.42 (t, J = 12.8 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 45 Calculated for ClN4O7S2: 745.25; Found: 745.96. Example 74 [ka]

[0312] Example 74 was synthesized in the same manner as Example 73 using Example 6. LCMS-ESI+(m / z): C 36 H 45 Calculated [M+H]+ for ClN4O7S2: 745.25; Found: 745.96. Example 75 [ka]

[0313] A solution of Example 5 (12 mg, 0.021 mmol), diphenyl carbonate (5 mg, 0.023 mmol), and DMAP (15 mg, 0.123 mmol) in 3 mL of acetonitrile was stirred at room temperature for 16 hours. (1-Methyl-1H-pyrazol-5-yl)methanamine (6.8 mg, 0.062 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. LC / MS showed the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified using HPLC to give Example 75. 1 H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.49 - 7.20 (m, 3H), 7.20 - 7.03 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 6.00 - 5.68 (m, 2H), 5.38 - 5.16 (m, 2H), 4.21 - 3.90 (m, 2H), 3.82 - 3.47 (m, 3H), 3.46 - 3.18 (m, 11H), 3.10 LCMS-ESI+ (m / z): [M+H]+ C 37 H 45 Calculated for ClN6O5S: 721.29; Found: 721.91. Example 76 [ka]

[0314] Example 76 was synthesized in the same manner as Example 75 using Example 6 and N-methylethanamine. LCMS-ESI+(m / z): C 35 H 45 Calculated [M+H]+ for ClN4O5S: 669.28; found: 669.88. Example 77 [ka]

[0315] Example 77 was synthesized in the same manner as Example 77 using N-methylethanamine. LCMS-ESI+(m / z): C 35 H 45 Calculated [M+H]+ for ClN4O5S: 669.28; found: 669.88. Example 78 [ka]

[0316] Example 78 was synthesized in the same manner as Example 76 using (1-methyl-1H-pyrazol-5-yl)methanol. LCMS-ESI+(m / z): C 37 H 44 Calculated [M+H]+ for ClN5O6S: 722.27; found: 723.24. Example 79 [ka]

[0317] Example 79 was synthesized in the same manner as Example 76 using pyridin-4-ylmethanamine. 1H NMR (400 MHz, methanol-d4) δ 8.70 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 6.0 Hz, 2H), 7.68 (dd, J = 8.9, 6.4 Hz, 1H), 7.41 - 7.16 (m, 2H), 7.18 - 6.98 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5.76 (t, J = 12.0 Hz, 1H), 4.64 (s, 2H), 4.21 - 3.46 (m, 6H), 3.39 (d, J = 14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J = 15.1, 10.8 Hz, 1H), 2.97 - 2.58 (m, 3H), 2.35 (d, J = 58.3 Hz, 3H), 2.19 - 1.68 (m, 6H), 1.54 - 1.17 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 44 Calculated for ClN5O5S: 718.28; Found: 719.76. Example 80 [ka]

[0318] Example 80 was synthesized in the same manner as Example 76 using pyrazin-2-ylmethanamine. 1H NMR (400 MHz, methanol-d4) δ 8.64 (s, 1H), 8.60 - 8.41 (m, 2H), 7.74 (dd, J = 8.5, 5.2 Hz, 1H), 7.29 (dd, J = 12.5, 8.1 Hz, 2H), 7.23 - 7.00 (m, 2H), 6.86 (dd, J = 16.3, 8.1 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5.76 (t, J = 12.0 Hz, 1H), 4.64 (s, 2H), 4.21 - 3.46 (m, 6H), 3.39 (d, J = 14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J = 15.1, 10.8 Hz, 1H), 2.97 - 2.58 (m, 3H), 2.35 (d, J = 58.3 Hz, 3H), 2.19 - 1.68 (m, 6H), 1.54 - 1.17 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 43 Calculated for ClN6O5S: 719.27; Found: 719.71. Example 81 [ka]

[0319] Example 81 was synthesized in the same manner as Example 18, using 3-cyclopropylpropanoic acid instead of 3-methoxypropionic acid. 1H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 - 7.05 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 5.93 - 5.76 (m, 2H), 4.06 (d, J = 12.1 Hz, 1H), 4.02 - 3.89 (m, 2H), 3.78 (d, J = 14.9 Hz, 1H), 3.71 (d, J = 14.3 Hz, 1H), 3.67 - 3.46 (m, 2H), 3.40 (d, J = 14.4 Hz, 1H), 3.34 (s, 1H), 3.25 (s, 3H), 3.11 (dd, J = 15.3, 10.8 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.47 (t, J = 7.3 Hz, 3H), 2.26 - 2.17 (m, 1H), 2.13 - 1.98 (m, 3H), 1.93 (s, 1H), 1.77 (t, J = 6.3 Hz, 2H), 1.53 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 13.1 Hz, 2H), 1.28 (s, 2H), 0.89 (t, J = 6.6 Hz, 1H), 0.80 - 0.68 (m, 1H), 0.48 - 0.39 (m, 2H), 0.08 (t, J = 4.7 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 46 Calculated for ClN3O5S: 680.29; Found: 680.98. Example 82 [ka]

[0320] Example 82 was synthesized in the same manner as Example 18, using 3-cyclopentylpropanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 39 H 50 Calculated [M+H]+ for ClN3O5S: 709.32; found: 709.36. Examples 83 and 84

[0321] Step 1: Preparation of trans-(±)-ethyl 2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylate: Sodium hydride (0.22 g, 9.1 mmol) and trimethylsulfoxonium iodide (1.4 g, 18.1 mmol) were stirred in 7 mL of DMSO at room temperature for 1 hour. Ethyl (E)-3-(1-methyl-1H-pyrazol-5-yl)acrylate (0.65 g, 3.6 mmol) was dissolved in 5 mL of DMSO / THF (1:1) and added to the reaction mixture. After completion of the reaction (3 hours, LC / MS), 1N HCl was added and the reaction mixture was extracted with diethyl ether. The combined organic layers were dried over MgSO, the solvent was removed, and the crude product was used without further purification. [ka]

[0322] Step 2: Preparation of trans(±)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid: To a solution of trans-(±)-ethyl 2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylate (0.4 g, 2.4 mmol) in 10 mL of methanol, 2 mL of 1 N NaOH was added, and the reaction was stirred at room temperature for 3 hours. The methanol was removed under reduced pressure, and the aqueous solution was acidified to pH 4 using concentrated HCl. The precipitate that formed was collected by filtration, washed with water, and air-dried to give the acid, which was used without further purification.

[0323] Step 3: Preparation of Example 83 and Example 84: Two diastereomers, Example 83 and Example 84, were synthesized in the same manner as Example 18 using trans(±)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid and Example 5. The two diastereomers were separated by supercritical fluid chromatography (Chiralpak AD-H, 5 μM, 21 × 250 mm, 50% MeOH, flow rate 65 mL / min, 100 bar).

[0324] Example 83 (less polar fraction): 1 H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.55 - 7.24 (m, 3H), 7.24 - 7.02 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 2.0 Hz, 1H), 5.85 (qd, J = 15.8, 9.5 Hz, 2H), 4.19 - 3.82 (m, 5H), 3.84 - 3.36 (m, 6H), 3.34 (s, 3H), 3.21 - 3.00 (m, 2H), 2.93 - 2.67 (m, 3H), 2.46 (dt, J = 10.6, 5.6 Hz, 3H), 2.24 (d, J = 8.1 Hz, 2H), 2.15 - 1.94 (m, 4H), 1.85 - 1.54 (m, 3H), 1.50 - 1.14 (m, 4H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 46 Calculated for ClN5O5S: 732.29; Found: 732.00.

[0325] Example 84 (more polar fraction): 1 H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.2, 1.8 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.11 (dt, J = 15.5, 6.4 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 5.61 (dd, J = 15.4, 9.0 Hz, 1H), 4.19 - 4.12 (m, 1H), 4.01 (dd, J = 21.8, 11.8 Hz, 2H), 3.94 - 3.85 (m, 5H), 3.74 - 3.66 (m, 3H), 3.50 (p, J = 1.6 Hz, 1H), 3.34 - 3.31 (m, 2H), 3.27 (s, 3H), 3.15 (p, J = 1.6 Hz, 1H), 3.08 - 3.01 (m, 1H), 2.88 - 2.74 (m, 3H), 2.56 - 1.70 (m, 10H), 1.59 - 1.54 (m, 1H), 1.46 - 1.39 (m, 1H), 1.18 - 1.36 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 46 Calculated value for ClN5O5S: 732.29; Actual value: 732.06. Example 85 [ka]

[0326] Example 85 was synthesized in the same manner as Example 18, using 4-(1H-pyrazol-1-yl)butanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, Tanol-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 1.9, 0.7 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.3, 1.9 Hz, 1H), 7.21 - 7.04 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.27 (t, J = 2.1 Hz, 1H), 5.97 - 5.74 (m, 2H), 4.20 (t, J = 6.8 Hz, 2H), 4.12 - 3.88 (m, 3H), 3.74 (dd, J = 26.9, 14.7 Hz, 2H), 3.66 - 3.47 (m, 2H), 3.38 (d, J = 32.3 Hz, 4H), 3.10 (dd, J = 15.0, 10.9 Hz, 1H), 2.93 - 2.60 (m, 3H), 2.61 - 2.30 (m, 4H), 2.31 - 1.71 (m, 12H), 1.41 (t, J = 13.2 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.29; Found: 720.97. Example 86 [ka]

[0327] Example 86 was synthesized in the same manner as Example 18, using 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 40 H 44 Calculated [M+H]+ for ClN5O5S: 742.28; found: 742.10. Example 87 [ka]

[0328] Example 87 was synthesized in the same manner as Example 18, using Example 5 and 3-(2-(trifluoromethyl)phenyl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 41 H 45 Calculated [M+H]+ for ClF3N3O5S: 784.2793; found: 784.392. Example 88 [ka]

[0329] Example 88 was synthesized in the same manner as Example 18, using 3-(furan-2-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform m-d) δ 7.70 (d, J = 8.5 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.22 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.07 (d, J = 2.3 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 5.85 (dt, J = 15.5, 5.2 Hz, 1H), 5.69 (dd, J = 15.8, 7.9 Hz, 1H), 4.12 - 3.95 (m, 2H), 3.60 (dd, J = 7.8, 3.4 Hz, 1H), 3.30 (d, J = 1.9 Hz, 3H), 3.08 - 2.94 (m, 4H), 2.82 - 2.64 (m, 6H), 2.30 (td, J = 14.7, 13.8, 6.2 Hz, 4H), 2.06 - 1.64 (m, 12H). LCMS-ESI+ (m / z): C 38 H 44Calculated value for ClN3O6S: 706.2712; Found: 706.305. Example 89 [ka] Preparation of 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid:

[0330] Step 1: Sodium hydride (70 mg, 3 mmol) was dissolved in THF (6 mL) and cooled to 0° C. Ethyl 2-(dimethoxyphosphoryl)acetate (650 mg, 3 mmol) was then added to the mixture and stirred for 20 minutes. 1,3-dimethyl-1H-pyrazole-5-carbaldehyde (300 mg, 2.417 mmol) was then added to the reaction and allowed to warm to room temperature for 30 minutes. After the reaction was deemed complete by TLC, the contents were diluted with ethyl acetate and aqueous ammonium chloride, and the organic layer was then dried over MgSO4, filtered, and concentrated. The crude reaction mixture was then purified on silica gel chromatography in 2 / 1 hexanes / ethyl acetate to give ethyl (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)acrylate (405 mg). LCMS-ESI+ (m / z): C 10 H 14 Calculated N2O2: 195.113; Measured: 195.132.

[0331] Step 2: Ethyl (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)acrylate (405 mg, 2 mmol) was placed in a reaction flask in ethanol (7 mL). Palladium on carbon was then added, the reaction was stirred, and the contents were purged and vented with nitrogen. Hydrogen gas from a balloon was then added, and the reaction was stirred for 3 hours. LCMS showed complete conversion to the hydrogenated product. The contents were then filtered through a fritted funnel and diluted with ethyl acetate. The palladium frit was wetted with water. The contents were concentrated, and the product was used in the next step without further purification to give ethyl 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoate. LCMS-ESI+(m / z): C 10 H 17Calculated [M+H] for N2O2: 197.129; Found: 197.090.

[0332] Step 3: Ethyl 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoate (404 mg, 2 mmol) was dissolved in THF (2 mL), ethanol (1 mL), and water (1 mL), then sodium hydroxide (412 mg, 10 mmol) was added. The reaction was then stirred for 1 hour. LCMS showed complete conversion. The reaction was diluted with DCM and then acidified with 1N HCl to pH 4. The organic layer was then dried over MgSO4 and concentrated to give 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid. LCMS-ESI+ (m / z): CH 13 Calculated [M+H] for N2O2: 169.0972; Found: 169.082.

[0333] Preparation of Example 89: Example 89 was synthesized in the same manner as Example 18, using 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.55 - 7.46 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 7.5 Hz, 2H), 3.99 (s, 3H), 3.89 (d, J = 15.3 Hz, 1H), 3.65 (t, J = 12.8 Hz, 2H), 3.56 - 3.50 (m, 1H), 3.39 (d, J = 14.3 Hz, 1H), 3.35 (s, 3H), 3.11 - 2.98 (m, 2H), 2.96 - 2.84 (m, 2H), 2.84 - 2.60 (m, 4H), 2.51 - 2.35 (m, 2H), 2.31 - 2.22 (m, 2H), 2.11 (d, J = 8.7 Hz, 2H), 2.08 (s, 3H), 1.99 (d, J = 17.1 Hz, 4H), 1.89 - 1.73 (m, 3H), 1.36 - 1.20 (m, 3H). LCMS-ESI+ (m / z): [M+H] C 39 H 48 Calculated value for ClN5O5S: 734.3137; Found: 734.400. Example 90 [ka]

[0334] Example 90 was synthesized in the same manner as Example 18, using 3-(4-chlorophenyl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 39 H 45 Calculated [M+H] for Cl2N3O5S: 750.253; found: 750.976. Example 91 [ka]

[0335] Example 91 was synthesized in the same manner as Example 18, using 3-(thiazol-2-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloro Form-d) δ 7.88 (d, J = 3.6 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.40 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.09 - 7.04 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 5.91 - 5.62 (m, 2H), 4.09 - 3.96 (m, 2H), 3.84 - 3.67 (m, 3H), 3.62 - 3.52 (m, 3H), 3.30 (s, 3H), 3.11 - 2.95 (m, 3H), 2.82 - 2.71 (m, LCMS-ESI+ (m / z): [M+H] C 37 H 43 Calculated for ClN4O5S2: 723.2436; Found: 723.971. Example 92 [ka] Preparation of 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoic acid:

[0336] Step 1: (1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methanol (750 mg, 4.16 mmol) was placed in a round-bottom flask and then dissolved in DCM (10 mL). Dess-Martin periodinane (2.2 g, 5 mmol) was then added. The reaction was stirred for 45 minutes. LCMS then indicated the reaction was complete, and the contents were diluted with aqueous sodium bicarbonate, and the organic layer was then dried over MgSO, then filtered and concentrated. The crude material was purified by silica gel chromatography in 1 / 1 hexanes ethyl acetate to give 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde. LCMS-ESI+ (m / z): [M+H] calculated for CHFNO: 179.043; found: 179.016.

[0337] Steps 2-4: 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoic acid was synthesized in the same manner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 90 (Steps 1-3). Preparation of Example 92:

[0338] Example 92 was synthesized in the same manner as Example 18, using 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.78 (d, J = 7.3 Hz, 2H), 4.91 (q, J = 8.3 Hz, 2H), 3.94 (s, 3H), 3.72 - 3.58 (m, 3H), 3.58 - 3.53 (m, 1H), 3.36 (s, 3H), 3.09 - 2.91 (m, 4H), 2.88 - 2.66 (m, 4H), 2.44 (s, 2H), 2.33 - 2.21 (m, 3H), 2.04 - 1.91 (m, 4H), 1.89 - 1.74 (m, 4H), 1.33 - 1.21 (m, 2H). LCMS-ESI+ (m / z): [M+H] C 39 H 45 Calculated value for ClN5O5S2: 788.2855; Found: 788.261. Example 93 [ka]

[0339] Example 93 was synthesized in the same manner as Example 18, using 3-(4-methylthiazol-5-yl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 38 H 45 Calculated [M+H] for ClN4O5S2: 737.2593; found: 737.220. Example 94 [ka]

[0340] Example 94 was synthesized in the same manner as Example 18, using 4,4,4-trifluorobutanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 8.5 Hz, 1H), 7.20 - 7.04 (m, 3H), 7.03 - 6.97 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.91 - 5.64 (m, 2H), 4.01 (q, J = 12.0 Hz, 3H), 3.73 (dd, J = 31.3, 14.6 Hz, 3H), 3.59 (dd, J = 8.1, 3.2 Hz, 1H), 3.31 (s, 3H), 3.18 (dt, J = 12.1, 6.0 Hz, 1H), 3.02 (dd, J = 15.2, 10.7 Hz, 1H), 2.80 - 2.63 (m, 4H), 2.59 - 2.46 (m, 2H), 2.39 - 2.27 (m, 3H), 2.08 - 1.90 (m, 5H), 1.88 - 1.78 (m, 2H), 1.76 - 1.65 (m, 2H), 0.98 - 0.77 (m, 2H). LCMS-ESI+ (m / z): [M+H] C 35 H 41 Calculated for ClF3N3O5S: 708.248; Found: 708.865. Example 95 [ka]

[0341] Example 95 was synthesized in the same manner as Example 18, using 5,5,5-trifluoropentanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform Mu-d) δ 7.61 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.6, 4.0 Hz, 2H), 5.89 - 5.66 (m, 2H), 3.99 (q, J = 11.8 Hz, 2H), 3.72 (dd, J = 29.4, 14.8 Hz, 3H), 3.57 (dd, J = 7.6, 3.1 Hz, 1H), 3.32 (s, 3H), 3.02 (dd, J = 15.1, 10.9 Hz, 1H), 2.80 - 2.67 (m, 3H), 2.65 - 2.53 (m, 2H), 2.46 - 2.14 (m, 7H), 1.97 (dq, J = 14.9, 7.4 Hz, 6H), 1.86 - 1.67 (m, 4H), 1.33 (t, J = 12.9 Hz, 2H). LCMS-ESI+ (m / z): [M+H] C 36 H 43 Calculated for ClF3N3O5S: 722.264; Found: 722.274. Example 96 [ka]

[0342] Example 96 was synthesized in the same manner as Example 18, using 2-phenoxyacetic acid instead of 3-methoxypropionic acid. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.3 Hz, 1H), 7.50 - 7.27 (m, 4H), 7.18 (dd, J = 8.5, 2.2 Hz, 1H), 7.12 - 6.97 (m, 4H), 6.93 (dd, J = 8.2, 2.8Hz, 1H), 5.95 - 5.65 (m, 2H), 4.10 (d, J = 12.0 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.91 - 3.83 (m, 1H), 3.75 (q, J = 14.1, 13.1 Hz, 2H), 3.61 (dd, J = 7.7, 3.4 Hz, 1H), 3.28 (s, 3H), 3.24 - 3.16 (m, 1H), 3.07 - 2.94 (m, 1H), 2.84 - 2.61 (m, 3H), 2.46 - 2.23 (m, 3H), 2.08 - 1.56 (m, 8H), 1.44 - 1.29 (m, 3H), 0.88 (t, J = 8.1 Hz, 1H). LCMS-ESI+ (m / z): [M+H]C 39 H 44 Calculated for ClN3O6S: 718.271; Found: 718.109. Example 97 [ka]

[0343] Example 97 was synthesized in the same manner as Example 18, using 3-phenylpropanoic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, chloroform-d) δ 7.67 (dd, J = 14.8, 8.6 Hz, 1H), 7.34–7.27 (m, 3H), 7.25–7.16 (m, 4H), 7.10 - 7.00 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 5.95 - 5.56 (m, 2H), 4.09 - 3.94 (m, 2H), 3.88 (q, J = 14.4, 11.1 Hz, 1H), 3.74 (dd, J = 25.2, 14.8 Hz, 3H), 3.59 (dd, J = 7.9, 3.3 Hz, 1H), 3.33 (s, 3H), 3.08 - 2.91 (m, 3H), 2.86 - 2.51 (m, 5H), 2.48 - 2.23 (m, 2H), 2.24 - 2.14 (m, 1H), 2.04 (t, J = 10.7 Hz, 2H), 1.98 - 1.63 (m, 6H), 1.41 - 1.23 (m, 2H), 0.86 (t, J = 10.0 Hz, 1H). LCMS-ESI+ (m / z): [M+H] C 40 H 46 Calculated value for ClN3O5S: 716.292; Actual value: 716.069. Example 98 [ka]

[0344] Example 98 was synthesized in the same manner as Example 18, using 1-methyl-1H-indole-2-carboxylic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 41 H 45 Calculated [M+H] for ClN4O5S: 741.287; found: 741.886. Example 99 [ka]

[0345] Example 99 was synthesized in the same manner as Example 18, using 3-(2-methylthiazol-4-yl)propanoic acid instead of 3-methoxypropionic acid. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 25.3, 8.7 Hz, 1H), 7.23 (s, 1H), 7.21 - 7.13 (m, 2H), 7.08 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.97 - 5.63 (m, 2H), 4.09 (d, J = 12.1 Hz, 1H), 4.01 (t, J = 10.3 Hz, 1H), 3.84 (t, J = 14.5 Hz, 1H), 3.73 (s, 3H), 3.60 (d, J = 7.4 Hz, 1H), 3.27 (d, J = 3.9 Hz, 3H), 3.06 - 2.91 (m, 1H), 2.78 (s, 2H), 2.65 (s, 2H), 2.28 (d, J = 31.5 Hz, 4H), 2.07 - 1.60 (m, 8H), 1.43 - 1.12 (m, 6H), 0.94 - 0.72 (m, 2H). LCMS-ESI+ (m / z): [M+H] C 38 H 45 Calculated value for ClN4O5S2: 737.295; Actual value: 737.040. Example 100 [ka] Preparation of 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid:

[0346] Step 1: 1-Methyl-1H-pyrazol-5-ol (250 mg, 3 mmol) was placed in a round-bottom flask, followed by the addition of potassium carbonate (387 mg, 3 mmol). THF (5 mL) was then added. Ethyl bromoacetate (547 mg, 3 mmol) was added, and the reaction was stirred at 50 °C for 1 hour. TLC indicated the consumption of 1-methyl-1H-pyrazol-5-ol. The contents were then diluted with ethyl acetate and water, and the organic layer was then dried over MgSO, filtered, and concentrated to give ethyl 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetate.

[0347] Step 2: Ethyl 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetate (0.265 mg, 1.44 mmol) was then diluted in THF (2 mL), water (1 mL) and ethanol (1 mL), then sodium hydroxide (115 mg, 2.88 mmol) was added. The reaction was stirred for 2 hours, then diluted with sec-butanol and 1N Diluted with HCl to pH 4, the organic layer was dried over MgSO, filtered, and concentrated to give 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid. LCMS-ESI+ (m / z): [M+H] calculated for C6H8N2O3: 157.061; found: 157.088.

[0348] Preparation of Example 100: Example 100 was synthesized in the same manner as Example 18, using 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, acetone-d6) δ 7.77 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.5, 2.3 Hz, 1H), 7.11 (d, J = 2.4 Hz, 2H), 7.04 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.96 - 5.78 (m, 2H), 4.13 - 3.92 (m, 4H), 3.79 (dd, J = 23.4, 14.6 Hz, 2H), 3.63 (dd, J = 13.4, 7.6 Hz, 1H), 3.53 (dd, J = 7.7, 3.0 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.90 - 2.80 (m, 2H), 2.62 (s, LCMS-ESI+ (m / z): [M+H] C 37 H 44 Calculated for ClN5O6S: 722.277; Found: 722.907. Example 101 [ka]

[0349] Example 101 was synthesized in the same manner as Example 18, using 3-(5-methylthiazol-4-yl)propanoic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): C 38 H 45 Calculated [M+H] for ClN4O5S2: 737.2953; found: 737.894. Example 102 [ka]

[0350] Example 102 was synthesized in the same manner as Example 18 using 3-(5-methyl-1,3,4-thiadiazol-2-yl)propanoic acid (prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde in the same manner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid as in Example 89). 1 H NMR (400 MHz, Roform-d) δ 7.64 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.91 - 5.64 (m, 2H), 4.01 (q, J = 12.1 Hz, 2H), 3.89 (s, 1H), 3.83 - 3.65 (m, 3H), 3.59 (dd, J = 8.2, 3.1 Hz, 1H), 3.50 - 3.35 (m, 2H), 3.32 (s, 3H), 3.04 (dd, J = 16.7, 9.6 Hz, 3H), 2.78 (s, 3H), 2.76 - 2.62 (m, 3H), 2.47 - 2.22 (m, 4H), 2.09 - 1.91 (m, 4H), 1.81 (p, J = 9.9 Hz, 2H), 1.71 (t, J = 9.3 Hz, 1H), 1.43 - 1.14 (m, 3H). LCMS-ESI+ (m / z): [M+H] C 37 H 44 Calculated value for ClN5O5S2: 738.255; Found: 738.054. (Example 103)

[0351] Example 103 was synthesized in the same manner as Example 18 using 3-(1,4-dimethyl-1H-pyrazol-5-yl)propanoic acid (prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde in the same manner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 89). 1 H NMR (400 MHz, chloroform) Lum-d) δ 7.54 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 - 6.99 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.90 - 5.66 (m, 2H), 4.06 - 3.94 (m, 4H), 3.85 (s, 1H), 3.66 (dd, J = 22.7, 14.0 Hz, 2H), 3.58 - 3.50 (m, 1H), 3.37 (d, J = 23.2 Hz, 3H), 3.04 (t, J = 12.4 Hz, 2H), 2.99 - 2.65 (m, 5H), 2.40 (d, J = 19.5 Hz, 2H), 2.24 (d, J = 11.3 Hz, 2H), 2.11 (s, 2H), 2.09 (s, 3H), 1.99 (d, J = 12.9 Hz, 4H), 1.90 - 1.65 (m, 3H), 1.37 - 1.20 (m, 3H), 0.80 (dd, J = 55.2, 11.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]C 39 H 48 Calculated for ClN5O5S: 734.314; Found: 734.132. [ka] Example 104 [ka]

[0352] Example 104 was synthesized in the same manner as Example 18, using 1-ethyl-1H-pyrazole-4-carboxylic acid instead of 3-methoxypropionic acid. 1 H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.93 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 6.93 (dd, J = 13.2, 8.6 Hz, 2H), 5.97 - 5.78 (m, 2H), 4.22 (q, J = 7.3 Hz, 2H), 3.98 (d, J = 15.3 Hz, 3H), 3.83 - 3.62 (m, 2H), 3.58 (dd, J = 8.3, 2.9 Hz, 1H), 3.52 - 3.40 (m, 2H), 3.35 (s, 3H), 3.19 - 2.99 (m, 2H), 2.86 - 2.68 (m, 3H), 2.49 (s, 2H), 2.37 - 2.24 (m, 2H), 2.08 (d, J = 12.7 Hz, 3H), 1.94 (s, 3H), 1.83 (t, J = 6.7 Hz, 2H), 1.46 (t, J = 7.3 Hz, 3H). LCMS-ESI+ (m / z): H+C 37 H 44 Calculated value for ClN5O5S: 706.22824; Found: 706.194. Example 105

[0353] Example 105 was synthesized in the same manner as Example 18, using 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid instead of 3-methoxypropionic acid. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (dt, J = 15.8, 5.2 Hz, 1H), 5.73 (dd, J = 15.9, 7.5 Hz, 1H), 4.15 (s, 2H), 4.12 - 3.92 (m, 4H), 3.92 - 3.63 (m, 4H), 3.55 (dddd, J = 20.5, 11.9, 6.3, 3.2 Hz, 3H), 3.32-3.25 (m, 4H), 3.01 (dd, J = 14.9, 11.0 Hz, 1H), 2.84 - 2.66 (m, 3H), 2.50 - 2.18 (m, 4H), 2.14 - 1.56 (m, 12H), 1.47 - 1.18 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 48 Calculated for ClN3O7S: 726.29; Found: 726.22. [ka] Example 106 [ka]

[0354] Step 1: N'-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimide amide was prepared in the same manner as Example 1 (Steps 4 and 5), using (S)-2-methylpent-4-ene-1-sulfonamide instead of (2R,3S)-3-methylhex-5-ene-2-sulfonamide. 1 H NMR (400 MHz, Chloroform-d) δ 5.75 (ddt, J = 19.5, 9.5, 7.0 Hz, 1H), 5.06 (d, J = 1.4 Hz, 1H), 5.03 (dq, J = 5.1, 1.7 Hz, 1H), 4.75 (d, J = 7.7 Hz, 2H), 3.13 (ddd, J = 18.6, 13.7, 4.6 Hz, 1H), 2.91 (ddd, J = 22.5, 13.8, 7.1 Hz, 1H), 2.32 - 2.16 (m, 2H), 2.16 - 2.02 (m, 2H), 1.10 (dd, J = 6.6, 4.2 Hz, 3H), 0.88 (s, 9H), 0.10 (d, J = 3.0 Hz, 6H).

[0355] Step 2: Preparation of intermediate 106-2: To a stirred solution of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carbonyl chloride (1.56 g, 3.11 mmol) in acetonitrile (30 mL) was added pyridazine (0.22 ml, 3.11 mmol) in acetonitrile (6 mL), followed by (2S)-N'-(tert-butyldimethylsilyl)-2-methylpent-4-ene-1-sulfonimideamide (0.9 g, 3.27 mmol) in acetonitrile (6 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel column (0-50% EtOAc in hexanes).

[0356] Step 3: Preparation of intermediate 106-3: To a stirred solution of intermediate 106-2 (1.54 g, 2.46 mmol) in CHCl (15 mL) was added triethylamine (0.69 mL, 4.92 mmol) in an ice bath, followed by the addition of di-tert-butyl dicarbonate (0.81 g, 3.69 mmol) and 4-(dimethylamino)-pyridine (120.17 mg, 0.98 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography. The fractions were concentrated, dissolved in EtOAc, and washed with 1% HCl solution, followed by saturated aqueous NaHCO. The organic phase was dried over MgSO, filtered, and concentrated, and the residue was purified again by silica gel column chromatography to give the desired product.

[0357] Step 4: Preparation of intermediate 106-4: The reaction mixture intermediate 106-3 (330 mg, 0.45 mmol), Hoveyda-Grubbs second-generation catalyst (85.18 mg, 0.14 mmol) in 1,2-dichloroethane (150 mL) was degassed with argon. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography. Two diastereomers were isolated (the less polar product is 106-4).

[0358] Step 5: Preparation of Example 106: Example 106 was synthesized in the same manner as Example 18, using 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid (3.61 mg, 0.023 mmol) instead of 3-methoxypropionic acid, and the less polar diastereomeric intermediate 106-4 (9 mg, 0.015 mmol). 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.10 (dt, J = 14.7, 7.0 Hz, 1H), 5.63 (dd, J = 15.3, 8.4 Hz, 1H), 4.22 (s, 2H), 4.15 (dd, J = 14.8, 6.9 Hz, 1H), 4.11 - 4.01 (m, 2H), 4.00 - 3.92 (m, 2H), 3.92 - 3.81 (m, 2H), 3.77 (d, J = 8.0 Hz, 1H), 3.71 (td, J = 10.0, 9.4, 4.9 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.29 (s, 3H), 3.07 (dd, J = 15.1, 9.7 Hz, 2H), 2.93 - 2.69 (m, 3H), 2.48 (d, J = 21.0 Hz, 3H), 2.37 - 2.06 (m, 4H), 2.06 - 1.88 (m, 4H), 1.88 - 1.73 (m, 3H), 1.65 (dtt, J = 13.4, 9.0, 4.3 Hz, 2H), 1.45 (t, J = 12.1 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H). LCMS-ESI+: C 39 H 50 Calculated value for ClN3O7S: 740.3 (M+H); Found: 740.0 (M+H). (Example 107) [ka]

[0359] Example 107 was synthesized in the same manner as Example 75 using intermediate 106-4 from Example 106 and cyclopropylmethanamine. 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 11.4 Hz, 2H), 7.02 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.06 (dd, J = 14.6, 7.3 Hz, 1H), 5.60 (dd, J = 15.3, 8.8 Hz, 1H), 4.25 (dd, J = 14.9, 6.7 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.84 (d, J = 15.1 Hz, 2H), 3.78 (dd, J = 8.9, 3.5 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.28 (s, 3H), 3.13 - 3.01 (m, 3H), 2.88 - 2.69 (m, 2H), 2.46 (dt, J = 23.9, 13.6 Hz, 3H), 2.18 (ddd, J = 36.0, 20.5, 10.7 Hz, 3H), 1.99 - 1.89 (m, 3H), 1.79 (dt, J = 17.4, 9.2 Hz, 3H), 1.43 (t, J = 11.9 Hz, 1H), 1.31 (s, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.08 - 0.97 (m, 1H), 0.57 - 0.47 (m, 2H), 0.25 (dt, J = 5.9, 4.4 Hz, 2H). LCMS-ESI+: C 37 H 47 Calculated for ClN4O5S: 695.3 (M+H); Found: 694.8 (M+H). Example 108 [ka]

[0360] Example 108 was synthesized in the same manner as Example 18 using 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid instead of 3-methoxypropionic acid and intermediate 49-3. 1H NMR (400 MHz, メタノール-d4) δ 7.75 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 - 7.12 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.00 - 5.93 (m, 1H), 5.59 (dd, J = 15.2, 9.2 Hz, 1H), 4.38 - 4.32 (m, 1H), 4.18 (s, 2H), 4.00 - 3.93 (m, 2H), 3.83 (d, J = 14.8 Hz, 1H), 3.76 - 3.65 (m, 3H), 3.52 - 3.45 (m, 3H), 3.37 - 3.34 (m, 3H), 3.24 (s, 3H), 3.16 - 3.06 (m, 1H), 2.86 - 2.73 (m, 3H), 2.49 - 1.72 (m, 12H), 1.67 - 1.58 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.50 - 1.42 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 52 ClN3O7S calculated value: 754.4; measured value: 754.2. (Example 109) Method 1

change

[0361] Step 1: (4S)-5-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]-4-methyl-pent-1-ene (106-1, 14.9 g, 53.9 mmol) was azeotroped with anhydrous toluene (3 × 50 mL) and dissolved in anhydrous tetrahydrofuran (250 mL) under an argon atmosphere. The solution was cooled to -50 °C (internal temperature probe). A solution of 2.5 M n-BuLi in hexanes (46.3 mL, 116 mmol) was added dropwise over 5 min. The mixture was allowed to stir for 15 min. Concurrently, (4-nitrophenyl)[(1S)-1-phenylethyl]carbonate (5-3-1, 20.1 g, 70.1 mmol) was azeotroped with toluene (3 × 50 mL). The material was dissolved in anhydrous tetrahydrofuran (50 mL) under an argon atmosphere. The solution was added to the reaction via cannula over 5 minutes. The reaction was initially yellow but turned very dark (green). After 15 minutes, the reaction was warmed to 0°C (ice bath). The reaction turned yellow during warming. After 1 hour, TLC (20% ethyl acetate / hexanes visualized with KMnO4 stain) showed the reaction was complete. The reaction was quenched with water (150 mL) at 0°C. Ethyl acetate (150 mL) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 75 mL). The combined organic phases were washed with saturated NaHCO3 (150 mL) and brine (150 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to give crude [(1S)-1-phenylethyl]N-[N-[tert-butyl(dimethyl)silyl]-S-[(2S)-2-methylpent-4-enyl]sulfonimidoyl]carbamate (109-1-1).

[0362] Step 2: A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 63.6 mL, 63.6 mmol) was added to a solution of 109-1-1 (22.5 g, 53.0 mmol) in anhydrous tetrahydrofuran at 0 °C. After 90 min at 0 °C, the reaction was complete. The solvent was removed under reduced pressure. The residue was diluted with water (150 mL) and ethyl acetate (150 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to flash chromatography (0–65% ethyl acetate / hexanes, 120 g gold Teledyne ISCO column with solid loading). An evaporative light scattering detector (ELSD) with UV was used for peak detection. Fractions containing the product were combined and the solvent removed under reduced pressure to give ((2S)-2-methylpent-4-en-1-ylsulfonimidoyl)carbamate as a mixture of diastereomers at sulfur. The solid was subjected to chiral SFC separation using a ChiralPak IC column with ethanol as a co-solvent. Alternatively, methanol was used as a co-solvent on a ChiralPak AD-H column. Fractions containing the same diastereomer were combined and the solvent removed under reduced pressure to give (S)-1-phenylethyl ((2S)-2-methylpent-4-en-1-ylsulfonimidoyl)carbamate as two diastereomers.

[0363] The first eluting diastereomer (109-1-2, 15% ethanol) Rt=3.05 min on ChiralPak IC with solvents, absolute stereochemistry tentatively assigned as shown): 1 H NMR (400 MHz, chloroform-d) δ 7.43 - 7.33 (m, 4H), 7.33 - 7.29 (m, 1H), 5.74 (q, J = 6.7 Hz, 1H), 5.62 (ddt, J = 16.0, 11.0, 7.1 Hz, 1H), 5.05 (d, J = 1.3 Hz, 1H), 5.04 - 4.99 (m, 1H), 3.43 (dd, J = 14.4, 4.5 Hz, 1H), 3.06 (dd, J = 14.4, 7.9 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.20 - 2.04 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H).

[0364] Second eluting diastereomer (109-1-3, Rt=4.92 min on ChiralPak IC with 15% ethanol co-solvent, absolute stereochemistry tentatively assigned as shown): 1 H NMR (400 MHz, chloroform-d) δ 7.44 - 7.32 (m, 4H), 7.32 - 7.30 (m, 1H), 5.79 - 5.73 (m, 1H), 5.73 - 5.66 (m, 1H), 5.16 - 5.05 (m, 2H), 3.38 (dd, J = 14.5, 4.4 Hz, 1H), 3.20 (dd, J = 14.4, 7.7 Hz, 1H), 2.27 (dq, J = 12.5, 6.8 Hz, 1H), 2.22 - 2.10 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H).

[0365] Step 3: i) Preparation of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (109-1-4): Methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate, 1-3 (11.2 g, 22.5 mmol) was dissolved in 2N The mixture was stirred overnight at 60° C. in a NaOH aqueous solution (10 mL) and a mixture of MeOH / THF (1 / 1) (200 mL). After cooling, the mixture was neutralized with HCl and concentrated. The resulting solid was suspended in water and then extracted with DCM. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give 109-1-4, which was used further without purification. LCMS-ESI+(m / z): C 28 H 32 [M+H]+ calculated for ClNO4: 482.20; found: 482.14.

[0366] ii) Preparation of intermediate 109-1-5: To a stirred solution of intermediate 109-1-4 (9.68 g, 20.1 mmol) in DCM (200 mL) was added intermediate 109-1-2 (first eluting diastereomer) (6.17 g, 19.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (7.62 g, 39.75 mmol), and 4-(dimethylamino)pyridine (4.21 g, 34.46 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give 109-1-5, which was used further without purification.

[0367] Step 4: To a solution of intermediate 109-1-5 (12.7 g, 16.4 mmol) in DCM (130 mL) was added TFA (25 mL). The reaction mixture was stirred at room temperature. After the reaction was completed, the solvent was removed under vacuum. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated to give 109-1-6, which was used further without purification.

[0368] Step 5: To a solution of intermediate 109-1-6 (10 g, 15.97 mmol) in DCM, triethylamine (4.45 mL, 31.94 mmol), 4-(dimethylamino)-pyridine (500 mg, 4.09 mmol), and di-tert-butyl dicarbonate (5.23 g, 23.95 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 N HCl (aq) and brine. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give intermediate 109-1-7.

[0369] Step 6: Intermediate 109-1-7 (1 g, 1.38 mmol), Hoveyda-Grubbs II (258.13 mg, 0.41 mmol) in 1,2-dichloroethane (400 mL) was degassed with argon. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO, 0-70% EtOAc / hexane) to give Example 109. 1 H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.2, 1.9 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.27 (ddd, J = 15.1, 7.9, 5.2 Hz, 1H), 5.99 (s, 2H), 5.56 (dd, J = 15.3, 8.2 Hz, 1H), 4.20 (s, 2H), 4.06 (t, J = 11.4 Hz, 2H), 3.92 - 3.82 (m, 1H), 3.82 - 3.69 (m, 2H), 3.47 (d, J = 5.6 Hz, 2H), 3.36 (d, J = 14.6 Hz, 1H), 3.28 (s, 3H), 3.02 (dd, J = 15.0, 11.0 Hz, 1H), 2.80 (dt, J = 11.3, 5.1 Hz, 2H), 2.63 - 2.53 (m, 1H), 2.47 - 2.36 (m, 2H), 2.26 (dt, J = 14.4, 7.3 Hz, 2H), 2.03 - 1.84 (m, 3H), 1.84 - 1.57 (m, 4H), 1.41 (t, J = 13.4 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 32 H 40 ClN3O4S calculated value: 598.2; measured value: 598.1. Method 2

change

[0370] Step 1: To a solution of intermediate 109-1-3 (second eluting diastereomer from Example 109-Method 1-Step 2, 1.1 g, 3.54 mmol) in DCM (50 mL) at 0 °C, triethylamine (1.48 mL, 10.63 mmol) and trifluoroacetic anhydride (1 mL, 7.08 mmol) were added. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction was quenched with brine. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated to give intermediate 109-2-1, which was used further without purification.

[0371] Step 2: To a solution of intermediate 109-2-1 (1.4 g, 3.44 mmol) in DCM (30 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature. After completion, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-50% EtOAc / hexanes) to give intermediate 109-2-2.

[0372] Step 3: To a stirred solution of intermediate 109-1-4 (1.5 g, 3.11 mmol) in DCM (200 mL), intermediate 109-2-2 (790 mg, 3.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1.5 g, 7.78 mmol), and 4-(dimethylamino)pyridine (760 mg, 6.22 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM and washed with 1 N HCl and brine. The organic phase was dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give intermediate 109-2-3.

[0373] Step 4: To a solution of intermediate 109-2-3 (72 mg, 0.1 mmol) in DCE (10 mL) was added TFA (0.02 mL, 0.2 mmol) and Hoveyda-Grubbs second-generation catalyst (12.46 mg, 0.02 mmol). The reaction mixture was degassed with argon and then stirred at 60 °C overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give intermediate 109-2-4.

[0374] Step 5: To a solution of intermediate 109-2-4 (130 mg, 0.19 mmol) in MeOH (10 mL) and HO (2 mL) was added potassium carbonate (129.4 mg, 0.94 mmol). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with water, and back-extracted with ethyl acetate. The organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (0-70% EtOAc / hexanes) to give Example 109. Method 3

[0375] Step 1: To a solution of intermediate 106-1 (690 mg, 2.5 mmol) in THF (10 mL) at -40 °C, n-butyllithium (1.6 M in hexanes, 1.87 mL) was added. The resulting mixture was stirred at -40 °C for 20 min. Then, a solution of (4-nitrophenyl)[(1S)-1-phenylethyl]carbonate (5-3-1, 1.43 g, 4.99 mmol) in THF (6 mL) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified using a silica gel column (0-20% EtOAc / hexane). The two diastereomers were separated. [ka]

[0376] First eluting diastereomer (109-3-1, absolute stereochemistry tentatively assigned as shown):1 H NMR (400 MHz, chloroform-d) δ 7.49 - 7.29 (m, 5H), 5.84 (dq, J = 23.2, 6.6 Hz, 1H), 5.74 - 5.47 (m, 1H), 5.08 - 4.93 (m, 2H), 3.32 (dd, J = 14.1, 4.6 Hz, 1H), 3.18 - 2.95 (m, 1H), 2.29 - 2.10 (m, 2H), 2.03 (ddt, J = 13.8, 6.9, 1.3 Hz, 1H), 1.59 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 0.93 (s, 9H), 0.21 (d, J = 3.1 Hz, 6H).

[0377] Second eluting diastereomer (109-3-2, absolute stereochemistry tentatively assigned as shown): 1 H NMR (400 MHz, chloroform-d) δ 7.45 - 7.25 (m, 5H), 5.81 (t, J = 6.6 Hz, 1H), 5.78 - 5.63 (m, 1H), 5.11 - 4.95 (m, 2H), 3.40 (dd, J = 13.9, 4.2 Hz, 1H), 3.07 (dd, J = 14.0, 7.5 Hz, 1H), 2.27 - 2.13 (m, 2H), 2.13 - 2.07 (m, 1H), 1.59 (d, J = 6.6 Hz, 3H), 1.09 (dd, J = 6.7, 3.2 Hz, 3H), 0.88 (s, 9H), 0.17 - 0.09 (m, 6H).

[0378] Step 2: To a stirred solution of intermediate 109-3-1 (40 mg, 0.094 mmol) in THF (5 mL) in an ice bath, tetrabutylammonium fluoride (1.0 M THF, 0.14 ml) was slowly added. The reaction mixture was stirred at 0 °C for 20 minutes, and then slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column (0-60% EtOAc / hexane) to give intermediate 109-1-2. 1H NMR (400 MHz, chloroform-d) δ 7.42 - 7.37 (m, 2H), 7.37 - 7.24 (m, 3H), 5.72 (q, J = 6.6 Hz, 1H), 5.62 (ddt, J = 15.9, 11.1, 7.1 Hz, 1H), 5.51 (s, 2H), 5.07 - 4.97 (m, 2H), 3.42 (dd, J = 14.4, 4.5 Hz, 1H), 3.06 (dd, J = 14.4, 7.9 Hz, 1H), 2.33 - 2.01 (m, 3H), 1.57 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). Method 4 [ka]

[0379] Step 1: Intermediate 109-1-3 was also prepared in a similar manner to Method 3-Step 2 (Example 109) using Intermediate 109-3-2 instead of Intermediate 109-3-1. Example 109 was synthesized in the same manner as Example 109 (Method 2) using Intermediate 109-1-3. Example 110 Method 1

[0380] Step 1: 1-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]hexane (1-5, 5.9 g, 20.1 mmol) was azeotroped with anhydrous toluene (3 × 20 mL) and dissolved in anhydrous tetrahydrofuran (150 mL) under an argon atmosphere. The solution was cooled to −50 °C (internal temperature probe). A solution of 2.5 M n-BuLi in hexane (17.3 mL, 43.3 mmol) was added dropwise over 5 min. The mixture was allowed to stir for 15 min. Concurrently, (4-nitrophenyl)[(1S)-1-phenylethyl]carbonate (5-3-1, 7.5 g, 26.2 mmol) was azeotroped with toluene (3 × 20 mL). The material was dissolved in anhydrous tetrahydrofuran (60 mL) under an argon atmosphere. The solution was added to the reaction via cannula over 5 min. The reaction was initially yellow but turned very dark (green). After 15 minutes, the reaction was warmed to 0°C (ice bath). The reaction turned yellow during warming. After 1 hour, TLC (20% EtOAc / hexanes visualized with KMnO4 stain) indicated the reaction was complete. The reaction was quenched with water (75 mL) at 0°C. EtOAc (50 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with saturated NaHCO3 (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure to give crude [(1S)-1-phenylethyl]N-[N-[tert-butyl(dimethyl)silyl]-S-[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonimidoyl]carbamate (110-1-1).

[0381] Step 2: A solution of TBAF (1.0 M, 19.7 mL, 19.7 mmol) was added to a solution of 110-1-1 (6.64 g, 15.1 mmol) in anhydrous THF at 0 °C. After 1 h at 0 °C, the reaction was complete. THF was removed under reduced pressure. The residue was diluted with water (80 mL) and EtOAc (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to flash chromatography (0–65% EtOAc / hexanes with solid loading on a 120 g gold isoco column). ELSD with UV was used for peak detection. The product-containing fractions were combined and the solvent removed under reduced pressure to give [(1S)-1-phenylethyl]N-[[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonimidoyl]carbamate as a mixture of diastereomers at sulfur. The solid was subjected to chiral SFC separation using a ChiralPak IC column with methanol as the co-solvent.

[0382] First eluting diastereomer (110-1-2, RT=2.37 min on ChiralPak IC with 15% methanol co-solvent, absolute stereochemistry tentatively assigned as shown). 1H NMR (400 MHz, chloroform-d) δ 7.45 - 7.33 (m, 4H), 7.33 - 7.30 (m, 1H), 5.73 (q, J = 6.7 Hz, 1H), 5.48 (dddd, J = 16.4, 10.1, 8.2, 6.0 Hz, 1H), 5.06 - 4.93 (m, 2H), 3.41 (qd, J = 7.0, 2.2 Hz, 1H), 2.53 - 2.39 (m, 1H), 2.07 (dt, J = 14.0, 6.2 Hz, 1H), 2.00 - 1.86 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H).

[0383] Second eluting diastereomer (110-1-3, Rt=3.92 min on ChiralPak IC with 15% methanol co-solvent, absolute stereochemistry tentatively assigned as shown). 1H NMR (400 MHz, chloroform-d) δ 7.43 - 7.32 (m, 4H), 7.33 - 7.29 (m, 1H), 5.75 (q, J = 6.6 Hz, 1H), 5.71 - 5.62 (m, 1H), 5.13 - 5.03 (m, 2H), 3.38 (qd, J = 7.1, 2.3 Hz, 1H), 2.47 (dtd, J = 8.9, 6.9, 2.2 Hz, 1H), 2.11 (dtt, J = 13.1, 6.5, 1.4 Hz, 1H), 2.07 - 1.96 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H). 1.31 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H).

[0384] Example 110 was synthesized in the same manner as Example 109 (Method 1 - Steps 3-6), using intermediate 110-1-2 instead of intermediate 109-1-2. 1H NMR (400 MHz, Chloroform-d) δ 7.778 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.3, 1.9 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.91 (dt, J = 15.8, 5.8 Hz, 1H), 5.69 (dd, J = 15.8, 6.8 Hz, 1H), 4.18 - 3.95 (m, 2H), 3.87 (dd, J = 14.9, 3.4 Hz, 1H), 3.73 (s, 5H), 3.41 - 3.23 (m, 4H), 3.01 (dd, J = 15.0, 10.9 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.62 (s, 2H), 2.46 (s, 1H), 2.31 - 2.01 (m, 3H), 1.99 - 1.64 (m, 6H), 1.46 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H). LCMS-ESI+ (m / z): H+ C 33 H 42 Calculated for ClN3O4S: 612.26; Found: 612.06. Method 2: [ka]

[0385] Step 1: To an ice-cold solution of intermediate 110-1-3 (second eluting diastereomer from Example 110-Method 1-Step 2, 3.6 g, 11.10 mmol) and trifluoroacetic anhydride (3.5 g, 16.64 mmol) in anhydrous dichloromethane, TEA (2.32 mL, 16.64 mmol) was added under argon, and the solution was then stirred for 30 minutes. The reaction mixture was concentrated to give intermediate 110-2-1.

[0386] Step 2: To a stirred mixture of dichloromethane / trifluoroacetic acid (3 / 1) (200 mL) was added intermediate 110-2-1 (4.2 g, 9.98 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by normal phase chromatography (SiO, 1:2 Hex:EtOAc) to give intermediate 110-2-2. 1H NMR (400 MHz, chloroform) Holm-d) δ 5.70 (dddd, J = 17.0, 10.2, 8.3, 5.8 Hz, 1H), 5.58 (s, 2H), 5.22 - 5.01 (m, 2H), 3.56 (qd, J = 7.0, 2.2 Hz, 1H), 2.63 - 2.42 (m, 1H), 2.19 (dtt, J = 15.1, 6.0, 1.6 Hz, 1H), 2.05 - 1.91 (m, 1H), 1.43 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H).

[0387] Step 3: To a stirred solution of intermediate 109-1-4 (4.0 g, 8.29 mmol) in DCM, EDCI (2.5 g, 16.6 mmol) and DMAP (2.0 g, 16.6 mmol) were added. The reaction mixture was stirred at room temperature for 10 min. Intermediate 110-2-2 (2.4 g, 9.13 mmol) was added, and the resulting suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and washed with DCM, aqueous NaHCO, 1N aqueous HCl, and brine. The organic layer was dried over MgSO, and the solvent was removed under reduced pressure to give the crude residue, which was subjected to column chromatography (SiO, 50–90% Hex / EtOAc) to give the desired intermediate 110-2-3.

[0388] Step 4: Intermediate 110-2-3 (1.2 g, 1.57 mmol), TFA (360 mg, 3.15 mmol), and Hoveyda Grubbs 2nd generation catalyst (196 mg, 0.32 mmol) were stirred in 1,2-dichloroethane (150 mL) at 60 °C for 2 h. More catalyst was added (196 mg, 0.32 mmol), and the mixture was stirred at 60 °C for 24 h. After concentration, the residue was purified by silica gel column chromatography (5-95% Hex / EtOAc) to give intermediate 110-2-4.

[0389] Step 5: To a stirred solution of intermediate 110-2-4 (200 mg, 0.28 mmol) in MeOH (10 mL) was added water (2 mL), followed by K2CO3 (195 mg, 1.41 mmol). The reaction mixture was stirred at 60 °C for 24 h. The mixture was evaporated under reduced pressure and then dissolved in DCM. Water was added, and the mixture was then extracted with DCM. The combined organic layers were washed with brine, dried over Mg2SO4, filtered, concentrated, and purified by silica gel column chromatography (50-90% hexanes / EtOAc) to give Example 110. Method 3:

[0390] Step 1: To a solution of intermediate 1-5 (Example 1 - Step 5, 1 g, 3.44 mmol) in THF (50 mL) at -50 °C, n-butyllithium (1.6 M in hexanes, 4.6 mL, 7.40 mmol) was added dropwise over 5 minutes. The mixture was allowed to stir for 15 minutes. Simultaneously, (4-nitrophenyl)[(1S)-1-phenylethyl]carbonate (5-3-1, 1.3 g, 4.47 mmol) was azeotroped with toluene (3 × 20 mL). The material was dissolved in anhydrous tetrahydrofuran (30 mL) under an argon atmosphere. The solution was added to the reaction via cannula over 5 minutes. The reaction was initially yellow but turned very dark (green). After 15 minutes, the reaction was warmed to 0 °C (ice bath). The reaction turned yellow during warming. After 3 hours, TLC (20% EtOAc / hexanes visualized with KMnO4 stain) indicated the reaction was complete. The reaction was quenched with water (75 mL) at 0 °C. EtOAc (50 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with saturated NaHCO3 (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was redissolved in hexanes and purified by flash column chromatography (silica gel, 0–100% dichloromethane in hexanes, ELSD detector). ELSD-active fractions were assayed by silica gel TLC (3:1 hexanes:ethyl acetate, KMnO4 stain), and diastereomeric products co-eluted with 70–100% dichloromethane. The crude product mixture was redissolved in hexane and purified again by flash column chromatography (silica gel, 0–20% ethyl acetate in hexane, ELSD detector). ELSD-active fractions were assayed by silica gel TLC (3:1 hexane:ethyl acetate, KMnO stain). The first eluting peak (110-3-1, absolute stereochemistry tentatively assigned as indicated) eluted with 10% ethyl acetate, while the later eluting peak (110-3-2, absolute stereochemistry tentatively assigned as indicated) eluted with 15% ethyl acetate. [ka]

[0391] Step 2: A solution of TBAF (1.0 M, 2.84 mL, 2.84 mmol) was added to a solution of intermediate 110-3-1 (830 mg, 1.89 mmol) in anhydrous THF at 0 °C. After 60 min at 0 °C, the reaction was complete. The solvent was removed under reduced pressure. The residue was diluted with water (80 mL) and EtOAc (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to flash chromatography (0–50% EtOAc / hexane, 80 g silica gel). ELSD with UV was used for peak detection. The product-containing fractions were combined, and the solvent was removed under reduced pressure to give intermediate 110-1-2.

[0392] Preparation of Example 110: Example 110 was synthesized in the same manner as Example 110 (Method 1) using intermediate 110-1-2. Method 4: [ka]

[0393] Step 1: Intermediate 110-1-3 was also prepared in a similar manner to Method 3-Step 2 (Example 110), using intermediate 110-3-2 instead of intermediate 110-3-1.

[0394] Preparation of Example 110: Example 110 was synthesized in the same manner as Example 109 (Method 2) using intermediate 110-1-3. Example 111 [ka]

[0395] To a mixture of Example 109 (10 mg, 0.0167 mmol) in DCM (0.6 mL) was added ACN (1.7 mL) at room temperature. 4-Dimethylaminopyridine (10.2 mg, 0.0836 mmol) and diphenyl carbonate (28.6 mg, 0.134 mmol) were then added to the mixture and stirred at room temperature. After 5 h, pyrimidin-2-amine (12.7 mg, 0.134 mmol) was added, and the reaction was heated at 60 °C for 5 h and then allowed to reach room temperature overnight. The reaction was concentrated, redissolved in DMF (1.2 mL), filtered, and purified by Gilson reverse-phase preparative HPLC eluting with 60–100% ACN / 0.1% TFA in HO. 1 H NMR (400 MHz, methanol-d4) δ 8.73 (d, J = 5.1 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.38 - 6.82 (m, 7H), 6.14 (dq, J = 14.4, 6.6 Hz, 1H), 5.62 (dd, J = 15.4, 8.3 Hz, 1H), 4.21 (dd, J = 14.8, 6.3 Hz, 1H), 4.12 - 4.01 (m, 3H), 3.91 - 3.64 (m, 3H), 3.29 (s, 3H), 3.08 (dd, J = 15.2, 10.0 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.60 - 2.37 (m, 3H), 2.32 - 2.06 (m, 3H), 2.02 - 1.67 (m, 7H), 1.45 (t, J = 11.1 Hz, 1H), 1.15 (dd, J = 8.4, 6.3 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 43 Calculated for ClN6O5S: 719.2; Found: 719.5. Example 112 [ka]

[0396] Example 112 was synthesized in the same manner as Example 111, using (3S)-tetrahydrofuran-3-amine hydrochloride instead of pyrimidin-2-amine, and Hunig's base (8.64 mg, 0.0669 mmol) was also added to the reaction. 1H NMR (400 MHz, Tanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.24 - 7.10 (m, 3H), 7.03 - 6.88 (m, 2H), 6.23 - 5.97 (m, 1H), 5.64 - 5.50 (m, 1H), 4.37 - 4.21 (m, 2H), 4.11 - 4.01 (m, 2H), 3.98 - 3.75 (m, 6H), 3.72 - 3.48 (m, 3H), 3.28 (s, 3H), 3.08 (dd, J = 15.3, 10.2 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.57 - 2.33 (m, 3H), 2.31 - 2.09 (m, 3H), 1.98 - 1.73 (m, 8H), 1.44 (t, J = 11.8 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H).LCMS-ESI+ (m / z): [M+H]+ C 37 H 47 Calculated for ClN4O6S: 711.3; Found: 710.8. Example 113 [ka]

[0397] To a mixture of 1-methylpyrazole-4-carboxylic acid (3.76 mg, 0.0298 mmol) in DCM (1.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.71 mg, 0.0298 mmol) and 4-dimethylaminopyridine (3.64 mg, 0.0298 mmol). The mixture was stirred at room temperature for 5 minutes, then Example 5 (8.7 mg, 0.0149 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was then concentrated, redissolved in DMF (1.2 mL), filtered, and purified by Gilson reverse-phase preparative HPLC eluting with 60-100% ACN / HO containing 0.1% TFA to give Example 113. 1 H NMR (400 MHz, methanol-d4) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.99 - 6.83 (m, 2H), 5.98 - 5.90 (m, 1H), 5.86 (dd, J = 16.0, 8.2 Hz, 1H), 3.97 (d, J = 29.0 Hz, 6H), 3.77 (d, J = 15.0 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.62 - 3.55 (m, 2H), 3.47 (d, J = 14.3 Hz, 1H), 3.37 (s, 3H), 3.16 (d, J = 26.2 Hz, 1H), 2.88 - 2.74 (m, 3H), 2.50 (s, 2H), 2.30 (d, J = 9.2 Hz, 2H), 2.10 (d, J = 14.0 Hz, 3H), 2.00 - 1.84 (m, 4H), 1.41 (d, J = 11.9 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 42 Calculated for ClN5O5S: 692.2; Found: 691.973. Example 114 [ka]

[0398] Example 114 was synthesized in the same manner as Example 75 using Example 109 and methyl 3-aminoazetidine-1-carboxylate. 1 H NMR (400 MHz, methanol-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.09 (d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.07 - 5.89 (m, 1H), 5.57 (dd, J = 15.3, 9.0 Hz, 1H), 4.60 - 4.41 (m, 1H), 4.25 (t, J = 8.5 Hz, 3H), 4.13 - 3.98 (m, 2H), 3.96 - 3.79 (m, 3H), 3.75 (dd, J = 9.0, 3.7 Hz, 1H), 3.69 - 3.62 (m, 1H), 3.66 (s, 3H), 3.29 - 3.23 (m, 1H), 3.25 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.88 - 2.66 (m, 2H), 2.53 - 2.28 (m, 3H), 2.24 - 2.05 (m, 3H), 2.00 - 1.65 (m, 7H), 1.42 (t, J = 12.4 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H). LCMS-ESI+: C 38 H 48 Calculated for ClNOS: 754.29 (M+H); Found: 753.97 (M+H). Example 115 [ka]

[0399] Example 115 was synthesized in the same manner as Example 75 using Example 109 and (1S,2R)-2-fluorocyclopropanamine. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.03 (dd, J = 15.0, 7.6 Hz, 1H), 5.59 (dd, J = 15.2, 8.9 Hz, 1H), 4.79 - 4.54 (m, 1H), 4.29 (dd, J = 14.9, 6.4 Hz, 1H), 4.14 - 4.01 (m, 2H), 3.91 - 3.73 (m, 3H), 3.68 (d, J = 14.5 Hz, 1H), 3.31 - 3.24 (m, 1H), 3.27 (s, 3H), 3.07 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.68 (dt, J = 10.2, 5.5 Hz, 1H), 2.57 - 2.31 (m, 3H), 2.28 - 2.07 (m, 3H), 2.03 - 1.65 (m, 6H), 1.44 (t, J = 12.5 Hz, 1H), 1.24 - 1.07 (m, 4H), 1.01 - 0.84 (m, 1H). LCMS-ESI+: C 36 H 44 Calculated for ClFN4O5S: 699.27 (M+H); Found: 698.73 (M+H). Example 116 [ka]

[0400] Example 116 was synthesized in the same manner as Example 75 using Example 109 and (1R,2S)-2-fluorocyclopropanamine. 1H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.11 - 5.97 (m, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.66 (dtd, J = 64.4, 5.7, 3.2 Hz, 1H), 4.30 (dd, J = 14.9, 6.3 Hz, 1H), 4.15 - 3.99 (m, 2H), 3.86 (d, J = 14.8 Hz, 2H), 3.78 (dd, J = 9.0, 3.7 Hz, 1H), 3.68 (d, J = 14.6 Hz, 1H), 3.31 - 3.28 (m, 1H), 3.27 (s, 3H), 3.07 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.67 (dt, J = 9.4, 5.3 Hz, 1H), 2.55 - 2.30 (m, 3H), 2.26 - 2.08 (m, 3H), 2.01 - 1.67 (m, 6H), 1.44 (t, J = 12.2 Hz, 1H), 1.21 - 1.06 (m, 4H), 1.02 - 0.87 (m, 1H). LCMS-ESI+: C 36 H 44 Calculated for ClFN4O5S: 699.27 (M+H); Found: 698.65 (M+H). Example 117 [ka]

[0401] Example 117 was prepared in a similar manner to Example 75 using (1S,2R)-2-methylcyclopropan-1-amine hydrochloride, triethylamine and Example 109. NMR (400 MHz, メタノール-d4) δ 7.76 (d, J = 8.5 Hz, 2H), 7.38 (s, 2H), 7.18 (d, J = 9.3 Hz, 2H), 7.12 (s, 2H), 6.85 (s, 2H), 6.24 (s, 2H), 5.59 (s, 2H), 4.60 (s, 1H), 4.11 - 3.97 (m, 4H), 3.83 - 3.66 (m, 9H), 2.80 (d, J = 19.4 Hz, 4H), 2.63 (s, 3H), 2.32 (s, 4H), 2.20 - 2.03 (m, 5H), 1.96 (s, 6H), 1.77 (s, 6H), 1.46 (s, 3H), 1.31 (s, 1H), 1.07 (d, J = 6.1 Hz, 23H), 0.83 (ddt, J = 12.2, 6.1, 3.0 Hz, 3H), 0.61 (ddd, J = 9.0, 5.1, 3.6 Hz, 4H), 0.51 - 0.39 (m, 6H). LCMS -ESI+ (m / z): [M+H] C 37 H 47 Calculated value of ClN4O5S: 695.32; The measured value is 694.99. (Example 118)

change

[0402] Synthesis of 5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid: To a solution of 5-chloro-1H-pyrrole-3-carboxylic acid (0.075 g; 0.515 mmol) in 1.0 mL of DMSO was added freshly ground potassium hydroxide (KOH (solid); 0.231 g; 4.12 mmol). The heterogeneous slurry was stirred for 50 min, after which iodomethane (MeI; 0.048 mL; 0.109 g; 0.773 mmol) was added. After stirring the mixture at ambient temperature for 4 h, the reaction mixture was diluted with 10 mL each of CHCl and 1 N HCl (aq). The biphasic mixture was stirred for at least 10 min, after which the layers were separated. The aqueous layer was back-extracted with 10 mL each of isopropyl acetate and ethyl acetate. The combined organic phases were washed with 10 mL of HO and dried over anhydrous NaSO. The organic phase was concentrated to dryness in vacuo and used directly in the next step (see below) (62 mg; yield 82.7%). 1 H NMR (400 MHz, DMSO-d) δ 11.98 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 3.60 (s, 3H), 2.55 (s, 1H). LCMS-ESI+ (m / z): [M+H] calculated for C6H6ClNO2: 160.01; found 160.07.

[0403] Example 118 was prepared in a similar manner to Example 106 using 5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid and Example 109. 1H NMR (400 MHz, メタノール-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.15 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.81 (d, J = 8.1 Hz, 1H), 6.48 (s, 1H), 6.17 (dd, J = 14.8, 7.4 Hz, 1H), 5.51 (dd, J = 15.4, 8.7 Hz, 1H), 4.15 (s, 1H), 4.10 (d, J = 7.1 Hz, 0H), 4.09 - 3.95 (m, 2H), 3.86 - 3.70 (m, 2H), 3.60 (s, 4H), 3.25 (s, 4H), 3.03 (dd, J = 15.0, 9.8 Hz, 1H), 2.86 - 2.67 (m, 2H), 2.59 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.22 - 2.05 (m, 4H), 1.99 (d, J = 9.6 Hz, 2H), 1.91 (d, J = 7.5 Hz, 2H), 1.79 (dd, J = 19.5, 8.7 Hz, 1H), 1.73 (s, 2H), 1.69 (d, J = 8.8 Hz, 0H), 1.41 (t, J = 12.7 Hz, 1H), 1.33 - 1.19 (m, 2H), 1.06 (d, J = 6.5 Hz, 3H), 0.89 (dd, J = 7.3, 3.8 Hz, 1H). LCMS-ESI+(m / z): [M+H] C 38 H 44 Cl2N4O5S calculated value: 739.24; measured value: 739.75 (M+H). (Example 119)

change

[0404] Example 119 was prepared in a similar manner to Example 18 using 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.66 (s, 0H), 7.52 (s, 1H), 7.40 - 7.32 (m, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (dd, J = 6.4, 2.1 Hz, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.22 (dt, J = 14.4, 6.9 Hz, 1H), 5.56 (dd, J = 15.4, 8.6 Hz, 1H), 4.22 - 3.98 (m, 3H), 3.87 - 3.74 (m, 2H), 3.78 - 3.61 (m, 4H), 3.55 (dt, J = 11.6, 2.8 Hz, 0H), 3.35 (s, 0H), 3.28 (s, 3H), 3.06 (dd, J = 15.2, 10.2 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.70 - 2.61 (m, 1H), 2.52 - 2.38 (m, 1H), 2.29 (s, 1H), 2.21 (dt, J = 14.1, 7.0 Hz, 1H), 2.12 (d, J = 13.7 Hz, 1H), 1.94 (d, J = 7.0 Hz, 3H), 1.88 - 1.69 (m, 2H), 1.44 (t, J = 11.9 Hz, 1H), 1.31 (s, 0H), 1.11 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, methanol-d4) δ -97.35. LCMS-ESI+(m / z): [M+H] C 37 H 42 Calculated value for ClF2N5O5S: 742.26; actual value 742.13. Example 120 [ka]

[0405] Example 118 was prepared in a similar manner to Example 18 using 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, methanol-d4) δ 8.11 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.41 - 7.24 (m, 3H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.22 (dt, J = 14.4, 6.8 Hz, 1H), 5.75 - 5.67 (m, 0H), 5.55 (dd, J = 15.4, 8.7 Hz, 1H), 5.07 (s, 0H), 4.31 (t, J = 5.1 Hz, 2H), 4.22 - 3.97 (m, 3H), 3.84 (d, J = 14.8 Hz, 1H), 3.82 - 3.63 (m, 7H), 3.61 - 3.51 (m, 0H), 3.29 (d, J = 12.4 Hz, 5H), 3.06 (dd, J = 15.0, 10.0 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.64 (d, J = 13.8 Hz, 1H), 2.43 (s, 2H), 2.27 (s, 1H), 2.23 - 2.08 (m, 3H), 1.94 (d, J = 6.3 Hz, 3H), 1.88 - 1.68 (m, 2H), 1.52 (d, J = 6.6 Hz, 1H), 1.50 - 1.38 (m, 1H), 1.31 (s, 3H), 1.10 (dd, J = 6.7, 3.6 Hz, 4H), 0.93 (d, J = 5.7 Hz, 0H), 0.90 (s, 2H), 0.12 (s, 1H). LCMS-ESI+(m / z): [M+H] C39 H 48 Calculated for ClN5O6S: 750.30; Found: 750.08. Example 121 [ka]

[0406] Example 121 was synthesized in the same manner as Example 18 using (S)-2-hydroxy-3-phenylpropionic acid and Example 109. 1H NMR (400 MHz, acetonite) Lil-d3) δ 7.72 (d, J = 8.5 Hz, 1H), 7.36 - 7.21 (m, 6H), 7.19 (dd, J = 8.6, 2.4 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.01 (dt, J = 14.0, 6.5 Hz, 1H), 5.57 (dd, J = 15.5, 7.9 Hz, 1H), 4.43 (dd, J = 8.1, 4.2 Hz, 1H), 4.06 (d, J = 12.1 Hz, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.86 (s, 1H), 3.80 (d, J = 15.3 Hz, 1H), 3.74 - 3.66 (m, 2H), 3.34 (d, J = 14.3 Hz, 1H), 3.20 (s, 3H), 3.17 (dd, J = 14.1, 4.2 Hz, 1H), 3.05 (dd, J = 15.2, 10.1 Hz, 1H), 2.94 (dd, J = 14.0, 8.2 Hz, 1H), 2.86 - 2.68 (m, 2H), 2.52 - 2.34 (m, 3H), 2.14 (t, J = 8.5 Hz, 2H), 2.10 - 2.00 (m, 1H), 1.90 - 1.59 (m, 9H), 1.41 (dt, J = 14.6, 7.8 Hz, 1H), 1.05 (d, J = 6.3 Hz, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 41 H 48 Calculated for ClN3O6S: 746.3; Found: 746.0. Example 122 [ka]

[0407] Example 122 was synthesized in the same manner as Example 18 using (R)-2-hydroxy-3-phenylpropionic acid and Example 109. 1H NMR (400 MHz, acetonite) Lil-d3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.36 - 7.27 (m, 4H), 7.28 - 7.22 (m, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (dd, J = 9.3, 2.2 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.00 (dt, J = 14.6, 6.9 Hz, 1H), 5.55 (dd, J = 15.6, 7.9 Hz, 1H), 4.49 (dd, J = 7.6, 4.1 Hz, 1H), 4.06 (d, J = 12.1 Hz, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.83 - 3.75 (m, 2H), 3.75 - 3.64 (m, 2H), 3.34 (d, J = 14.3 Hz, 1H), 3.20 (s, 3H), 3.15 (dd, J = 14.1, 4.1 Hz, 1H), 3.04 (dd, J = 15.1, 10.3 Hz, 1H), 2.96 (dd, J = 14.1, 7.6 Hz, 1H), 2.86 - 2.64 (m, 2H), 2.49 - 2.32 (m, 3H), 2.11 - 1.99 (m, 2H), 1.92 - 1.57 (m, 10H), 1.40 (dt, J = 15.1, 8.0 Hz, 1H), 0.99 (d, J = 6.9 Hz, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 41 H 48 Calculated for ClN3O6S: 746.3; Found: 746.0. Example 123 [ka]

[0408] Example 123 was synthesized in the same manner as Example 18 using 1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, acetone Nitrile-d3) δ 8.29 (s, 1H), 7.90 (d, J = 0.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 8.2, 1.9 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.01 (dt, J = 13.7, 6.6 Hz, 1H), 5.60 (dd, J = 15.4, 8.4 Hz, 1H), 4.54 (hept, J = 6.6 Hz, 1H), 4.12 (dd, J = 14.8, 6.3 Hz, 1H), 3.97 (s, 2H), 3.86 - 3.67 (m, 3H), 3.63 (d, J = 14.4 Hz, 1H), 3.35 (d, J = 14.4 Hz, 1H), 3.21 (s, 3H), 3.06 (dd, J = 15.2, 10.2 Hz, 1H), 2.86 - 2.65 (m, 2H), 2.59 (d, J = 13.3 Hz, 1H), 2.47 - 2.32 (m, 2H), 2.19 (dq, J = 14.5, 7.2 Hz, 2H), 2.08 - 1.97 (m, 2H), 1.90 (d, J = 4.0 Hz, 2H), 1.83 - 1.63 (m, 3H), 1.46 (t, J = 6.8 Hz, 6H), 1.34 (dt, J = 13.3, 8.0 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -77.37. LCMS-ESI+ (m / z): [M+H]+ C 39 H 48 Calculated for ClN5O5S: 734.3; Found: 733.8. Example 124 [ka]

[0409] Example 124 was synthesized in the same manner as Example 18 using 2-((4-methyltetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example 109. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.72 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.04 (dt, J = 14.7, 6.7 Hz, 1H), 5.58 (ddd, J = 15.5, 7.5, 1.4 Hz, 1H), 4.08 (d, J = 1.0 Hz, 2H), 4.05 (d, J = 12.1 Hz, 1H), 3.99 (d, J = 12.1 Hz, 1H), 3.90 (dd, J = 15.0, 5.3 Hz, 1H), 3.81 (d, J = 7.1 Hz, 1H), 3.79 - 3.75 (m, 1H), 3.75 - 3.66 (m, 3H), 3.61 (dt, J = 11.6, 4.2 Hz, 2H), 3.36 (d, J = 14.5 Hz, 1H), 3.21 (s, 3H), 3.05 (dd, J = 15.1, 10.8 Hz, 1H), 2.85 - 2.66 (m, 2H), 2.57 - 2.45 (m, 2H), 2.45 - 2.34 (m, 1H), 2.33 - 2.21 (m, 1H), 2.15 (dt, J = 14.7, 7.4 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.92 - 1.85 (m, 3H), 1.84 - 1.56 (m, 8H), 1.40 (dt, J = 14.9, 7.6 Hz, 1H), 1.25 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 40 H 52 Calculated for ClN3O7S: 754.3; Found: 753.9. Example 125 [ka]

[0410] Example 125 was synthesized in the same manner as Example 18 using 6-oxaspiro[3.4]octane-2-carboxylic acid and Example 109. 1 H NMR (400 MHz, acetonitrile) Tolyl-d3) δ 7.59 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.2, 1.9 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.15 - 5.99 (m, 1H), 5.64 (dd, J = 15.5, 8.2 Hz, 1H), 4.01 - 3.90 (m, 3H), 3.85 (ddd, J = 14.7, 4.9, 3.1 Hz, 1H), 3.79 - 3.64 (m, 6H), 3.61 (d, J = 5.6 Hz, 2H), 3.45 - 3.29 (m, 2H), 3.26 (s, 4H), 3.07 (dd, J = 15.2, 10.1 Hz, 1H), 2.75 (dtt, J = 43.7, 17.9, 8.8 Hz, 4H), 2.51 - 2.13 (m, 7H), 2.10 - 1.99 (m, 3H), 1.95 - 1.89 (m, 2H), 1.88 - 1.63 (m, 2H), 1.43 - 1.23 (m, 2H), 1.10 (dd, J = 6.8, 1.1 Hz, 3H). LCMS-ESI+ (m / z): H+C 40 H 50 Calculated value for ClN3O6S: 736.3; Actual value: 736.12. Example 126 [ka]

[0411] Example 126 was synthesized in the same manner as Example 18 using 3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, Tanol-d4) δ 8.23 ​​(s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.1, 1.9 Hz, 1H), 7.13 (s, 1H), 7.11 (s, 2H), 7.00 - 6.87 (m, 2H), 6.04 (dd, J = 15.0, 7.3 Hz, 1H), 5.62 (dd, J = 15.2, 8.9 Hz, 1H), 4.37 (dd, J = 14.8, 6.4 Hz, 1H), 4.07 (s, 2H), 3.89 (s, 3H), 3.88 - 3.75 (m, 3H), 3.67 (d, J = 14.2 Hz, 1H), 3.28 (s, 3H), 3.19 - 3.00 (m, 1H), 2.91 - 2.70 (m, 2H), 2.62 - 2.45 (m, 1H), 2.44 - 2.07 (m, 4H), 2.05 - 1.73 (m, 3H), 1.44 (t, J = 12.7 Hz, 1H), 1.31 (s, 1H), 1.17 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m / z): C 37 H 43 C l2 Calculated value for N5O5S: 739.24; Found: 739.99. Example 127 [ka]

[0412] Example 127 was synthesized in the same manner as Example 18 using cis-3-methoxycyclobutanecarboxylic acid and Example 109. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (dd, J = 9.1, 2.1 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.13 (dt, J = 14.4, 6.9 Hz, 1H), 5.61 (dd, J = 15.4, 8.5 Hz, 1H), 4.17 (dd, J = 14.8, 6.7 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.96 (dd, J = 14.8, 5.3 Hz, 1H), 3.91 - 3.80 (m, 2H), 3.76 (d, J = 8.6 Hz, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.27 (d, J = 13.7 Hz, 7H), 3.06 (dd, J = 15.1, 9.8 Hz, 1H), 2.88 - 2.70 (m, 3H), 2.58 - 2.47 (m, 3H), 2.45 (s, 2H), 2.34 - 2.19 (m, 2H), 2.14 (dd, J = 19.5, 10.9 Hz, 3H), 1.95 (s, 3H), 1.90 - 1.70 (m, 3H), 1.44 (t, J = 12.4 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H). LCMS-ESI+: C 38 H 48 Calculated for ClN3O6S: 710.3 (M+H); Found: 710.1 (M+H). Example 128 [ka]

[0413] Example 128 was synthesized in the same manner as Example 18 using trans-3-methoxycyclobutanecarboxylic acid and Example 109. 1H NMR (400 MHz, メタノール-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.1, 1.9 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (dd, J = 4.1, 2.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.5, 6.9 Hz, 1H), 5.62 (dd, J = 15.4, 8.4 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.06 (dd, J = 7.6, 3.7 Hz, 2H), 4.03 - 3.93 (m, 2H), 3.85 (d, J = 15.0 Hz, 1H), 3.77 (dd, J = 8.5, 2.8 Hz, 1H), 3.69 (d, J = 14.2 Hz, 1H), 3.36 (s, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 3.21 - 3.12 (m, 1H), 3.07 (dd, J = 15.2, 9.8 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.57 (qd, J = 8.1, 4.1 Hz, 2H), 2.46 (s, 2H), 2.36 - 2.17 (m, 3H), 2.12 (d, J LCMS-ESI+: C 38 H 48 ClN3O6S calculated value: 710.3 (M+H); measured value: 710.1 (M+H). (Example 129)

change

[0414] Example 129 was synthesized in the same manner as Example 75 using Example 109 and trans-rac-(1R,2S)-2-(1-methylpyrazol-4-yl)cyclopropanamine hydrochloride and triethylamine. 1 H NMR (400 MHz, methanol-d4) δ 7.67 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.10 - 6.01 (m, 1H), 5.70 - 5.59 (m, 1H), 4.23 (dd, J = 14.8, 6.8 Hz, 1H), 4.02 (s, 2H), 3.83 (s, 5H), 3.65 (d, J = 14.2 Hz, 1H), 3.37 (s, 1H), 3.30 (s, 4H), 3.08 (dd, J = 15.2, 9.9 Hz, 1H), 2.92 - 2.51 (m, 5H), 2.45 (s, 2H), 2.23 (s, 2H), 2.08 (t, J = 11.5 Hz, 2H), 2.02 - 1.85 (m, 4H), 1.81 (d, J = 7.5 Hz, 2H), 1.40 (t, J = 12.9 Hz, 1H), 1.19 - 1.12 (m, 3H), 1.03 (q, J = 6.3 Hz, 1H). LCMS-ESI+: C 40 H 49 Calculated for ClN6O5S: 761.3 (M+H); Found: 760.8 (M+H). Example 130 [ka]

[0415] Example 130 was synthesized in the same manner as Example 18 using 1-ethylpyrrole-3-carboxylic acid and Example 109. 1H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.18 - 7.08 (m, 3H), 6.90 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 3.0, 2.1 Hz, 1H), 6.64 (dd, J = 2.9, 1.8 Hz, 1H), 6.12 (dt, J = 14.4, 6.6 Hz, 1H), 5.62 (dd, J = 15.4, 8.5 Hz, 1H), 4.24 (dd, J = 14.6, 6.3 Hz, 1H), 4.12 - 3.98 (m, 4H), 3.86 (d, J = 15.0 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.69 (d, J = 14.3 Hz, 1H), 3.38 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.1, 10.0 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.57 (dd, J = 12.9, 6.5 Hz, 1H), 2.46 (s, 2H), 2.32 - 2.15 (m, 2H), 2.12 (d, J = 13.7 Hz, 1H), 1.96 (d, J = LCMS-ESI+: C 39 H 47 Calculation of ClN4O5S Value: 719.3 (M+H); Found: 718.8 (M+H). Example 131 [ka]

[0416] Example 131 was synthesized in the same manner as Example 75 using Example 109 and 1-(methoxymethyl)cyclopropanamine. 1H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.25 - 7.14 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.01 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.03 (dd, J = 14.7, 7.4 Hz, 1H), 5.59 (dd, J = 15.3, 8.9 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.13 - 4.00 (m, 2H), 3.90 - 3.73 (m, 3H), 3.68 (d, J = 14.2 Hz, 1H), 3.46 (d, J = 8.2 Hz, 1H), 3.39 (s, 3H), 3.27 (s, 4H), 3.07 (dd, J = 15.3, 10.2 Hz, 1H), 2.92 - 2.70 (m, 3H), 2.48 (d, J = 7.6 Hz, 2H), 2.39 (d, J = 9.2 Hz, 1H), 2.19 (dt, J = 14.1, 7.0 Hz, 1H), 2.12 (d, J = 13.1 Hz, 2H), 2.01 - 1.87 (m, 3H), 1.77 (tq, J = 17.6, 9.3, 8.8 Hz, 3H), 1.44 (t, J = 11.6 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 12.6 Hz, 3H). LCMS-ESI+: C 38 H 49 Calculated for ClN4O6S: 725.3 (M+H); Found: 724.8 (M+H). Example 132 [ka]

[0417] Example 132 was synthesized in the same manner as Example 75 using Example 109 and 2-methoxyethan-1-amine. 1H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.06 (dd, J = 15.0, 6.9 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.27 (dd, J = 14.7, 6.5 Hz, 1H), 4.14 - 3.96 (m, 2H), 3.91 - 3.62 (m, 4H), 3.49 (d, J = 5.3 Hz, 2H), 3.38 (s, 3H), 3.27 (s, 3H), 3.07 (dd, J = 15.2, 10.2 Hz, 1H), 2.91 - 2.66 (m, 3H), 2.57 - 2.28 (m, 3H), 2.28 - 2.04 (m, 3H), 2.02 - 1.87 (m, 3H), 1.87 - 1.66 (m, 3H), 1.54 - 1.36 (m, 2H), 1.31 (s, 1H), 1.13 (d, J = 6.6 Hz, 3H). LCMS-ESI+: C 36 H 47 Calculated value for ClN4O6S: 699.3 (M+H); Found: 698.6 (M+H). Example 133 [ka]

[0418] Example 133 was synthesized in the same manner as Example 18 using 2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example 110. 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.12 - 6.05 (m, 1H), 5.56 (dd, J = 15.2, 8.8 Hz, 1H), 4.18 - 4.11 (m, 2H), 4.08 - 3.83 (m, 4H), 3.81 - 3.72 (m, 2H), 3.68 (s, 2H), 3.61 (d, J = 14.4 Hz, 1H), 3.55 - 3.40 (m, 3H), 3.37 - 3.31 (m, 2H), 3.26 (s, 3H), 3.16 - 3.08 (m, 1H), 2.88 - 2.69 (m, 3H), 2.51 - 1.61 (m, 12H), 1.54 - 1.46 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). LCMS-ESI+: C 40 H 51 Calculated for ClFN3O7S: 772.3 (M+H); Found: 772.2 (M+H). Example 134 [ka]

[0419] Example 134 was synthesized in the same manner as Example 18 using 1-ethyl-1H-pyrazole-4-carboxylic acid and Example 109. 1H NMR (400 MHz, methanol-d4) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.99 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.07 (dt, J = 14.3, 6.7 Hz, 1H), 5.62 (dd, J = 15.3, 8.8 Hz, 1H), 4.34 (dd, J = 14.8, 6.5 Hz, 1H), 4.24 (q, J = 7.3 Hz, 2H), 4.06 (d, J = 1.5 Hz, 2H), 3.92 (dd, J = 14.7, 5.2 Hz, 1H), 3.84 (d, J = 15.1 Hz, 1H), 3.78 (dd, J = 8.8, 3.3 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.36 (d, J = 2.5 Hz, 1H), 3.29 (s, 3H), 3.09 (dd, J = 15.2, 9.9 Hz, 1H), 2.93 - 2.65 (m, 3H), 2.56 (d, J = 10.0 Hz, 1H), 2.43 (dd, J = 17.5, 8.9 Hz, 2H), 2.25 (dt, J = 26.4, 9.7 Hz, 2H), 2.11 (d, J = 13.5 Hz, 1H), 1.98 (dd, J = 16.3, 5.2 Hz, 2H), 1.82 (dt, J = 23.0, 9.3 Hz, 4H), 1.50 (t, J = 7.3 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H). LCMS-ESI+: C 38 H 46 ClN5O5S calculated value: 720.3 (M+H); measured value: 719.0 (M+H). (Example 135)

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[0420] Step 1: Preparation of methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate: A solution of pyrrolecarboxaldehyde (5.0 g, 0.053 mol) in dry DMF (10 mL) was added dropwise to a stirred suspension of 60% sodium hydride (oil dispersion) (2.56 g, 0.063 mol) in dry DMF (40 mL) under a nitrogen atmosphere. The temperature of the mixture was maintained at 0°C. After the addition was complete, stirring was continued at the same temperature for 30 minutes. A solution of methyl 3-bromopropanoate (13.17 g, 0.079 mol) was then added dropwise, and the temperature was allowed to rise to room temperature. The reaction mixture was stirred at this temperature for 48 hours. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, the solvent removed under reduced pressure, and purified by normal phase chromatography (silica gel column, 0-80% EtOAc / hexanes) to give methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate.

[0421] Step 2: Preparation of methyl 3H-pyrrolidine-6-carboxylate: To a solution of methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate (2.0 g, 11.04 mmol) in MeOH (20 mL) was added NaOMe (2.62 g, 12.14 mmol). The reaction mixture was stirred at 45 °C for 48 h. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and purified by normal phase chromatography (silica gel column, 0-80% EtOAc / hexanes) to give the intermediate methyl 3H-pyrrolidine-6-carboxylate. 1 H NMR (400 MHz, chloroform-d) δ 7.58 (p, J = 1.2 Hz, 1H), 6.60 (dtd, J = 6.1, 2.2, 0.7 Hz, 1H), 6.36 (q, J = 0.9 Hz, 1H), 6.31 - 6.21 (m, 1H), 4.50 (tt, J = 2.2, 1.0 Hz, 2H), 3.83 (s, 3H).

[0422] Step 3: Preparation of 3H-pyrrolidine-6-carboxylic acid: To a stirred solution of methyl 3H-pyrrolidine-6-carboxylate (0.3 g, 1.8 mmol) in methanol (6 mL), 2N LiOH (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. 2N HCl (1 mL) was added to the reaction mixture, and the mixture was concentrated. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 3H-pyrrolidine-6-carboxylic acid.

[0423] Step 4: Example 135 was synthesized in the same manner as Example 18 using 3H-pyrrolidine-6-carboxylic acid and Example 109. 1H NMR (400 MHz, chloroform-d) δ 7.86 - 7.61 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 6.6 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.44 (s, 1H), 6.34 (d, J = 6.1 Hz, 1H), 6.04 - 5.86 (m, 1H), 5.62 (dd, J = 15.7, 7.7 Hz, 1H), 4.56 (s, 2H), 4.20 - 3.94 (m, 3H), 3.82 (dd, J = 42.9, 13.7 Hz, 3H), 3.58 - 3.39 (m, 1H), 3.29 (s, 3H), 3.11 - 2.88 (m, 2H), 2.88 - 2.69 (m, 2H), 2.46 (t, J = 30.6 Hz, 4H), 2.16 - 1.66 (m, 7H), 1.28 (s, 2H), 1.13 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 45 Calculated for ClN4O5S: 729.26; Found: 729.30. Example 136 [ka]

[0424] Step 1: Preparation of methyl 2,3-dihydro-1H-pyrrolidine-6-carboxylate: Methyl 3H-pyrrolidine-6-carboxylate (300 mg, 1.85 mmol) and rhodium (5% on alumina) were mixed in ethanol (10 mL). The mixture was degassed, hydrogen gas was injected, and the mixture was stirred for 5 hours. The mixture was filtered through silica and concentrated. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give methyl 2,3-dihydro-1H-pyrrolidine-6-carboxylate. 1 H NMR (400 MHz, chloroform-d) δ 7.21 (d, J = 1.4 Hz, 1H), 6.22 (q, J = 1.2 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.78 (s, 3H), 2.80 (ddd, J = 7.7, 6.7, 1.2 Hz, 2H), 2.48 (tt, J = 8.0, 6.8 Hz, 2H).

[0425] Step 2: 2,3-Dihydro-1H-pyrrolidine-6-carboxylic acid was synthesized in the same manner as Example 133 (Step 3) using methyl 2,3-dihydro-1H-pyrrolidine-6-carboxylate instead of methyl 3H-pyrrolidine-6-carboxylate.

[0426] Step 3: Example 136 was synthesized in the same manner as Example 18 using 2,3-dihydro-1H-pyrrolidine-6-carboxylic acid and Example 109. 1H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 8.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.25 - 7.15 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 1.4 Hz, 1H), 6.05 - 5.89 (m, 1H), 5.62 (dd, J = 15.6, 7.5 Hz, 1H), 4.18 - 3.69 (m, 7H), 3.30 (s, 4H), 3.08 - 2.94 (m, 1H), 2.92 - 2.74 (m, 3H), 2.61 - 2.32 (m, 5H), 2.21 - 1.62 (m, 13H), 1.41 (t, J = 12.9 Hz, 1H), 1.13 (d, J = 6.8 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 47 Calculated value for ClN4O5S: 731.30; Actual value: 731.22. Example 137 [ka]

[0427] Example 137 was synthesized in the same manner as Example 18 using 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example 110. 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.4, 2.5 Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.52 (dd, J = 15.2, 8.9 Hz, 1H), 4.81 (dd, J = 3.3, 1.1 Hz, 2H), 4.57 (s, 1H), 4.18 - 3.96 (m, 3H), 3.92 - 3.79 (m, 2H), 3.76 - 3.65 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J = 15.2, 9.9 Hz, 1H), 2.87 - 2.70 (m, 3H), 2.42 (dt, J = 25.8, 9.3 Hz, 3H), 2.29 - 1.93 (m, 5H), 1.82 (q, LCMS-ESI+ (m / z): [M+H]+ C 41 H 49 Calculated for ClN4O6S: 761.29; Found: 761.22. Example 138 [ka]

[0428] Example 138 was synthesized in the same manner as Example 18 using 1-methyl-1H-pyrazole-4-carboxylic acid and Example 110. 1H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 0.7 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.18 - 7.07 (m, 2H), 7.06 - 6.89 (m, 2H), 5.96 (dd, J = 15.1, 8.6 Hz, 1H), 5.53 (dd, J = 15.2, 9.0 Hz, 1H), 4.67 (d, J = 7.3 Hz, 2H), 4.12 (s, 2H), 3.99 (s, 2H), 3.86 (d, J = 15.0 Hz, 2H), 3.76 - 3.61 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J = 15.2, 10.2 Hz, 2H), 2.79 (d, J = 15.3 Hz, 3H), 2.41 (dt, J = 45.0, 9.2 Hz, 3H), 2.27 - 1.92 (m, 5H), 1.84 (t, J = 8.9 Hz, 2H), 1.70 - 1.58 (m, 3H), 1.41 (t, J = 12.4 Hz, 2H), 0.96 (d, J = 6.2 Hz, 2H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated for ClN5O5S: 720.29; Found: 720.23. Example 139 [ka]

[0429] Example 139 was synthesized in the same manner as Example 18 using 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example 109. 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 15.0, 1.8 Hz, 2H), 7.18 (dd, J = 8.4, 2.3 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.37 (q, J = 1.2 Hz, 1H), 5.99 (dt, J = 13.7, 6.5 Hz, 1H), 5.62 (dd, J = 15.6, 7.7 Hz, 1H), 4.84 (d, J = 1.1 Hz, 2H), 4.18 - 3.95 (m, 6H), 3.94 - 3.69 (m, 4H), 3.31 (s, 4H), 3.09 - 2.95 (m, 2H), 2.90 - 2.68 (m, 2H), 2.59 - 2.25 (m, 4H), 2.21 - 2.03 (m, 2H), 2.02 - 1.82 (m, 3H), 1.81 - 1.60 (m, 3H), 1.41 (t, J = 12.7 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 47 Calculated value of ClN4O6S: 747.29; actual value: 747.04. (Example 140)

change

[0430] A mixture of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid (2.61 mg, 0.02 mmol) and Example 109 (8.0 mg, 0.0134 mmol) in DCM (1.0 mL) was cooled to 0 °C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.11 mg, 0.0268 mmol) was added, followed by DMAP (3.27 mg, 0.0267 mmol). The reaction was removed from the cooling bath and stirred at ambient temperature overnight. The reaction was then concentrated by removing the DCM, diluted with DMF (1 mL), filtered, and purified by Gilson reverse-phase preparative HPLC (60-100% ACN / HO containing 0.1% TFA) to give Example 140. H NMR (400 MHz, meta Nord-d4) δ 7.76 - 7.67 (m, 1H), 7.31 (dd, J = 8.2, 1.9 Hz, 1H), 7.14 - 7.04 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.63 (dd, J = 15.4, 8.4 Hz, 1H), 4.14 (dd, J = 14.8, 6.9 Hz, 1H), 4.08 - 3.93 (m, 3H), 3.88 - 3.73 (m, 2H), 3.67 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.12 - 2.98 (m, 1H), 2.92 - 2.70 (m, 3H), 2.59 - 2.20 (m, 8H), 2.16 - 2.03 (m, 2H), 2.03 - 1.71 (m, 7H), 1.38 (s, 4H), 1.14 (d, J = 6.9 Hz, 3H). LCMS-ESI+ (m / z): Calculate [M+H]+ C 38 H 48 Calculated for ClN3O6S: 710.3; Found: 710.1. Example 141 [ka]

[0431] Example 141 was synthesized in the same manner as Example 140, using racemic 1-methyl-4,5,6,7-tetrahydroindazole-6-carboxylic acid in place of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid. The later eluting peak from reverse-phase preparative HPLC was arbitrarily assigned as "S" and the actual stereochemistry was not determined. 1H NMR (400 MHz, Tanol-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (dd, J = 8.5, 2.1 Hz, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.64 (dd, J = 15.4, 8.3 Hz, 1H), 4.15 (dd, J = 14.8, 7.0 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.96 (dd, J = 14.8, 4.9 Hz, 1H), 3.88 - 3.64 (m, 6H), 3.30 (s, 3H), 3.13 - 3.02 (m, 1H), 2.99 - 2.66 (m, 6H), 2.65 - 2.29 (m, 5H), 2.26 - 2.06 (m, 3H), 2.01 - 1.69 (m, 8H), 1.51 - 1.38 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H). LCMS-ESI+ (m / z): Calculation [M+H] C 41 H 50 ClN5O5S: 760.3; Found: 760.1. Example 142 [ka]

[0432] Example 142 was synthesized in the same manner as Example 140, using 3-(1-methylpyrazol-4-yl)propanoic acid instead of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid, and DMF (1.0 mL) was also added as a co-solvent for this reaction. (400 MHz, methanol-d4) δ 7.75 - 7.69 (m, 1H), 7.51 (s, 1H), 7.45 - 7.41 (m, 1H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 7.14 - 7.05 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.18 - 6.06 (m, 1H), 5.62 (dd, J = 15.5, 8.4 Hz, 1H), 4.14 - 3.97 (m, 3H), 3.92 (dd, J = 14.8, 4.8 Hz, 1H), 3.87 - 3.73 (m, 5H), 3.67 (d, J = 14.2 Hz, 1H), 3.30 (s, 3H), 3.11 - 3.00 (m, 1H), 2.90 - 2.74 (m, 4H), 2.74 - 2.66 (m, 2H), 2.57 - 2.38 (m, 3H), 2.31 - 2.19 (m, 1H), 2.14 - 2.05 (m, 1H), 2.03 - 1.71 (m, 8H), 1.47 - 1.36 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 48 ClN5O5S 734.35; Calculated found: 734.07. (Example 143) [ka]

[0433] Example 143 was synthesized in the same manner as Example 140, using isochroman-3-carboxylic acid instead of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid. The earlier eluting peak from reverse-phase preparative HPLC was arbitrarily assigned as "R" and the actual stereochemistry was not determined. 1H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.2, 1.9 Hz, 1H), 7.25 - 7.15 (m, 4H), 7.14 - 7.05 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.10 (dt, J = 14.5, 6.9 Hz, 1H), 5.64 (dd, J = 15.4, 8.3 Hz, 1H), 5.06-4.89 (m, 2H) 4.44 (dd, J = 9.7, 4.7 Hz, 1H), 4.22 - 4.01 (m, 3H), 3.95 (dd, J = 14.9, 5.0 Hz, 1H), 3.85 (d, J = 14.9 Hz, 1H), 3.77 (dd, J = 8.4, 3.0 Hz, 1H), 3.70 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.18 - 3.02 (m, 3H), 2.90 - 2.75 (m, 2H), 2.56 - 2.40 (m, 3H), 2.34 - 2.22 (m, 1H), 2.22 - 2.07 (m, 2H), 2.00 - 1.71 (m, 7H), 1.51 - 1.39 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 42 H 48 Calculated for ClN3O6S: 758.37; Found: 758.07. Example 144 [ka]

[0434] Example 109 (350 mg, 0.59 mmol) was dissolved in DCM (5.9 mL) at room temperature, and triethylamine (0.24 g, 2.34 mmol) was added, followed by isocyanatocyclopropane (107 mg, 1.3 mmol) in DCM (1 mL). After stirring the resulting mixture at room temperature for 2 h, the reaction was concentrated by removing the DCM, and the resulting residue was redissolved in EtOAc (30 mL) and washed with 1 N HCl (15 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated NaHCO (15 mL), brine (15 mL), dried over sodium sulfate, filtered, concentrated, redissolved in DCM, mixed with silica gel, concentrated to dryness, and purified by two combiflash runs (12 g silica gel, 0–10% DCM / 2.0 N NH in MeOH, dry loading). The desired fractions were combined and concentrated to give Example 144. 1 H NMR (400 MHz, acetone-d6) δ 7.75 (d, J = 8.5 Hz, 1H), 7.32 - 7.05 (m, 4H), 6.84 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.2, 6.6 Hz, 1H), 5.56 (dd, J = 15.4, 8.4 Hz, 1H), 4.04 (q, J = 11.9 Hz, 3H), 3.85 (d, J = 15.1 Hz, 1H), 3.71 (d, J = 14.8 Hz, 2H), 3.39 (d, J = 14.2 Hz, 1H), 3.23 (s, 3H), 3.12 (dd, J = 15.0, 9.8 Hz, 1H), 2.89 - 2.71 (m, 3H), 2.69 - 2.60 (m, 1H), 2.58 - 2.40 (m, 3H), 2.20 - 2.10 (m, 3H), 2.00 - 1.89 (m, 3H), 1.83 - 1.69 (m, 3H), 1.51 - 1.34 (m, 1H), 1.08 (d, J = 6.3 Hz, 3H), 0.66 (d, J = 6.9 Hz, 2H), 0.56 - 0.48 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 36 H 45 Calculated for ClN4O5S: 681.28; Found: 680.81. Example 145 [ka]

[0435] Step 1: tert-Butyl but-3-enoate (1.40 mL, 5.75 mmol) was added via syringe to a stirred solution of 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 17.2 mL, 9 mmol) over 2 min at 0 °C, and the resulting mixture was warmed to room temperature. After 4.5 h, 5-bromo-1H-pyrrole-3-carbaldehyde (1.00 g, 5.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (210 mg, 0.287 mmol), potassium carbonate (1.59 g, 11.5 mmol), and N,N-dimethylformamide (30 mL) were added sequentially, and the resulting mixture was heated to 75 °C. After 50 min, the reaction mixture was heated to 100 °C. After 23 h, the resulting mixture was cooled to room temperature, and diethyl ether (400 mL) and saturated aqueous ammonium chloride (50 mL) were added sequentially. The organic layer was washed with water (2 × 350 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0–80% ethyl acetate in hexanes) to give 145-1.

[0436] Step 2: Aqueous lithium hydroxide (2.0 M, 11.0 mL, 22 mmol) was added via syringe to a vigorously stirred solution of 145-1 (517 mg, 2.18 mmol) in tetrahydrofuran (17 mL), water (5.0 mL), and methanol (5.0 mL) at room temperature. After 1 h, the resulting mixture was heated to 70 °C. After 3.5 h, the resulting mixture was cooled to room temperature, and aqueous hydrogen chloride (2.0 M, 20 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (24 mL) and N,N-dimethylformamide (4.0 mL), 4-dimethylaminopyridine (400 mg, 3.27 mmol) was added, and the resulting mixture was stirred at room temperature. After 2 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (774 mg, 4.36 mmol) was added. After 14 hours, diethyl ether (120 mL) was added. The organic layer was washed sequentially with aqueous hydrogen chloride (0.05 M, 100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-80% ethyl acetate in hexanes) to give 145-2.

[0437] Step 3: A mixture of aqueous sodium chlorite (2.0 M, 469 mL, 0.94 mmol) and sodium dihydrogen phosphate monohydrate (120 mg, 0.868 mmol) was added via syringe to a vigorously stirred mixture of 145-2 (22 mg, 0.14 mmol) and 2-methyl-2-butene (143 mL, 1.35 mmol) in tert-butanol (0.4 mL) at room temperature. After 16.5 h, aqueous hydrogen chloride (2.0 M, 20 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 145-3.

[0438] Step 4: Preparation of Example 145: Example 145 was synthesized in the same manner as Example 18 using 145-3 and Example 109. 1 H NMR (400 MHz, acetone-d6) δ 7.88 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.19 - 7.12 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 1.7 Hz, 1H), 6.20 - 6.06 (m, 1H), 5.60 (dd, J = 15.4, 8.4 Hz, 1H), 4.11 (d, J = 12.1 Hz, 1H), 4.05 (d, J = 12.1 Hz, 1H), 3.93 - 3.65 (m, 3H), 3.40 (d, J = 14.2 Hz, 1H), 3.24 (s, 3H), 3.24 - 3.08 (m, 1H), 2.96 - 1.22 (m, 23H), 1.13 (d, J = 6.2 Hz, 3H). LCMS-ESI+: C 41 H 48 Calculated for ClN4O6S: 759.3 (M+H); Found: 759.0 (M+H). Example 146 [ka]

[0439] Example 146 was synthesized in the same manner as Example 18 using 2-methylthiazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, methanol-d4) δ 8.28 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.04 (dt, J = 14.4, 6.8 Hz, 1H), 5.60 (dd, J = 15.4, 8.7 Hz, 1H), 4.34 (dd, J = 15.0, 6.4 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.98 (dd, J = 15.0, 5.7 Hz, 1H), 3.85 (d, J = 15.0 Hz, 1H), 3.76 (dd, J = 8.8, 3.5 Hz, 1H), 3.69 (d, J = 14.3 Hz, 1H), 3.33 (s, 1H), 3.26 (s, 3H), 3.07 (dd, J = 15.3, 10.0 Hz, 1H), 2.77 (s, 3H), 2.53 - 2.35 (m, 3H), 2.24 (tt, J = 14.3, 7.2 Hz, 1H), 2.11 (d, J = 13.9 Hz, 2H), 1.97 - 1.88 (m, 1H), 1.79 (dt, J = 20.3, 8.5 Hz, 2H), 1.49 - 1.38 (m, 1H), 1.29 (s, 1H), 1.11 (d, J = 6.7 Hz, 3H). LCMS-ESI+ (m / z): H+C 37 H 43 Calculated for ClN4O5S2: 723.248; Found: 723.221. Example 147 [ka]

[0440] Example 147 was synthesized in the same manner as Example 18 using 1-methyl-1H-pyrrole-3-carboxylic acid and Example 109. 1 H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (s, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 2.7 Hz, 1H), 6.66 - 6.53 (m, 1H), 6.16 - 6.00 (m, 1H), 5.59 (dd, J = 15.3, 8.5 Hz, 1H), 4.23 (dd, J = 16.1, 5.8 Hz, 1H), 4.10 - 3.98 (m, 2H), 3.85 (d, J = 14.9 Hz, 1H), 3.77 (d, J = 8.5 Hz, 1H), 3.72 (s, 3H), 3.68 (d, J = 14.3 Hz, 1H), 3.27 (s, 3H), 3.10 - 3.00 (m, 1H), 2.80 (s, 2H), 2.44 (s, 2H), 2.28 - 2.15 (m, 1H), 2.10 (d, J = 15.0 Hz, 1H), 1.76 (s, 2H), 1.49 - 1.38 (m, 1H), 1.29 (s, 2H), 1.12 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m / z): H+C 38 H 45 Calculated for ClN4O5S: 705.288; Found: 705.295. Example 148 [ka]

[0441] Example 148 was synthesized in the same manner as Example 18 using 1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. 1 H NMR (400 MHz, methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.17 (t, J = 9.6 Hz, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.35 - 6.01 (m, 1H), 5.55 (dd, J = 15.2, 8.6 Hz, 1H), 4.03 (q, J = 12.1 Hz, 2H), 3.84 (d, J = 14.9 Hz, 1H), 3.78 (d, J = 8.6 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.42 (s, 2H), 3.27 (d, J = 1.4 Hz, 3H), 3.11 - 2.99 (m, 1H), 2.89 (s, 6H), 2.80 (s, 1H), 2.60 (s, 0H), 2.43 (s, 2H), 2.23 - 2.08 (m, 1H), 2.06 - 1.97 (m, 1H), 1.92 (d, J = 10.7 Hz, 2H), 1.76 (d, J = 6.9 Hz, 3H), 1.42 (t, J = 13.0 Hz, 1H), 1.23 (d, J = 7.5 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m / z): H+C 37 H 44 ClN5O5S calculated value: 706.28; measured value: 706.27. (Example 149)

change

[0442] Example 149 was synthesized in the same manner as Example 75 using Example 109 and cis-3-methoxycyclobutan-1-amine hydrochloride. 1H NMR (400 MHz, acetone-d6) δ 7.75 (d, J = 8.5 Hz, 1H), 7.39 (br s, 1H), 7.31 - 7.15 (m, 2H), 7.10 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.23 (br s, 1H), 5.57 (br s, 1H), 4.05 (q, J = 10.0 Hz, 2H), 4.00 (m, 2H) 3.88 - 3.61 (m, 4H), 3.44 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.13 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.68 (m, 2H), 2.67 - 2.37 (m, 2H), 2.37 - 2.16 (m, 7H), 2.16 -2.07 (m, 3H), 1.95 LCMS-ESI+: C 38 H 50 Calculated for ClN4O6S: 725.3 (M+H); Found: 724.8 (M+H). Example 150 [ka]

[0443] Example 150 was synthesized in the same manner as Example 75 using Example 109 and trans-3-methoxycyclobutan-1-amine hydrochloride. 1H NMR (400 MHz, acetone) t-d6) δ 7.64 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.07 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.16 - 6.02 (m, 1H), 5.67 (dd, J = 15.5, 8.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 1H), 4.00 (m, 2H) 3.88 - 3.61 (m, 4H), 3.44 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.13 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.68 (m, 2H), 2.67 - 2.37 (m, 2H), 2.37 - 2.16 (m, 7H), 2.16 - 2.07 (m, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.74 (m, 1H), 1.48 - 1.33 (m, 1H), 1.29 (s, 1H), 1.14 (d, J = 6.4 Hz, 3H). LCMS-ESI+: C 38 H 50 Calculated for ClN4O6S: 725.3 (M+H); Found: 724.5 (M+H). Example 151 [ka]

[0444] Example 151 was synthesized in the same manner as Example 18 using 1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109. LCMS-ESI+(m / z): C 39 H 46 Calculated [M+H]+ for ClN5O5S: 732.3; found: 732.3. Example 152 [ka]

[0445] Example 152 was synthesized in the same manner as Example 18 using 1-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid and Example 110. 1 H NMR (400 MHz, methanol-d4) δ 8.11 (s, 1H), 7.96 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.16 - 6.09 (m, 1H), 5.59 - 5.50 (m, 2H), 5.05 (d, J = 6.8 Hz, 4H), 4.31 - 4.25 (m, 1H), 4.15 - 4.00 (m, 3H), 3.84 (d, J = 14.8 Hz, 1H), 3.78 (d, J = 8.4 Hz, 1H), 3.62 (d, J = 14.4 Hz, 1H), 3.37 - 3.30 (m, 2H), 3.24 (s, 3H), 3.10 - 3.04 (m, 1H), 2.85 - 2.72 (m, 2H), 2.47 - 1.68 (m, 10H), 1.51 (d, J = 6.8 Hz, 3H), 1.48 - 1.41 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 48 Calculated for ClN5O6S: 762.3; Found: 762.1. Example 153 [ka]

[0446] Example 153 was synthesized in the same manner as Example 18, using 1-ethyl-1H-pyrazole-4-carboxylic acid and Example 110 in place of 3-methoxypropionic acid. 1 H NMR (400 MHz, methanol-d4) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (dd, J = 8.6, 2.2 Hz, 1H), 7.11 (d, J = 2.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 1H), 6.15 - 6.08 (m, 1H), 5.57 (dd, J = 15.6, 8.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.78 - 3.75 (m, 2H), 3.60 (d, J = 14.4 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 2.86 - 2.73 (m, 2H), 2.50 - 1.71 (m, 10H), 1.52 - 1.44 (m, 7H), 1.21 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ H+C 39 H 48 Calculated for ClN5O5S: 734.4; Found: 734.2. Example 154 [ka]

[0447] Example 154 was synthesized in the same manner as Example 18 using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12 mL). 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08 mmol, 2 equiv.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (400 mg, 2.08 mmol, 2 equiv.) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then DMAP (253 mg, 2.08 mmol, 2 equiv.) was added in one portion. The reaction mixture was stirred at room temperature overnight, and the progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by Gilson reverse phase preparative HPLC (60-100% ACN / H 2 O containing 0.1% TFA) to give Example 154. 1 H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22 - 7.10 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.20 - 6.05 (m, 1H), 5.63 (dd, J = 15.5, 8.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.06 (s, 4H), 3.91 - 3.83 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.72 (d, J = 14.4 Hz, 1H), 3.38 (d, J = 14.5 Hz, 1H), 3.30 (s, 3H), 3.09 (dd, J = 15.1, 10.0 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.51 (d, J = 26.7 Hz, 2H), 2.24 (dd, J = 10.9, 6.0 Hz, 2H), 2.12 (d, J = 13.7 Hz, 1H), 2.02 - 1.70 (m, 4H), 1.54 - 1.40 (m, 1H), 1.14 (d, J = 6.1 Hz, 3H). LCMS-ESI+ (m / z): C 38 H 46 Calculated for ClN5O6S: 735.28; Found: 735.94. Example 155 [ka]

[0448] Example 155 was synthesized in the same manner as Example 75 using Example 109 and (3R)-tetrahydrofuran-3-amine. 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.99 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.10 - 5.98 (m, 1H), 5.60 (dd, J = 15.4, 8.8 Hz, 1H), 4.35 - 4.23 (m, 2H), 4.10 - 4.01 (m, 2H), 3.96 - 3.75 (m, 6H), 3.72 - 3.62 (m, 3H), 3.28 (s, 3H), 3.08 (dd, J = 15.1, 10.2 Hz, 1H), 2.84 - 2.72 (m, LCMS-ESI+ (m / z): H+C 37 H 47 Calculated for ClN4O6S: 711.29; Found: 710.79. Example 156 [ka]

[0449] Example 156 was synthesized in the same manner as Example 18, substituting Example 109 for Example 5 and 1-cyclopropyl-1H-pyrrole-3-carboxylic acid for 3-methoxypropionic acid. 1H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 2.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.95 - 6.84 (m, 2H), 6.61 (dd, J = 3.0, 1.8 Hz, 1H), 6.11 (dt, J = 14.5, 6.8 Hz, 1H), 5.61 (dd, J = 15.4, 8.6 Hz, 1H), 4.27 (dd, J = 14.8, 6.4 Hz, 1H), 4.14 - 3.94 (m, 3H), 3.87 (d, J = 15.1 Hz, 1H), 3.79 (d, J = 7.5 Hz, 1H), 3.70 (d, J = 14.2 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.36 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.0, 9.4 Hz, 2H), 2.89 - 2.71 (m, 2H), 2.60 - 2.35 (m, 3H), 2.32 - 2.06 (m, 3H), 1.94 (d, J = 11.6 Hz, 3H), 1.88 - 1.66 (m, 3H), 1.45 (t, J = 12.1 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H), 1.08 - 0.93 (m, 4H). LCMS-ESI+ (m / z): [M+H]+ C 40 H 47 Calculated for ClN4O5S: 731.35; Found: 729.83. Example 157 [ka]

[0450] Example 157 was prepared in a similar manner to Example 18 using 3,4-dihydro-1H-2-benzopyran-7-carboxylic acid and Example 109. 1 H NMR (400 MHz, Acetonitrile-d3) δ 7.87 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.96 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.92 (dt, J = 14.2, 6.5 Hz, 1H), 5.55 (dd, J = 15.3, 8.9 Hz, 1H), 4.77 (s, 2H), 4.33 (dd, J = 15.3, 5.6 Hz, 1H), 4.05 (d, J = 2.2 Hz, 2H), 3.94 (t, J = 5.7 Hz, 2H), 3.84 - 3.64 (m, 3H), 3.26 (d, J = 14.3 Hz, 1H), 3.18 (s, 3H), 3.05 (dd, J = 15.3, 10.4 Hz, 1H), 2.89 (t, J = 5.7 Hz, 2H), 2.84 - 2.65 (m, 3H), 2.50 - 2.21 (m, 3H), 2.19 - 2.00 (m, 3H), 1.91 - 1.81 (m, 3H), 1.79 - 1.63 (m, 3H), 1.47 - 1.35 (m, 1H), 1.05 (d, J = 6.3 Hz, 3H). LCMS-ESI + (m / z): [M+H] + C 42 H 48 Calculated for ClN3O6S: 758.33; Measured value: 758.0. Example 158 [ka]

[0451] Example 158 was prepared in a similar manner to Example 18 using 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid and Example 109. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.87 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 5.98 (dt, J = 13.9, 6.5 Hz, 1H), 5.58 (dd, J = 15.4, 8.4 Hz, 1H), 4.56 (d, J = 2.7 Hz, 2H), 4.13 (dd, J = 15.0, 5.9 Hz, 1H), 4.00 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.82 - 3.70 (m, 3H), 3.66 (d, J = 15.1 Hz, 1H), 3.32 (d, J = 14.6 Hz, 1H), 3.20 (s, 3H), 3.05 (dd, J = 15.3, 10.1 Hz, 1H), 2.84 - 2.65 (m, 3H), 2.52 (dd, J = 11.6, 5.3 Hz, 1H), 2.40 (dt, J = 16.5, 6.2 Hz, 2H), 2.27 - 2.08 (m, 3H), 2.07 - 1.98 (m, 1H), 1.91 - 1.81 (m, 3H), 1.81 - 1.62 (m, 3H), 1.37 (dt, J = 15.1, 7.8 Hz, 1H), 1.06 (d, J = 6.3 Hz, 3H). LCMS-ESI +(m / z): [M+H] + C 40 H 47 Calculated for ClN4O6S: 747.30; Measured Value: 747.0. Example 159 [ka]

[0452] Example 109 (11 mg, 0.018 mmol), (1S,2R)-2-methylcyclopropane-1-carboxylic ac...

Claims

[Claim 1] The invention described in this specification.

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